Saroglitazar Magnesium for Treatment of Primary Biliary Cholangitis

Study Overview
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Brief Summary
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Saroglitazar Magnesium 1 mg and 2 mg tablets for treatment of subjects with Primary Biliary Cholangitis (PBC)

Detailed Description
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A Multicenter, Randomized, Double-blind, Placebo controlled, Phase 2b/3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium in Subjects with Primary Biliary Cholangitis

Official Title
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A Multicenter, Randomized, Double-blind, Placebo Controlled, Phase 2b/3 Study to Evaluate the Efficacy and Safety of Saroglitazar Magnesium in Subjects With Primary Biliary Cholangitis

Conditions
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Primary Biliary Cholangitis

Intervention / Treatment
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* Drug: Saroglitazar Magnesium 1 mg
* Drug: Saroglitazar Magnesium 2 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, between 18 and 75 years of age, both inclusive at screening. Subjects on Ursodeoxycholic acid (UDCA) for at least 12 months at a therapeutic dose (at least 13 mg/kg per day) and a stable dose for 6 months prior to Screening Visit and having ALP ≥ 1.67 x ULN. OR Subjects who are unable to tolerate UDCA and did not receive UDCA for at least 3 months prior to the date of screening and having ALP ≥ 1.67 x ULN. History of confirmed PBC diagnosis, based on American Association for the Study of Liver Disease [AASLD] and European Association for Study of the Liver [EASL] Practice Guidelines, as demonstrated by the presence of at least ≥ 2 of the following 3 diagnostic factors: History of elevated ALP levels for at least 6 months prior to screening The subjects should have positive anti-mitochondrial antibodies (AMA) titer OR if AMA is negative or in low titer (< 1:80), then the subjects should have PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]) Liver biopsy consistent with PBC ALP ≥ 1.67 x ULN at both Visits 1 and 2 and with < 30% variance between the levels from Visit 1 to Visit 2 Total bilirubin < 2 x ULN at screening (Visit 1) Must provide written informed consent and agree to comply with the trial protocol Exclusion Criteria: Consumption of 2 standard alcohol drinks per day if male and 1 standard alcohol drink per day if female for at least 3 consecutive months (12 consecutive weeks) within 5 year before screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor). History or presence of other concomitant liver diseases at screening: Chronic hepatitis B or C virus (HBV, HCV) infection. (Note: However, If the subject has been treated for the HCV infection and has been cured for a duration of more than 2 years from screening, such subjects can be enrolled in the study) Primary sclerosing cholangitis (PSC). Alcoholic liver disease. Autoimmune hepatitis (AIH) indicative of PBC with overlap syndrome. Note: The Paris criteria are commonly used to define the presence of PBC with features of AIH and have been endorsed by EASL and AASLD. According to these criteria, a diagnosis can be made in a patient with PBC as follows: At least two of the following: I. ALP > 2 x ULN or GGT > 5 x ULN. II. AMA > 1:40. III. Florid bile duct lesion on histology. AND At least two of the following three features: I. ALT > 5 x ULN. II. Immunoglobulin G serum levels > 2 x ULN or smooth muscle autoantibody positive. III. Moderate to severe interface hepatitis on histology. Hemochromatosis. Non-alcoholic steatohepatitis (NASH) on historical biopsy. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, encephalopathy, known large esophageal varices or history of variceal bleeding and active or history of hepatorenal syndrome at screening. Clinically silent compensated cirrhosis (at screening), defined as (a) nodular liver contour by abdominal imaging with at least one sign of liver dysfunction (> ULN INR or < LLN serum albumin); or (b) prolonged INR (> ULN) and diminished albumin (< LLN); or (c) platelet count <140x109/L with INR > ULN or serum albumin < LLN. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years, including known cancers. Use of thiazolidinediones or fibrates (within 12 weeks prior to screening). Use of obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (Note: Prednisone dose should not be 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). Use of drugs that are known CYP2C8 inhibitors/substrate within 4 weeks prior to screening (refer to Appendix 7 for List of Known CYP2C8 Inhibitors/Substrate). 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 (OLT) or listed for OLT. Type 1 diabetes mellitus. Unstable cardiovascular disease, including: Unstable angina, (i.e., new or worsening symptoms of coronary heart disease in the 12 weeks before screening and throughout the Screening Period), acute coronary syndrome in the 24 weeks before screening and throughout the Screening Period, acute myocardial infarction in the 12 weeks before screening and throughout the Screening Period or heart failure of New York Heart Association class (III - IV) or worsening congestive heart failure, or coronary artery intervention, in the 24 weeks before screening and throughout the Screening Period. History/current unstable cardiac dysrhythmias. Uncontrolled hypertension at screening. Stroke or transient ischemic attack in the 24 weeks before screening. History of intracranial hemorrhage, arteriovenous malformation, bleeding disorder, coagulation disorders, or screening blood tests that, in the opinion of the Investigator, indicate altered coagulability (e.g., PT, INR, aPTT) at screening. An uncontrolled thyroid disorder Uncontrolled hyperthyroidism: defined as any history of hyperthyroidism that has either not been treated with either radioactive iodine and/or surgery or that has been treated with radioactive iodine and/or surgery, but has required ongoing continuous or intermittent use of thyroid hormone synthesis inhibitors (i.e., methimazole or propylthiouracil) in the 24 weeks before screening. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening. History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 x ULN at screening. Subjects whose ALT, AST, or ALP exceeds by more than 50% on Visit 2 reading compared to Visit 1. Note: If the ALT, AST, or ALP values on Visit 2 exceed by more than 50% from Visit 1, then a third value will be measured (within 1- 2 weeks) to assess for the trend. If the third value shows continued increase ≥ 10%, then subject is considered ineligible for randomization. Any of the following laboratory values at screening: Platelets < 100 × 109/L Albumin < 3.2 g/dL eGFR < 60 mL/min/1.73 m2 ALP > 10 x ULN ALT or AST > 250 U/L Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to end of study). History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium. Known allergy, sensitivity, or intolerance to the study drug, comparator, or formulation ingredients. Pregnancy-related exclusions, including: Pregnant/lactating female (including positive pregnancy test at screening). Fertile women and men, UNLESS using effective contraceptive methods (such as an intra-uterine device or other mechanical contraception method with condom or diaphragm and spermicide) throughout the study. For male subjects, contraception measures (condom and spermicide) must be taken during the study, either by the male participant or his female partner. (Note: Enrolled females otherwise must be surgically sterilized for at least 24 weeks before screening or postmenopausal, defined as 52 weeks with no menses without an alternative medical cause or following sexual abstinence.) History or other evidence of severe illness or any other conditions that would make the subject, 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, Randomized, Double-blind, Placebo controlled, Phase 2b/3 Safety and Efficacy Study . 192 subjects (64 subjects in each treatment arm) will be randomised in a ratio of 1:1:1 in Saroglitazar Magnesium 1 mg, Saroglitazar Magnesium 2 mg, and Placebo arm, respectively
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saroglitazar Magnesium 2 mg<br>Saroglitazar Magnesium 2 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (52 weeks). | Drug: Saroglitazar Magnesium 2 mg<br>* Subjects randomized to Saroglitazar Magnesium 2 mg arm will receive Saroglitazar Magnesium 2 mg treatment until the optimal dose (1 or 2 mg) is selected at interim analysis, after which these subjects will receive Saroglitazar Magnesium Optimal Dose (1 or 2 mg) up to Week 52. If the selection of optimal dose is inconclusive at the interim analysis, all subjects in this arm will continue to receive Saroglitazar Magnesium 2 mg as per the initial treatment assignment for the entire treatment period up to Week 52.<br>|
| Experimental: Saroglitazar Magnesium 1 mg<br>Saroglitazar Magnesium 1 mg tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (52 weeks). | Drug: Saroglitazar Magnesium 1 mg<br>* Subjects randomized to Saroglitazar Magnesium 1 mg arm will receive Saroglitazar Magnesium 1 mg treatment until the optimal dose (1 or 2 mg) is selected at interim analysis, after which these subjects will receive Saroglitazar Magnesium Optimal Dose (1 or 2 mg) up to Week 52. If the selection of optimal dose is inconclusive at the interim analysis, all subjects in this arm will continue to receive Saroglitazar Magnesium 1 mg as per the initial treatment assignment for the entire treatment period up to Week 52.<br>|
| Placebo Comparator: Placebo<br>Placebo tablet orally administered once daily in the morning before breakfast without food, for the duration of treatment (52 weeks). | Drug: Placebo<br>* Subjects randomized to placebo arm will receive placebo treatment for the entire treatment period up to Week 52.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure biochemical response of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo based on the composite endpoints of Alkaline Phosphatase (ALP) and total bilirubin | Number of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin [ALP < 1.67 x ULN, ≥ 15% decrease in ALP relative to baseline, and total bilirubin ≤ ULN or direct bilirubin ≤ ULN in patients with known Gilbert's syndrome] | From baseline to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the biochemical response of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo based on the composite endpoints of Alkaline Phosphatase (ALP) and total bilirubin | Number of subjects with biochemical response based on the composite endpoints of ALP and total bilirubin [ALP < 1.67 x ULN, ≥ 15% decrease in ALP, and total bilirubin ≤ ULN or direct bilirubin ≤ ULN in patients with known Gilbert's syndrome] | From baseline to week 4, 8, 16, and 24 | 
| To assess the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to changes in ALP values | Number of subjects with improvement of at least 15%, 30%, 40%, and 50% in ALP values | From baseline to week 24 and week 52 | 
| To study the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to changes in ALP values | Number of subjects with changes (absolute and percentage) in ALP values | From baseline to week 24 and week 52 | 
| To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to changes in ALP values | Number of subjects with complete normalization of ALP | From baseline to week 24 and week 52 | 
| To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 or 2 mg) relative to Placebo with respect to improvement in liver stiffness measurement (LSM) of at least 25% relative to baseline assessed by FibroScan®. | Number of subjects with at least 25% decrease in LSM | From baseline to week 24 and week 52 | 
| To evaluate the effect of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo for the change in liver enzyme parameters (ALT, AST, GGT, total bilirubin, and albumin). | Number of subjects with changes in liver enzyme parameters (ALT, AST, GGT, total bilirubin and albumin) | From baseline to weeks 16, 24 and 52 | 
| To evaluate the effect of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo for the change in lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C). | Number of subjects with changes in lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C). | From baseline to week 24 and week 52 | 
| To evaluate the effect of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo for the change in serum bile acids. | Number of subjects with changes in serum bile acids | From baseline to week 24 and week 52 | 
| To assess the change in health related quality of life using PBC 40 questionnaire following treatment with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo | Number of subjects with changes in quality of life using PBC 40 questionnaire domains. It assesses six psychometric domains, each with a 5 point scale. Score of 1 (not at all) indicates minimum score and score of 5 (very much) indicates maximum score for each domain. Higher score indicates worse outcomes. | From baseline to weeks 16, 24 and 52 | 
| To assess the change in Pruritus using 5-Domains (5-D) itch scale following treatment with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo | Number of subjects with changes in 5-Domains (5-D) itch scale. It assesses five domains with respect to pruritus intensity. Score of 1 indicates minimum score and score of 5 indicates maximum score for each domain. Higher score indicates worse outcomes. | From baseline to weeks 4, 8,16, 24 and 52 | 
| To assess the change in Pruritus using Patient Global Impression of Change scale following treatment with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo | Number of subjects with changes in Patient Global Impression of Change scale. It is a 7 point scale depicting a patient's rating of overall improvement. Score of 1 indicates minimum score and score of 7 indicates maximum score. Higher score indicates worse outcomes. | From baseline to weeks 4, 8,16, 24 and 52 | 
| To assess the change in Pruritus using Patient Global Therapeutic Benefit scale following treatment with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo | Number of subjects with in changes Patient Global Therapeutic Benefit scale. This is a 5-point scale in which 1 designates the best outcome and 5 designates the worst outcome. Higher score means worse outcomes. | From baseline to weeks 4, 8,16, 24 and 52 | 
| To assess the change in Pruritus using Patient Global Impression of Worst Itch Severity scale with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo | Number of subjects with changes in Patient Global Impression of Worst Itch Severity scale. This is a 5-point scale in which 1 designates the best outcome and 5 designates the worst outcome. Higher score means worse outcomes. | From baseline to weeks 4, 8,16, 24 and 52 | 
| To analyze the treatment-related adverse events/Serious adverse events (as assessed by CTCAE V 5.0 or higher) of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo. | Number of subjects with treatment-related adverse events as assessed by CTCAE v5.0 or higher | Week 52 | 
| To evaluate the adverse events of special interest i.e., drug-induced liver injury (DILI) of Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo. | Number of subjects with adverse events of special interest i.e., drug-induced liver injury (DILI) | Week 52 | 
| To assess the clinically significant changes in clinical laboratory test results in subjects treated with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to placebo | Number of subjects with clinically significant changes in clinical laboratory test results (of hematology, biochemistry, and urinalysis) | Week 52 | 
| To evaluate the clinically significant changes in vital signs in subjects treated with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo. | Number of subjects with clinically significant changes in vital signs | Week 52 | 
| To assess the clinically significant changes in 12-lead electrocardiogram in subjects treated with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal dose (1 or 2 mg) relative to Placebo | Number of subjects with clinically significant changes (in heart rates & rhythm, conduction defects, QTc interval) in 12-lead electrocardiogram | Week 52 | 
| To evaluate the changes in body weight in subjects treated with Saroglitazar Magnesium 1 mg/Optimal Dose (1 or 2 mg) and Saroglitazar Magnesium 2 mg/Optimal Dose (1 or 2 mg) relative to Placebo. | Number of subjects with changes in body weight | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Saroglitazar Magnesium, Primary Biliary Cholangitis, PBC