Study to Evaluate Safety, Tolerability and Efficacy in patients with Primary Biliary Cholangitis of Saroglitazar Magnesium-III (EPICS-III).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Zydus Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

23 Jan 2023 → 7 May 2025

Decision date (initial)

2024-12-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Zydus Therapeutics Inc.

External identifiers

EU CT number

2024-518718-14-00

EudraCT number

2022-001634-10

ClinicalTrials.gov

NCT05133336

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To demonstrate the superiority of Saroglitazar Magnesium Optimal Dose (1 mg) dosed once daily relative to Placebo with respect to biochemical response based on the composite endpoints of ALP and total bilirubin at Week 52 in subjects with PBC.

Secondary objectives 7

1. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo on normalization of ALP values at Week 52.
2. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo on pruritis assessed by 5-D itch scale
3. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) dosed once daily relative to Placebo with respect to biochemical response based on the composite endpoints of ALP and total bilirubin in subjects with PBC at Weeks 4, 8, 16, and 24.
4. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo with respect to change from baseline in ALP
5. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo on quality of life assessed by the PBC 40 questionnaire
6. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo with respect to improvement in liver stiffness measurement (LSM) of at least 25% at Weeks 24 and 52 relative to baseline assessed by Liver elastography/FibroScan®
7. To evaluate the effect of Saroglitazar Magnesium Optimal Dose (1 mg) relative to Placebo on liver enzymes and lipid parameters

Conditions and MedDRA coding

Primary Biliary Cholangitis (PBC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

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 the 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 22

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: a. Chronic hepatitis B or C virus (HBV, HCV, respectively) 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) b. Primary sclerosing cholangitis (PSC) c. Alcoholic liver disease d. 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 subject 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) based 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.
4. 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
5. Use of thiazolidinediones or fibrates (within 12 weeks prior to screening)
6. 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)
7. 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.
8. Type 1 diabetes mellitus
9. 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 to 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.
10. 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.
11. An uncontrolled thyroid disorder a. 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 b. Uncontrolled hypothyroidism: defined as the initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening
12. History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 x ULN at screening
13. For subjects with elevated baseline ALT or AST; ALT or AST exceeding by more than 50% on Visit 2 compared to Visit 1. Note: If the ALT or AST 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 the trend. If the third value shows a continued increase ≥ 10%, then the subject is considered ineligible for randomization.
14. Any of the following laboratory values at screening: a. Platelets < 50 × 109/L Albumin < 2.8 g/dL c. eGFR < 45 mL/min/1.73 m2 d. ALP > 10 × ULN e. ALT or AST > 250 U/L
15. Participation in another interventional clinical study and receipt of any other investigational medication (within 12 weeks prior to randomization up to end of study).
16. History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial non-melanoma skin cancer.
17. Contraindications to Saroglitazar Magnesium or has any conditions affecting the ability to evaluate the effects of Saroglitazar Magnesium.
18. Known allergy, sensitivity, or intolerance to the study drug, comparator, or formulation ingredients.
19. 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
20. 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).
21. Cirrhosis with Child-Pugh-Turcotte (CPT) class B or C having score of 7 or above at screening (Refer Appendix 10)
22. Subjects with Model for End Stage Liver Disease 3.0 (MELD 3.0) score of 12 or above.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects with a 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] at Week 52.

Secondary endpoints 7

1. Proportion of subjects with complete normalization of ALP defined as (ALP≤ULN) at Week 52.
2. Change from baseline in 5-D itch score at Week 24 and Week 52 in subjects with baseline 5-D itch score of ≥ 12
3. Proportion of subjects with a 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] at Weeks 4, 8, 16, and 24.
4. Proportion of subjects with ALP improvement of at least 15%, 30%, 40%, and 50% at Weeks 24 and 52. • Absolute and percent change from baseline in ALP values at Weeks 24 and 52.
5. Change from baseline in quality of life (PBC 40) questionnaire domains (total score and domain score) at Weeks 16, 24, and 52.
6. Proportion of subjects with a decrease in LSM of at least 25% at Weeks 24 and Week 52 relative to baseline
7. Change from baseline in liver enzyme parameters (ALT, AST, GGT, and total bilirubin [direct and indirect bilirubin]) at Weeks 16, 24, and 52. • Change from baseline in lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C) at Weeks 24 and 52.Change from baseline in serum bile acids at Weeks 24 and 52.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Zydus Therapeutics Inc.

Sponsor organisation

Zydus Therapeutics Inc.

Address

73 Route 31 North

City

Pennington

Postcode

08534-3601

Country

United States

Scientific contact point

Organisation

Zydus Therapeutics Inc.

Contact name

Dr. Deven V. Parmar MD FCP

Public contact point

Organisation

Zydus Therapeutics Inc.

Contact name

Dr. Deven V. Parmar MD FCP

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications