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

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

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

Study Overview

• Status: Completed
• Conditions: Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Oltipraz; Drug: Placebos

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bucheon, Korea, Republic of
    • Soonchunhyang University Bucheon Hospital
  • Bucheon, Korea, Republic of
    • Catholic University Bucheon ST. Mary's Hospital
  • Busan, Korea, Republic of, 49201
    • Dong-A University Hospital
  • Daegu, Korea, Republic of
    • Keimyung University Dongsan Medical Center
  • Gangneung-si, Korea, Republic of
    • Gangneung Asan Medical Center
  • Goyang-si, Korea, Republic of, 410-719
    • NHUS Ilsan Hospital
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Yonsei University Gangnam Severance Hospital
  • Seoul, Korea, Republic of
    • National Medical Center
  • Seoul, Korea, Republic of
    • Korea University Guro Hospital
  • Seoul, Korea, Republic of
    • Severance Hospital
  • Seoul, Korea, Republic of
    • Soonchunhyang University Seoul Hospital
  • Seoul, Korea, Republic of
    • Chung-Ang University Hosptial
  • Seoul, Korea, Republic of
    • Hanyang University Hospital
  • Seoul, Korea, Republic of, 156-707
    • Boramae Hospital
  • Seoul, Korea, Republic of
    • Hallym University Gangnam Sungsim Hospital
  • Suwon, Korea, Republic of
    • Ajou University School of Medicine
  • Wanju, Korea, Republic of
    • Wonju Severance Christian Hospital
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of, 411-706
      • Inje University Ilsan Paik Hospital
    • Uijeongbu-si, Gyeonggi-do, Korea, Republic of
      • The Catholic University of Korea, Uijeongbu St. Mary's Hospital
  • Junggu
    • Incheon, Junggu, Korea, Republic of
      • Inha University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Abdominal ultrasonography of Screening indicates that the liver is brighter than the spleen or kidneys, causing suspected fatty liver
  2. Persons with liver fat content is 20% or more on the MRS
  3. 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)
  4. 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

  1. Platelet ≥ 130,000/㎣
  2. White blood cell (WBC) ≥ 3,000/㎣
  3. Absolute neutrophil count (ANC) ≥ 1,500/㎣
  4. Albumin ≥ 3.5 g/dL
  5. Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
  6. 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

  1. Malignant tumour with liver cancer

  2. Malignant tumor excluding liver cancer, However, registration is possible in the following cases

     1. If the investigator determines that the patient has been completely cured after maintaining the condition for at least five years
     2. 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.
  3. autoimmune disease (e.g., inflammatory bowel disease, autoimmune hemolytic disease, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, rheumatoid arthritis, severe psoriasis, etc.)
  4. Bariatric surgery within 24 weeks before screening

• A Person who has comorbidity of the following diseases at the time of screening

  1. Liver cirrhosis identified by an epidemiological or histological examination
  2. 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
  3. A Person who has been infected or has Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).
  4. Type 1 diabetes or type 2 diabetes (hemoglobin A1c (HbA1c) > 9%)
  5. A person who has positive result of Human immunodeficiency virus antibody (HIV Ab).
  6. 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

  1. 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
  2. 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
  3. 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

  4. 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.

     1. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oltipraz; Oltipraz 30mg	Drug: Oltipraz; Total 90mg, By mouth, TID
Placebo Comparator: Placebo; Placebo 30mg	Drug: Placebos; Total 90mg, By mouth, TID; Other Names: Placebo

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Variation of biomarkers	Adipokine (leptin, adiponectin, resistin, TNF-α, IL-6)	8 weeks, 16 weeks and 24 weeks
The Variation of biomarkers	CK-18 (M30, M65)	8 weeks, 16 weeks and 24 weeks
The Variation of biomarkers	Hepcidine	8 weeks, 16 weeks and 24 weeks
Variation of liver fat assessed as tissue samples acquired by liver biopsy	Variation of liver fat assessed as tissue samples acquired by liver biopsy at 24 weeks compared to the baseline	24 weeks compared to the baseline
Variation of Steatosis assessed as tissue samples acquired by liver biopsy	Variation of Steatosis at 24 weeks compared to the baseline	24 weeks compared to the baseline
Variation of lobular inflammation assessed as tissue samples acquired by liver biopsy	Variation of lobular inflammation at 24 weeks compared to the baseline	24 weeks compared to the baseline
Variation of ballooning assessed as tissue samples acquired by liver biopsy	Variation of ballooning at 24 weeks compared to the baseline	24 weeks compared to the baseline
NAFLD activity scores (NAS)	Variation of NAFLD activity scores (NAS) at 24 weeks compared to the baseline	24 weeks compared to the baseline
Correlation between MRS and ultrasound, fibroscan, FIB-4, and biopsy results	Correlation between MRS and ultrasound, fibroscan, FIB-4, and biopsy results	24 weeks compared to the baseline

Collaborators and Investigators

• Sponsor: PharmaKing
• Investigators: Principal Investigator: Yun-Jun Kim, MD.PhD, Seoul Nat'l Uni. Hospital; Principal Investigator: Changuk Kim, MD.PhD, The Catholic University of Korea, Uijeongbu St. Mary's Hospital; Principal Investigator: Gapjin Chun, MD.PhD, Gangneung Asan Medical Center; Principal Investigator: Taehui Lee, MD.PhD, Kunyang University Hospital; Principal Investigator: Byeongguk Jang, MD.PhD, Keimyung University Dongsan Medical Center; Principal Investigator: Yanghyeon Baek, MD.PhD, Dong-A University Hospital; Principal Investigator: Byeonggwan Kim, MD.PhD, Boramae Hospital; Principal Investigator: Yeongseok Kim, MD.PhD, Soonchunhyang university hospital; Principal Investigator: Jaeyeong Chang, MD.PhD, Soonchunhyang university hospital; Principal Investigator: Jaeyeong Jung, MD.PhD, Ajou University School of Medicine; Principal Investigator: Hyeonung Lee, MD.PhD, Yonsei University Gangnam Severance Hospital; Principal Investigator: Doyeong Kim, MD.PhD, Severance Hospital; Principal Investigator: Munyeong Kim, MD.PhD, Wonju Severance Christian Hospital; Principal Investigator: Junseong Lee, MD.PhD, Inje University Ilsan Baek Hospital; Principal Investigator: Jinu Lee, MD.PhD, Inha University Hospital; Principal Investigator: Hyeongjun Kim, MD.PhD, Chung-Ang University Hosptial, Chung-Ang University College of Medicine; Principal Investigator: Sanghun Park, MD.PhD, Hallym University Gangnam Sungsim Hospital; Principal Investigator: Daewon Jun, MD.PhD, Hanyang University; Principal Investigator: Chun Kyun Lee, MD.PhD, National Health Insurance Service Ilsan Hospital; Principal Investigator: Jaeyun Jung, MD.PhD, National Medical Center; Principal Investigator: Jihun Kim, MD.PhD, Korea University Guro Hospital; Principal Investigator: Huieon Kim, MD.PhD, Catholic University Bucheon ST. Mary's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2019
• Primary Completion (Actual): September 2, 2022
• Study Completion (Actual): September 26, 2022

Study Registration Dates

• First Submitted: September 19, 2019
• First Submitted That Met QC Criteria: October 25, 2019
• First Posted (Actual): October 29, 2019

Study Record Updates

• Last Update Posted (Actual): October 6, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Antiparasitic Agents; Anticarcinogenic Agents; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Oltipraz
• Other Study ID Numbers: PMK-N01GI1-P3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No