Clinical trial NCT04142749: Oltipraz for Liver Fat Reduction in Patients With Non-alcoholic Fatty Liver Disease Except for Liver Cirrhosis
Official title: A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Oltipraz
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Alcoholic Fatty Liver Disease
Lead sponsor: PharmaKing
Sponsor class: INDUSTRY
First posted: 2019-10-29
Enrollment: 146
Sex: ALL
Minimum age (years): 19
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Variation of liver fat assessed
timeFrame: 24 weeks compared to the baseline
Secondary outcomes:
measure: The variation in the amount of liver fat
timeFrame: 24 weeks compared to the baseline
measure: Variation of liver fat certificate grade
timeFrame: 24 weeks compared to the baseline
measure: Variation of NFS variation
timeFrame: 24 weeks compared to the baseline
measure: Variation of liver elasticities and fatty acids
timeFrame: 24 weeks compared to the baseline
measure: FIB-4
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: BMI
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: Variation of ALT, AST, γ-glutamyl transferase (GGT)
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: Cholesterol (total, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglyceride (TG)
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: Variation of Homeostatic model adjustment-insulin resistance (HOMA-IR) index
timeFrame: 24 weeks compared to the baseline
measure: Waist circumference
timeFrame: 24 weeks compared to the baseline
Other outcomes:
measure: The Variation of biomarkers
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: The Variation of biomarkers
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: The Variation of biomarkers
timeFrame: 8 weeks, 16 weeks and 24 weeks
measure: Variation of liver fat assessed as tissue samples acquired by liver biopsy
timeFrame: 24 weeks compared to the baseline
measure: Variation of Steatosis assessed as tissue samples acquired by liver biopsy
timeFrame: 24 weeks compared to the baseline
measure: Variation of lobular inflammation assessed as tissue samples acquired by liver biopsy
timeFrame: 24 weeks compared to the baseline
measure: Variation of ballooning assessed as tissue samples acquired by liver biopsy
timeFrame: 24 weeks compared to the baseline
measure: NAFLD activity scores (NAS)
timeFrame: 24 weeks compared to the baseline
measure: Correlation between MRS and ultrasound, fibroscan, FIB-4, and biopsy results
timeFrame: 24 weeks compared to the baseline
Locations:
city: Goyang-si
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
state: Gyeonggi-do
city: Uijeongbu-si
country: Korea, Republic of
facility: The Catholic University of Korea, Uijeongbu ST. Mary's Hospital
state: Gyeonggi-do
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
state: Junggu
city: Bucheon
country: Korea, Republic of
facility: Catholic University Bucheon ST. Mary's Hospital
city: Bucheon
country: Korea, Republic of
facility: Soonchunhyang University Bucheon Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Gangneung-si
country: Korea, Republic of
facility: Gangneung Asan Medical Center
city: Goyang-si
country: Korea, Republic of
facility: NHUS Ilsan Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Boramae Hospital
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hosptial
city: Seoul
country: Korea, Republic of
facility: Hallym University Gangnam Sungsim Hospital
city: Seoul
country: Korea, Republic of
facility: Hanyang University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: National Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Soonchunhyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Gangnam Severance Hospital
city: Suwon
country: Korea, Republic of
facility: Ajou University School of Medicine
city: Wanju
country: Korea, Republic of
facility: Wonju Severance Christian Hospital
Study officials:
affiliation: Seoul Nat'l Uni. Hospital
name: Yun-Jun Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Catholic University of Korea, Uijeongbu ST. Mary's Hospital
name: Changuk Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gangneung Asan Medical Center
name: Gapjin Chun, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kunyang University Hospital
name: Taehui Lee, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Keimyung University Dongsan Medical Center
name: Byeongguk Jang, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dong-A University Hospital
name: Yanghyeon Baek, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boramae Hospital
name: Byeonggwan Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Soonchunhyang University Hospital
name: Yeongseok Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Soonchunhyang University Hospital
name: Jaeyeong Chang, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ajou University School of Medicine
name: Jaeyeong Jung, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yonsei University Gangnam Severance Hospital
name: Hyeonung Lee, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Severance Hospital
name: Doyeong Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wonju Severance Christian Hospital
name: Munyeong Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inje University Ilsan Baek Hospital
name: Junseong Lee, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inha University Hospital
name: Jinu Lee, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Chung-Ang University Hosptial, Chung-Ang University College of Medicine
name: Hyeongjun Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hallym University Gangnam Sungsim Hospital
name: Sanghun Park, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hanyang University
name: Daewon Jun, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Health Insurance Service Ilsan Hospital
name: Chun Kyun Lee, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National medical center
name: Jaeyun Jung, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University Guro Hospital
name: Jihun Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Catholic University Bucheon ST. Mary's Hospital
name: Huieon Kim, MD.PhD
role: PRINCIPAL_INVESTIGATOR
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