A Phase II Clinical Trial of Chiglitazar for NASH

Study Overview
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Brief Summary
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The study is to evaluate the efficacy and safety of chiglitazar monotherapy in patients with non-clcoholic steatohepatitis (NASH).

Detailed Description
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The study is a non-invasive exploratory phase II trial in patients who were clinically diagnosed as non-alcoholic steatohepatitis (NASH) with liver fibrosis accompanied by elevated triglycerides (TG) and insulin resistance. The efficacy and safety of chiglitazar tablets 48mg and 64mg will be compared with placebo in the 18-week-treament.

Official Title
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A Multi-Center, Randomised, Double-blind, Placebo Controlled Phase II Clinical Study of Chiglitazar in Patients With Nonalcoholic Steatohepatitis Accompanied by Elevated Triglycerides and Insulin Resistance

Conditions
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NASH

Intervention / Treatment
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* Drug: chiglitazar sodium tablets
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Before any evaluation, an informed consent form voluntarily signed by the patient must be obtained; 18 -75 years old (at the time of screening visit V1), male or female; MRI-PDFF ≥ 8% ; Liver stiffness value ( LSM ) 7.0-11.0kPa ; Triglyceride ( TG ) ≥1.7mmol/L and ≤5.6 mmol/L; HOMA-IR ≥ 2.5 ; Serum Alanine aminotransferease (ALT) ≥ the upper limit of normal during screening. Exclusion Criteria: Type 1 diabetes; Any of the following for type 2 diabetes: HbA1c ≥ 8.5% during screening At the time of screening, ≥ 2 oral hypoglycemic drugs combinations Receiving any of the following medications at screening: Thiazolidinediones (TZD) drugs, fibrates, glucagon-like peptide-1 (GLP-1) receptor agonists, insulin Existing other liver diseases or history of liver diseases History of transient ischemic attack or cerebrovascular accident; History of myocardial infarction, or coronary angioplasty or coronary artery bypass surgery, unstable angina, heart failure (New York Heart Association NYHA grade III / IV ), or ECG signs of left ventricular hypertrophy, or serious arrhythmias ； During screening, blood pressure ≥ 160/100 mmHg ; Previous or planned ( during the study period) bariatric surgery; Liver transplantation history or planned liver transplantation; Liver biopsy show liver cirrhosis or clinically diagnosed as cirrhosis; Weight loss of more than 5% in 6 months before screening; History of edema of lower limbs or whole body; diagnosed as osteoporosis or any other known bone disease; Donated blood or lost blood >400 ml within 8 weeks before the first medication; With MRI scan contraindications; In the past 5 years, there was a history of malignant tumors of any organ system; Human immunodeficiency virus ( HIV ) test is positive; Heavy drinking of alcohol for more than 3 months in a year; Heavy smoking >30 per day within 1 year; History of drug abuse in 12 months; Drugs cumulatively for more than 1 month in the previous 3 months before screening, such as obeticholic acid ( OCA ), berberine; Drugs that may cause liver damage for more than 2 weeks within 1 year before screening; Patients received the following medications unless they have received a stable dose for at least 1 month before screening :Beta-blockers, thiazide diuretics, statins, niacin, ezetimibe, thyroid hormone; The calculated eGFR < 60 mL/(min*1.73m^2 ); There is clinical evidence of liver decompensation or severe liver damage; Low density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol/L during screening ; Platelet < 100×10^9 /L ; Patient participating in other clinical trials of drugs or medical devices within 3 months prior to screening ; Pregnant or breastfeeding women.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chiglitazar low dose<br>3 tablets of drug and 1 tablet of placebo p.o. per day | Drug: chiglitazar sodium tablets<br>* the drugs will be given orally once a day<br>* Other names: Carfloglitazar;|
| Experimental: Chiglitazar high dose<br>4 tablets p.o. per day | Drug: chiglitazar sodium tablets<br>* the drugs will be given orally once a day<br>* Other names: Carfloglitazar;|
| Placebo Comparator: control group<br>4 placebo tablets p.o. per day | Drug: Placebo<br>* no active drug contained<br>* Other names: simulant of chiglitazar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline to week 18 in liver fat content as measured by MRI using the proton density fat fraction (MRI-PDFF) | center reading for the primary endpoint | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the change in liver fat content from baseline as shown by MRI-PDFF after 18 weeks treatment | Absolute decrease in liver fat content Proportion of patients with Liver fat content absolute decrease ≥5% Proportion of patients with Liver fat content relative decrease ≥30% proportion | 18 weeks | 
| ALT changes from baseline | changes from baseline in liver enzymes | 6,12,18 weeks | 
| FIB-4 changes from baseline | changes from baseline in Fibrosis 4 Score | 6,12,18 weeks | 
| insulin resistance changes | Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | 6,12,18 weeks | 
| Changes from baseline in TG | blood sample | 6,12,18 weeks | 
| change from baseline in Liver stiffness measurement (LSM) with Fibroscan | to evlaute the severity of liver fibrosis | 6,12,18 weeks | 
| change from baseline in Cytokeratin18 (CK-18) | to evaluate the severity of liver damage | 6,12,18 weeks | 
| Maximum Plasma Concentration [Cmax] of chiglitazar after 1 dose, 6 weeks and 12 weeks of treatment | population PK | 0, 6,12 weeks | 
| The area under the plasma drug concentration-time curve [AUC] of chiglitazar after 1 dose, 6 weeks and 12 weeks of treatment | population PK | 0, 6,12 weeks |