A Study of Chiglitazar in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes Mellitus

Chiglitazar in Combination With Anti-Inflammatory and Hepatoprotective Therapy for the Treatment in MASH Associated With T2DM: a Prospective, Multicentre, Randomised, Double-blind, Placebo-controlled Study

This trial aims to evaluate the efficacy and safety of chiglitazar as a combination therapy for patients with MASH and T2DM.

Metabolic dysfunction-associated steatohepatitis (MASH), used to be called non-alcoholic steatohepatitis (NASH), is a manifestation of the metabolic syndrome in the liver, particularly when co-occurring with type 2 diabetes (T2DM), presents a significant therapeutic challenge due to a higher risk of fibrosis progression and adverse outcomes. While new treatments for MASH are emerging, their efficacy in the T2DM subpopulation remains an area of unmet need. Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist that regulates key pathways in lipid metabolism, glucose homeostasis, and inflammation. This trial aims to evaluate the efficacy and safety of chiglitazar as a combination therapy for patients with MASH and T2DM.

This is a prospective, multicentre, randomised, double-blind, placebo-controlled study. The trial will enroll 300 adult patients aged 18-75 years with biopsy-confirmed MASH and fibrosis stage F1b or higher. Participants will be randomised (1:1) to receive either chiglitazar 48 mg daily or a matching placebo. All participants will also receive background therapy consisting of vitamin E (100 mg three times a day) and polyene phosphatidylcholine (456 mg three times a day). The treatment duration is 72 weeks. The primary efficacy endpoint is the resolution of steatohepatitis with no worsening of liver fibrosis. Key secondary endpoints include improvement in liver fibrosis by at least one stage and changes in metabolic and liver safety biomarkers.

Inclusion Criteria:

1. Men and women aged at least 18 years and under 75 years (inclusive) at the time of obtaining consent.
2. Participants must be diagnosed as T2DM and HbA1c ≤ 9.5% at time of screening.
3. Participants must take Fibroscan examination with the result of CAP ≥ 238 dB/m and LSM>8.5 kPa.
4. Diagnosis of MASH by liver biopsy, with NAFLD Activity Score (NAS) ≥4 with ≥1 point for each component, and fibrosis stage 1b or more over according to the NASH Clinical Research Network (CRN) scoring system. (or liver biopsy not more than 6 months prior to screening)
5. Stable body weight (≤10% body weight change) for at least 3 months.
6. Possess good understanding and behavior and be able to take the medication daily as required by the trial.
7. Willing to sign the informed consent.

Exclusion Criteria:

1. Alcohol consumption >20g ethyl alcohol/day for women and >40g ethyl alcohol/day for men.

2. Evidence of other forms of chronic liver disease:

   1. Alcoholic liver disease,
   2. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) or hepatitis B DNA,
   3. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA or positive hepatitis C antibody (anti-HCV),
   4. Evidence of autoimmune liver disease as defined by compatible liver histology,
   5. Current drug-induced liver disease as defined on the basis of typical exposure and history,
   6. Suspected or proven liver cancer,
   7. Any other type of liver disease other than MASH.

3. Uncontrolled T2DM defined as HbA1c >9.5% at time of screening or Type 1 diabetes mellitus (T1DM).

4. Patients with T2DM who have a history of diabetic ketoacidosis, proliferative diabetic retinopathy, diabetic maculopathy or severe non-proliferative diabetic retinopathy that requires acute treatment.

5. Any of the following cardiovascular conditions within 6 months prior to screening:

   1. acute myocardial infarction (MI),
   2. cerebrovascular accident (stroke),
   3. unstable angina,
   4. hospitalization due to congestive heart failure (CHF)
   5. New York Heart Association Functional Classification IV CHF

6. History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years.

7. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg).

8. Renal impairment measured as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2.

9. Known clinically significant gastric emptying abnormality (for example, severe diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect gastrointestinal motility.

10. Have a known self or family history (first-degree relative) of multiple endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma (MTC).

11. Evidence of untreated hypothyroidism or hyperthyroidism based on clinical or laboratory evaluation.

12. A transplanted organ (corneal transplants allowed) or awaiting an organ transplant.

13. Women of childbearing potential: positive pregnancy test during screening or at randomization or unwillingness to use an effective form of birth control during the trial (at least include one barrier contraceptive method) and breast feeding.

14. Use of drugs associated with hepatic steatosis (e.g., amiodarone, methotrexate, tamoxifen) for more than 2 weeks in the 3 months prior to screening.

15. Current use of medication is associated with weight gain, except when on stable dose for at least 3 months prior to screening and remaining on stable dose during the study.

16. Receiving or having received (within 3 months of screening) chronic (>2 weeks) systemic glucocorticoid therapy.

17. Use of treatment targeting MASH for more than 2 weeks in the 3 months prior to screening (GLP-1 receptor agonists or PPAR pan agonists).

18. Any other condition which in the opinion of investigator would impede compliance or hinder completion of the study.