Clinical trial NCT04853082: Limonene on Regulating Metabolism-related Fatty Liver Disease (MAFLD) and Analysis of TCM Constitution
Official title: Clinical Trial of Limonene on Regulating Metabolism-related Fatty Liver Disease (MAFLD) and Analysis of TCM Constitution
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Fatty Liver
Keywords: Metabolic associated fatty liver disease (MAFLD)
Limonene
Efficacy
Safety
Lead sponsor: Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Shanghai Shen Kang Hospital Development Center
name: Longhua Hospital
name: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine
First posted: 2021-04-21
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Exploratory Clinical Trial；Randomized Controlled Trial
Primary purpose: TREATMENT

Brief summary: The prevention and treatment of metabolic-related fatty liver disease (MAFLD) involves many fields in preventive medicine and clinical medicine. So far, western medicine has not yet completed the elucidation of the mechanism of this type of disease, and there is a lack of effective therapeutic drugs.The purpose of this study was to evaluate the effectiveness and safety of limonene capsules (marketed product in China) in the treatment of metabolic-related fatty liver disease and related lipid-lowering mechanisms.

Detailed description: In April 2020, in the famous journal "Journal of Hepatology" in the field of liver disease, an internationally renowned liver disease expert group jointly proposed to replace non-alcoholic fatty liver disease (NAFLD) with metabolic associated fatty liver disease (MAFLD) . The concept of non-alcoholic fatty liver disease (NAFLD) was first proposed by Ludwig in 1980. It specifically refers to the excessive deposition of liver fat without excessive drinking. It is a type of liver that is closely related to insulin resistance and genetic susceptibility. Non-alcoholic fatty liver disease (NAFLD) is China country's largest chronic liver disease and the primary cause of abnormal liver enzymes in health examinations. It can lead to liver disability and death. It is also closely related to a variety of metabolic diseases and the high incidence of colorectal tumors. Western medicine has not yet fully elucidated its mechanism, and no drugs have been officially approved for the clinical treatment of NAFLD.

The new MAFLD nomenclature highlights the central role of metabolic factors in causing liver fat deposition in this type of liver disease. Traditional Chinese medicine believes that the abnormal accumulation of fat in the liver of such fatty liver patients is a pathological product of the microscopic loss of water and valley essence. It belongs to phlegm stasis, which blocks the liver collaterals. It coincides with the core of the metabolic etiology of recent liver disease experts.

Limonene is widely found in the essential oils of traditional Chinese medicine tangerine peel, green peel and other plants. Its taste is sour, sweet and pungent.It is returned to the liver and gallbladder meridian. It has an aromatic odor effect.

A large number of animal and cell experiments in the early stage have shown that limonene can inhibit the differentiation of adipocytes (pre-adipocytes) and promote the apoptosis of mature adipocytes, which is related to the inhibition of fatty acid synthesis. Toxicity load experiments show that limonene has very low toxicity. The accumulation of lipids in the liver of mice has a regulatory effect with significantly reducing the content of liver cholesterol and triglycerides, and also has a certain effect on lipid metabolism disorders, hyperglycemia and other metabolic syndromes. It can alleviate the effects of high-fat diet and N- Efficacy of nitro-L-arginine methyl ester-induced resistance to non-alcoholic fatty liver in rats. The main indication of limonene capsules (marketed product in China) is liver and gallbladder diseases. Traditional Chinese medicine believes that liver and gallbladder are related to each other. This comprehensively shows that limonene capsules are promising to be developed as a pure Chinese medicine product for the safe and effective treatment of MAFLD.

However, there has been no clinical evaluation of the clinical efficacy of limonene in the treatment of metabolic-related fatty liver disease. As a typical aromatic Chinese medicine, the mechanism of limonene in the treatment of fatty liver urgently needs to be revealed by modern medicine and molecular biology techniques.

This study intends to use a randomized, double-blind, placebo-controlled method to evaluate the effect of limonene on improving the degree of fat infiltration in patients with metabolic-related fatty liver disease (MAFLD), and to evaluate its body mass index BMI, waist circumference, waist-to-hip ratio, subcutaneous fat thickness, fat percentage, changes in metabolic components, safety,etc. The study also intends to use metabonomics, genomics, and molecular biology techniques to study the clinical relationship between metabolites and physiological and pathological changes in patients with liver fat infiltration, and to detect changes in key proteins and lipid components after drug intervention, which is to reveal mechanism on treatment of metabolic-related fatty liver disease by limonene. It is aimed to study the difference in the efficacy of limonene for people with different constitutions of traditional Chinese medicine (TCM) combined with the analysis of the constitution of TCM, and to clarify the modern scientific attributes of TCM therapy. Finally the study will develop a safe and efficient drug treatment technology to control liver fat infiltration , and to promote the development of clinical disciplines in the treatment of metabolic-related fatty liver disease.

Eligibility criteria: Inclusion Criteria:

1. Clinical diagnosis and imaging diagnosis of MAFLD and BMI index greater than or equal to 23kg/m2；
2. The age of the recruiter is between 18-65 years old;
3. Those who can cooperate with various treatments and data measurements according to the treatment cycle, and can persist in completing the test;
4. Those who accept and are willing to sign the informed consent.

Exclusion Criteria:

Potential recruiters who meet the inclusion criteria will be excluded if they meet any of the following:

1. Those who routinely take prescription drugs (except regular contraceptive drugs) or those who use auxiliary Chinese and Western drugs to treat non-alcoholic fatty liver;
2. Patients suffering from viral hepatitis, autoimmune hepatitis, hepatolenticular degeneration, hypothyroidism, infection, and biliary tract diseases that lead to abnormal liver function;
3. Patients who have taken the following drugs in the past 4 weeks: hypoglycemic drugs, lipid-lowering drugs (such as statins, fibrates, etc.) and drugs that may affect liver fat content (such as: silybin, ursodeoxycholic acid) , Bicyclic alcohol, phosphatidylcholine and vitamin E, glucocorticoid);
4. Patients with diabetes or those who have undergone bariatric surgery;
5. People who have gained or lost weight by 10 kg or more in the past two months;
6. People who are allergic to limonene capsules; or people who are allergic to citrus foods; people who especially like to eat a lot of citrus foods (daily dosage more than 100 grams);
7. Patients with severe cardiac insufficiency and malignant tumors;
8. Patients who have a history of mental illness and cannot cooperate with this project;
9. Pregnant and lactating women, or women or men who are willing to become pregnant or give birth during the study;
10. Participate in any other clinical trials;
11. Other situations where the researcher thinks it is inappropriate to participate in this research.

Primary outcomes:
measure: Difference of controlled attenuation parameter (CAP) in liver fat
timeFrame: at baseline and twelve weeks after administration
measure: Difference of rate of BMI index
timeFrame: at baseline, four, twelve weeks after administration
Secondary outcomes:
measure: Difference of waist circumference
timeFrame: at baseline, four, twelve weeks after administration
measure: Difference of aspartate transaminase (AST) index
timeFrame: at baseline, four, twelve weeks after administration
measure: Difference of glutamic transpeptidase (GGT) index
timeFrame: at baseline, four, twelve weeks after administration
measure: Difference of alanine transaminase (ALT) index
timeFrame: at baseline, four, twelve weeks after administration
measure: Difference of total cholesterol (TC) index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of glycerin trilaurate (TG) index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of low-density lipoprotein cholesterol (LDL-C) index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of high-density liptein cholesterol（HDL-C）index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of apolipoprotein E (ApoE) index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of insulin index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of glycated hemoglobin（GHb）index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of blood sugar index
timeFrame: at baseline, twelve weeks after administration
measure: Difference of the Short Form 36 physical component summary (SF-36 PCS) score
timeFrame: at baseline, two，four，six，eight，ten weeks, twelve and sixteen weeks after administration
measure: Difference of the Chronic Liver Disease Questionnaire (CLDQ)
timeFrame: at baseline, two，four，six，eight，ten weeks, twelve and sixteen weeks after administration
measure: Difference of the Traditional Chinese of Medicine ( TCM ) Physique Questionnaire
timeFrame: at baseline, two，four，six，eight，ten weeks, twelve and sixteen weeks after administration
Other outcomes:
measure: Difference of CRP related to the mechanism of action
timeFrame: at baseline, twelve weeks after administration
measure: Difference of IL6 related to the mechanism of action
timeFrame: at baseline, twelve weeks after administration
measure: Difference of TNF-a related to the mechanism of action
timeFrame: at baseline, twelve weeks after administration
measure: Difference of lipidomics metabolites of blood
timeFrame: at baseline, twelve weeks after administration
measure: Adverse Events
timeFrame: sixteen weeks
Locations:
city: Shanghai
country: China
facility: Longhua Hospital
state: Shanghai
Study officials:
affiliation: Shanghai Shen Kang Hospital Development Center;Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine
name: Biyun Qian, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Longhua Hospital
name: Xiaoyun Chen, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Shanghai Jiao Tong University School of Medicine
name: Hongsheng Tan, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour JF, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Jarvinen H, Fan JG, Gronbaek H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng MH, Fouad Y, Chan WK, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020 Jul;73(1):202-209. doi: 10.1016/j.jhep.2020.03.039. Epub 2020 Apr 8.