Efficacy and Safety Evaluation of Saroglitazar Magnesium in Primary Biliary Cholangitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2b/3 Trial
- Trial ID
- 2024-518718-14-00
- Protocol
- SARO.21.001
- Sponsor
- Zydus Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superiority of **Saroglitazar Magnesium** Optimal Dose (1 mg) dosed once daily relative to Placebo in achieving a biochemical response based on the composite endpoints of alkaline phosphatase (ALP) and total bilirubin at Week 52 in subjects with **Primary Biliary Cholangitis (PBC)**. This is clinically relevant as it aims to improve liver function and reduce disease progression in PBC patients.
Secondary objectives include:
- Evaluating the effect of Saroglitazar Magnesium on the normalization of ALP values at Week 52.
- Assessing the impact on pruritus using the 5-D itch scale.
- Determining the biochemical response based on ALP and total bilirubin at Weeks 4, 8, 16, and 24.
- Measuring changes from baseline in ALP levels.
- Evaluating quality of life improvements using the PBC 40 questionnaire.
- Assessing liver stiffness improvement of at least 25% at Weeks 24 and 52 using Liver elastography/FibroScan®.
- Evaluating changes in liver enzymes and lipid parameters.
Participants
The clinical trial for **Primary Biliary Cholangitis (PBC)** involves a total of 190 participants. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have a history of confirmed PBC diagnosis, as per the guidelines of the American Association for the Study of Liver Disease and the European Association for Study of the Liver. The trial includes individuals who have been on ursodeoxycholic acid (UDCA) for at least 12 months at a therapeutic dose, with a stable dose for 6 months prior to screening, or those unable to tolerate UDCA for at least 3 months prior to screening. The participants must have an alkaline phosphatase (ALP) level of at least 1.67 times the upper limit of normal (ULN) and a total bilirubin level of less than 2 times the ULN at screening. The trial does not include a vulnerable population, and all participants must provide written informed consent and agree to comply with the trial protocol. The selection process ensures that the participants meet these specific criteria to maintain the integrity and focus of the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Saroglitazar Magnesium** in subjects with **Primary Biliary Cholangitis (PBC)**. The trial is categorized as a Phase 2b/3 study and aims to demonstrate the superiority of Saroglitazar Magnesium at an optimal dose of 1 mg, administered once daily, compared to a placebo. The primary endpoint is the proportion of subjects achieving a biochemical response based on composite endpoints of alkaline phosphatase (ALP) and total bilirubin at Week 52. Secondary endpoints include the normalization of ALP, changes in itch scores, and quality of life assessments.
The trial duration is estimated to conclude by May 31, 2025, with recruitment having commenced on January 27, 2023. Participants will be involved in the study for a maximum treatment period of 52 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits at Weeks 4, 8, 16, 24, and 52 to monitor progress and collect data, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be between 18 and 75 years of age, with a confirmed diagnosis of PBC, and specific biochemical markers. Exclusion criteria are not explicitly detailed in the provided data.
Participants may be withdrawn from the study if they do not comply with the protocol, experience adverse effects, or if the investigator deems it necessary for their safety. The trial is conducted under strict regulatory guidelines to ensure the integrity of the data and the safety of the participants. The study employs a placebo as a comparator, formulated as tablets without the active ingredient, Saroglitazar Magnesium. The trial's design and methodology are structured to provide robust data on the efficacy and safety of Saroglitazar Magnesium in treating PBC.
Treatment
The clinical trial involves the administration of **Saroglitazar Magnesium**, an investigational medication, to evaluate its efficacy and safety in subjects with Primary Biliary Cholangitis (PBC). **Saroglitazar Magnesium** is provided in the form of uncoated tablets, with each tablet containing the active substance **Saroglitazar Hemimagnesium**. The medication is administered orally at a dosage of 1 mg once daily. The maximum daily dose is 2 mg, and the treatment period extends up to 52 weeks. The investigational product is manufactured by Zydus Therapeutics Inc. Compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.
The comparator in this study is a **Placebo**, formulated as tablets that contain the same excipients as the investigational product, excluding **Saroglitazar Magnesium Micronized**. The placebo is administered orally, following the same dosing schedule as the investigational medication, to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the investigational product's efficacy by providing a baseline for comparison. Participant compliance with the placebo regimen is similarly monitored to ensure the integrity of the study results.
Efficacy
The efficacy of Saroglitazar Magnesium in the treatment of **Primary Biliary Cholangitis** (PBC) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of subjects achieving a biochemical response, defined by a composite of alkaline phosphatase (ALP) and total bilirubin levels, at Week 52. Specifically, this includes ALP levels less than 1.67 times the upper limit of normal (ULN), a reduction of at least 15% in ALP from baseline, and total bilirubin levels at or below ULN, or direct bilirubin at or below ULN in subjects with known Gilbert’s syndrome.
Secondary endpoints include the proportion of subjects with complete normalization of ALP (ALP ≤ ULN) at Week 52, changes from baseline in the 5-D itch score at Weeks 24 and 52 for subjects with a baseline score of ≥ 12, and the proportion of subjects achieving a biochemical response at Weeks 4, 8, 16, and 24. Additional secondary measures involve the proportion of subjects with ALP improvements of at least 15%, 30%, 40%, and 50% at Weeks 24 and 52, as well as absolute and percentage changes in ALP values at these timepoints. Changes in quality of life, as measured by the PBC-40 questionnaire, will be evaluated at Weeks 16, 24, and 52. Furthermore, the study will assess changes in liver enzyme parameters (ALT, AST, GGT, and total bilirubin) and lipid parameters (TG, LDL-C, HDL-C, VLDL-C, total cholesterol, and non-HDL-C) at Weeks 16, 24, and 52, along with changes in serum bile acids at Weeks 24 and 52.
These efficacy parameters will be collected and analyzed at specified intervals throughout the trial, using validated laboratory tests and patient-reported outcomes to ensure accurate and reliable data collection. The trial is designed to demonstrate the superiority of Saroglitazar Magnesium over placebo in achieving these endpoints, thereby providing a comprehensive evaluation of its efficacy in managing PBC.
Inclusion and Exclusion Criteria
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 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.
- 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
- ALP ≥ 1.67 x ULN at both Visits 1 and 2 and < 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: 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
- 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.
- 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)
- 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: 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.
- 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 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
- History of myopathies or evidence of active muscle disease demonstrated by CPK ≥ 5 x ULN at screening
- 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.
- 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
- 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: 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
- 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).
- Cirrhosis with Child-Pugh-Turcotte (CPT) class B or C having score of 7 or above at screening (Refer Appendix 10)
- Subjects with Model for End Stage Liver Disease 3.0 (MELD 3.0) score of 12 or above.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Iceland | Not Recruiting | 22 Dec 2022 | 6 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
The comparator will be Placebo, which will be formulated as tablets, and will contain the protocol mentioned
excipients without Saroglitazar Magnesium Micronized | Placebo | N/A | — | — | — | N/A |
Saroglitazar Magnesium | Test | UNCOATED TABLETS | ORAL | 2 | 52 | PRD11731770 |