Saroglitazar Magnesium for Treatment of Primary Biliary Cholangitis

Primary Biliary Cholangitis Clinical Trial

— EPICS-III  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05133336
• Other study ID #: SARO.21.001
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: April 1, 2022
• Est. completion date: May 14, 2025

Study information

• Verified date: May 2024
• Source: Zydus Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 186
• Est. completion date: May 14, 2025
• Est. primary completion date: May 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Males or females, between 18 and 75 years of age, both inclusive at screening.

2. 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.

3. 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
• Positive anti-mitochondrial antibodies (AMA) titer OR positive 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]) if AMA is negative
• Liver biopsy consistent with PBC

4. ALP = 1.67 x ULN at both Visits 1 and 2 and < 30% variance between the levels from Visit 1 to Visit 2

5. Total bilirubin < 2 x ULN at screening (Visit 1)

6. Must provide written informed consent and agree to comply with the trial protocol.

Exclusion Criteria:

1. 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).

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

1. 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)

2. Primary sclerosing cholangitis (PSC).

3. Alcoholic liver disease.

4. 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 positive 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. e. Hemochromatosis. f. Non-alcoholic steatohepatitis (NASH) on historical biopsy. 3.Cirrhosis with complications, including history or presence of: 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. 5.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. 6.Use of thiazolidinediones or fibrates (within 12 weeks prior to screening). 7.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 a-methyl-dopa, sodium valproic acid, isoniazid, or nitrofurantoin) (within 12 weeks prior to screening). 9.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. 10.Type 1 diabetes mellitus. 11.Unstable cardiovascular disease, including: a. 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. b. History/current unstable cardiac dysrhythmias. c. Uncontrolled hypertension at screening. d. Stroke or transient ischemic attack in the 24 weeks before screening. 12.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. 13.An uncontrolled thyroid disorder

1. 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.

2. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening. 14.History of myopathies or evidence of active muscle disease demonstrated by CPK = 5 x ULN at screening. 15.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. 16.Any of the following laboratory values at screening: a. Platelets < 50 × 109/L b. Albumin < 2.8 g/dL c. eGFR < 45 mL/min/1.73 m2 d. ALP > 10 x ULN e. ALT or AST > 250 U/L 17.Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to end of study). 18.History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer. 19.Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium. 20.Known allergy, sensitivity, or intolerance to the study drug, comparator, or formulation ingredients. 21.Pregnancy-related exclusions, including: a. Pregnant/lactating female (including positive pregnancy test at screening). b. Pregnancy should be avoided by male and female subjects either by true abstinence or the use of an acceptable effective contraceptive measures for the duration of the study and for at least 1 month after the end of the study treatment. Refer Appendix 8 Contraceptive Guidance 22.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). 23.Cirrhosis with Child-Pugh-Turcotte (CPT) Class B or C having score of 7 or above at screening 24.Subjects with Model for End Stage Liver Disease (MELD 3.0) score of 12 or above

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis

Intervention

Drug:
• Saroglitazar Magnesium 1 mg
Subjects randomized to Saroglitazar Magnesium 1 mg arm will receive Saroglitazar Magnesium 1 mg treatment for the entire treatment period up to Week 52.
• Saroglitazar Magnesium 2 mg
Subjects randomized to Saroglitazar Magnesium 2 mg arm are switched to Saroglitazar Magnesium 1 mg treatment up to Week 52
• Placebo
Subjects randomized to placebo arm will receive placebo treatment for the entire treatment period up to Week 52.

Locations

Country	Name	City	State
Argentina	Zydus AR001	Buenos Aires
Argentina	Zydus AR003	Buenos Aires
Argentina	Zydus AR004	Buenos Aires
Argentina	Zydus AR005	Buenos Aires
Argentina	Zydus AR006	Buenos Aires
Argentina	Zydus AR007	Buenos Aires
Argentina	Zydus AR009	Buenos Aires
Argentina	Zydus AR012	Buenos Aires
Argentina	Zydus AR013	Buenos Aires
Argentina	Zydus AR010	Santa Fe
Iceland	Zydus IS001	Reykjavik
Turkey	Zydus TR014	Adana
Turkey	Zydus TR016	Altindag
Turkey	Zydus TR004	Ankara
Turkey	Zydus TR005	Bursa
Turkey	Zydus TR017	Cebeci
Turkey	Zydus TR008	Gaziantep
Turkey	Zydus TR001	Istanbul
Turkey	Zydus TR003	Istanbul
Turkey	Zydus TR009	Istanbul
Turkey	Zydus TR010	Istanbul
Turkey	Zydus TR002	Izmir
Turkey	Zydus TR013	Izmir
Turkey	Zydus TR011	Kocaeli
Turkey	Zydus TR015	Melikgazi
Turkey	Zydus TR006	Mersin
United States	Zydus US022	Aurora	Colorado
United States	Zydus US007	Birmingham	Alabama
United States	Zydus US002	Charlotte	North Carolina
United States	Zydus US016	Charlottesville	Virginia
United States	Zydus US014	Cincinnati	Ohio
United States	Zydus US004	Houston	Texas
United States	Zydus US042	Houston	Texas
United States	Zydus US001	Indianapolis	Indiana
United States	Zydus US034	Iowa City	Iowa
United States	Zydus US027	Jacksonville	Florida
United States	Zydus US006	Lakewood Ranch	Florida
United States	Zydus US013	Los Angeles	California
United States	Zydus US038	Manhasset	New York
United States	Zydus US020	Marietta	Georgia
United States	Zydus US036	Marrero	Louisiana
United States	Zydus US005	Miami	Florida
United States	Zydus US031	Murray	Utah
United States	Zydus US037	New Haven	Connecticut
United States	Zydus US041	Newport News	Virginia
United States	Zydus US024	Omaha	Nebraska
United States	Zydus US011	Pasadena	California
United States	Zydus US015	Philadelphia	Pennsylvania
United States	Zydus US039	Richmond	Virginia
United States	Zydus US023	Rochester	Minnesota
United States	Zydus US035	Rochester	New York
United States	Zydus US043	Sacramento	California
United States	Zydus US030	Saint Louis	Missouri
United States	Zydus US028	Sarasota	Florida
United States	Zydus US033	Seattle	Washington
United States	Zydus US019	Tampa	Florida
United States	Zydus US021	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Zydus Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Iceland,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion 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 subjects with known Gilbert's syndrome	From baseline to week 52
Secondary	Proportion of subjects with complete normalization of ALP.	ALP=ULN	From baseline to week 52
Secondary	Pruritis assessed by 5 D itch scales	Change from baseline in 5-D itch score	From baseline to Week 24 and Week 52
Secondary	Proportion 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 subjects with known Gilbert's syndrome	From baseline to Weeks 4, 8, 16, and 24.
Secondary	Proportion of subjects change from baseline in ALP	ALP improvement of at least 15%, 30%, 40%, and 50% Absolute and percent change from baseline in ALP values	From baseline to Weeks 24 and 52.
Secondary	Quality of life assessed by the PBC 40 questionnaire	Change from baseline in quality of life (PBC 40) questionnaire domains (total score and domain score)	From baseline to Weeks 16, 24, and 52.
Secondary	Improvement in liver stiffness measurement (LSM) of at least 25% relative to baseline assessed by Liver elastography/FibroScan®	Proportion of subjects with a decrease in LSM of at least 25%	From baseline to Weeks 24 and Week 52
Secondary	To effect on liver enzymes	Change from baseline in liver enzyme parameters (ALT, AST, GGT, and total bilirubin [direct and indirect bilirubin])	From baseline at Weeks 16, 24, and 52.
Secondary	The effect on liver enzymes	Change from baseline in serum bile acids	From baseline to week 24 and week 52
Secondary	The effect on lipid parameters	Change from baseline in lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C)	From baseline to weeks 24 and 52