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

Non-Alcoholic Fatty Liver Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04142749
• Other study ID #: PMK-N01GI1-P3
• Status: Completed
• Phase: Phase 3
• Start date: November 15, 2019
• Est. completion date: September 26, 2022

Study information

• Verified date: October 2022
• Source: PharmaKing
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: September 26, 2022
• Est. primary completion date: September 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

Intervention

Drug:
• Oltipraz
Total 90mg, By mouth, TID
• Placebos
Total 90mg, By mouth, TID

Locations

Country	Name	City	State
Korea, Republic of	Catholic University Bucheon ST. Mary's Hospital	Bucheon
Korea, Republic of	Soonchunhyang University Bucheon Hospital	Bucheon
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Keimyung University Dongsan Medical Center	Daegu
Korea, Republic of	Gangneung Asan Medical Center	Gangneung-si
Korea, Republic of	Inje University Ilsan Paik Hospital	Goyang-si	Gyeonggi-do
Korea, Republic of	NHUS Ilsan Hospital	Goyang-si
Korea, Republic of	Inha University Hospital	Incheon	Junggu
Korea, Republic of	Boramae Hospital	Seoul
Korea, Republic of	Chung-Ang University Hosptial	Seoul
Korea, Republic of	Hallym University Gangnam Sungsim Hospital	Seoul
Korea, Republic of	Hanyang University Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	National Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	Soonchunhyang University Seoul Hospital	Seoul
Korea, Republic of	Yonsei University Gangnam Severance Hospital	Seoul
Korea, Republic of	Ajou University School of Medicine	Suwon
Korea, Republic of	The Catholic University of Korea, Uijeongbu ST. Mary's Hospital	Uijeongbu-si	Gyeonggi-do
Korea, Republic of	Wonju Severance Christian Hospital	Wanju

Sponsors (1)

Lead Sponsor	Collaborator
PharmaKing

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Variation of biomarkers	Adipokine (leptin, adiponectin, resistin, TNF-a, IL-6)	8 weeks, 16 weeks and 24 weeks
Other	The Variation of biomarkers	CK-18 (M30, M65)	8 weeks, 16 weeks and 24 weeks
Other	The Variation of biomarkers	Hepcidine	8 weeks, 16 weeks and 24 weeks
Other	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
Other	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
Other	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
Other	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
Other	NAFLD activity scores (NAS)	Variation of NAFLD activity scores (NAS) at 24 weeks compared to the baseline	24 weeks compared to the baseline
Other	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
Primary	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	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
Secondary	Variation of liver fat certificate grade	Variation of liver fat certificate grade assessed by ultrasonic waves	24 weeks compared to the baseline
Secondary	Variation of NFS variation	Variation of NFS at 24 weeks compared to the baseline	24 weeks compared to the baseline
Secondary	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
Secondary	FIB-4	Variation of FIB-4 from 8 weeks, 16 weeks and 24 weeks to baseline	8 weeks, 16 weeks and 24 weeks
Secondary	BMI	BMI variation at 8 weeks, 16 weeks and 24 weeks relative to the baseline	8 weeks, 16 weeks and 24 weeks
Secondary	Variation of ALT, AST, ?-glutamyl transferase (GGT)	Variation of ALT, AST, ?-glutamyl transferase (GGT) in time of 8 weeks, 16 weeks and 24 weeks relative to the baseline	8 weeks, 16 weeks and 24 weeks
Secondary	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
Secondary	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
Secondary	Waist circumference	The variation of waist circumference compared to the baseline at 24 weeks	24 weeks compared to the baseline