Oltipraz for Liver Fat Reduction in Patients With Non-alcoholic Fatty Liver Disease Except for Liver Cirrhosis

Study Overview
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Brief Summary
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Oltipraz inhibits fatty acid synthesis through AMPK-S6K1 pathway and LXRg-SREBP-1c pathway in liver.

Detailed Description
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Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. And it is well known that the modulation of S6K1 by oltipraz inhibited the development of insulin resistance and hyperglycemia through the AMPK-S6K1 pathway.Also some research reported that LXRg (a member of the nuclear hormone receptor)-mediated increases in SREBP-1c (the sterol regulatory element-binding protein-1c gene) promote the expression of lipogenic genes and enhance fatty acid synthesis and oltipraz inhibits LXRg and SREBP-c. Therefore, Oltipraz inhibits fatty acid synthesis through AMPK-S6K1 pathway and LXRg-SREBP-1c pathway in liver.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Oltipraz

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Oltipraz
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A person the ages of 19 and 75 years old Patients with non-alcoholic fatty liver disease other than cirrhosis that meets all of the following criteria: Abdominal ultrasonography of Screening indicates that the liver is brighter than the spleen or kidneys, causing suspected fatty liver Persons with liver fat content is 20% or more on the MRS Those who do not have significant alcohol intake within two years before screening (men: no more than 210 g per week; women: no more than 140 g per week) Those who with an alcohol use disorder identification test (AUDIT) result point is no more than 7, during screening. Persons with body mass index (BMI) more than 23 kg/m2 during screening A person who satisfies the following laboratory test results when screening Platelet ≥ 130,000/㎣ White blood cell (WBC) ≥ 3,000/㎣ Absolute neutrophil count (ANC) ≥ 1,500/㎣ Albumin ≥ 3.5 g/dL Serum creatinine ≤ 1.5 X upper limit of normal (ULN) ULN < Alanine transaminase (ALT) or aspartate transaminase (AST) ≤ 250 IU/L A person who is willing to maintain the same lifestyle (exercise, alcohol intake, diet, etc.) maintained for at least four weeks before screening during the clinical trial period. A person who voluntarily agrees to participate in this clinical trial Exclusion Criteria: A person who has history of following disease or surgery Malignant tumour with liver cancer Malignant tumor excluding liver cancer, However, registration is possible in the following cases If the investigator determines that the patient has been completely cured after maintaining the condition for at least five years In case of basal cell or squamous cell carcinoma of the skin, the patient is able to maintain a complete condition for more than three years in the case of cainoma in the cervix (CIN) and carcinema in situ (CIS), and other areas. autoimmune disease (e.g., inflammatory bowel disease, autoimmune hemolytic disease, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, rheumatoid arthritis, severe psoriasis, etc.) Bariatric surgery within 24 weeks before screening A Person who has comorbidity of the following diseases at the time of screening Liver cirrhosis identified by an epidemiological or histological examination Cumulative disease (e.g., alcohol liver disease, toxic hepatitis, autoimmune liver disease, metabolic liver disease, biliary closure, etc.) that may indicates liver abnormalities other than non-alcoholic fatty liver disease A Person who has been infected or has Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). Type 1 diabetes or type 2 diabetes (hemoglobin A1c (HbA1c) > 9%) A person who has positive result of Human immunodeficiency virus antibody (HIV Ab). A persons with conditions that may affect the effectiveness and safety by investigator A person with AST/ALT ratio of more than 2 at screening The person who has the following medication history Persons administered vitamin E (≥ 800 IU/day) or thiazolidatedione drugs or glucagon-like peptide-1 (GLP-1) agonist drugs within 12 weeks prior to screening Persons who were given antiobestic drug within 12 weeks of screening For example; antiobestic drug with Central nervous system action: Amfepramone, bupropion and naltrexone, cathine, clobenzorex, dexfenfluramine, ephedrine combinations, etilamfetamine, fenfluramine, lorcaserin, mazindol, mefenorex, phentermine, sibutramine, Peripheral neurotic Obesity drugs: Orlistat, Rimonabant, etc A person who received medications that could cause fatty liver disease within 8 weeks prior to screening For example; Administration of systemic glucocorticoids for more than two weeks Anabolic steroid-based drug, Estrogen-based drug, Azole-based antimicrobial agent, Nucleoside, Nucleotide reverse transcriptase inhibitor-based drug, Tetracycline-based drug, Amiodarone, tamoxifen, methotrexate, valproic acid, etc A person who administered drugs that may affect the progress of non-alcoholic fatty liver disease within 4 weeks prior to screening or who require administration during clinical trials For example; Silymarin, biphenyl dimethyl dicarboxylate (DDB), ursodeoxycholic acid (UDCA), S-adenosyl-L-methionine (SAMe), betaine, pentoxyfylline, sodium-glucose cotransporter-2 (SGLT-2) inhibitor, omega 3 fatty acid, etc. However, the following drugs can be registered if they are under stable dosage for at least 12 weeks and are expected to remain unchanged during clinical trials; Sulfonylurea-based drug, metformin, insulin, dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor), a-glucosidase inhibitor (a-GI), meglitinide-based drug, statin-based drug, fibrate-based drug, nicotinic acid, ezetimibe, beta-blockers based drug, thiazide based drug A person who receive non-drug treatment that may affect the liver within 4 weeks prior to screening. A person who administered/treated with other clinical trials/medical devices within 4 weeks prior to screening Those who are not able to MRS(I) A female who is pregnant, may be pregnant, or is lactating A person who is not willing to use appropriate contraceptives during this clinical trial. A person who is hypersensitive to the Investigational Product A person who is deemed ineligible for clinical trials by the investigator

Ages Eligible for Study
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Minimum Age: 19 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oltipraz<br>Oltipraz 30mg | Drug: Oltipraz<br>* Total 90mg, By mouth, TID<br>|
| Placebo Comparator: Placebo<br>Placebo 30mg | Drug: Placebos<br>* Total 90mg, By mouth, TID<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation of liver fat assessed | Variation of liver fat assessed by MRS at 24 weeks compared to the baseline (%) | 24 weeks compared to the baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The variation in the amount of liver fat | The variation in the amount of liver fat assessed by the MRS at the time of 24 weeks compared to the baseline | 24 weeks compared to the baseline | 
| Variation of liver fat certificate grade | Variation of liver fat certificate grade assessed by ultrasonic waves | 24 weeks compared to the baseline | 
| Variation of NFS variation | Variation of NFS at 24 weeks compared to the baseline | 24 weeks compared to the baseline | 
| Variation of liver elasticities and fatty acids | Variation of liver elasticities and fatty acids assessed by fibroscan at 24 weeks time compared to baseline | 24 weeks compared to the baseline | 
| FIB-4 | Variation of FIB-4 from 8 weeks, 16 weeks and 24 weeks to baseline | 8 weeks, 16 weeks and 24 weeks | 
| BMI | BMI variation at 8 weeks, 16 weeks and 24 weeks relative to the baseline | 8 weeks, 16 weeks and 24 weeks | 
| Variation of ALT, AST, γ-glutamyl transferase (GGT) | Variation of ALT, AST, γ-glutamyl transferase (GGT) in time of 8 weeks, 16 weeks and 24 weeks relative to the baseline | 8 weeks, 16 weeks and 24 weeks | 
| Cholesterol (total, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglyceride (TG) | Variation of Cholesterol (total, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglyceride (TG) | 8 weeks, 16 weeks and 24 weeks | 
| Variation of Homeostatic model adjustment-insulin resistance (HOMA-IR) index | Variation of Homeostatic model adjustment-insulin resistance (HOMA-IR = fasting insulin (μU/mL) × fasting glucose (mmol/L) / 22.5) | 24 weeks compared to the baseline | 
| Waist circumference | The variation of waist circumference compared to the baseline at 24 weeks | 24 weeks compared to the baseline |