A Clinical Study to Evaluate the Effect of SIM01 in Female With NAFLD

Study Overview
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Brief Summary
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Non-alcoholic fatty liver disease is one of the most common chronic liver diseases worldwide. Available data indicates that probiotics may regulate the gut microbiota and improve liver function in females with non-alcoholic fatty liver disease. In this study, we aim to investigate if the synbiotics (prebiotics and probiotics) are efficacious subjects in liver function improvement in female subjects with Non-alcoholic fatty liver disease.

Detailed Description
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Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide.(1) The prevalence of NAFLD is estimated to be about 20%-30% in the Western world (2) and increasing in Asia. The prevalence of NAFLD across Asia varies from 5% to 40%.(3,4) In one study with a sample of 922 subjects using proton-magnetic resonance spectroscopy and transient elastography, 252 subjects had intrahepatic triglyceride content ≥5%, and the population prevalence of NAFLD in Hong Kong Chinese was 27.3%.1 NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis, liver failure and liver cancer, and is believed to be the leading etiology for cryptogenic cirrhosis.(5,6) NAFLD is also strongly associated with obesity and metabolic syndrome and is shown to be an independent cardiovascular risk factor.(7,8) At present, there is no standard pharmacologic therapy available for NAFLD currently. Current management for NAFLD includes diet and lifestyle changes, management of underlying metabolic risk factors and pharmacological therapies. Insulin-sensitizing medication such as Pioglitazone has been shown to improve histological NASH in terms of steatosis, inflammation, ballooning, NAFLD Activity Score (NAS score) and resolution of NASH. (9) However, the long-term efficacy and safety of Pioglitazone are unknown, and not all patients respond to Pioglitazone. Vitamin E is a fat-soluble compound which prevents liver injury by blocking intrinsic apoptotic pathways and by protecting against mitochondrial toxicity. (10) It also improves histological NASH in terms of steatosis, inflammation, ballooning, NAS score, and resolution of NASH at a dose of 800 IU/day. (9) However, the long-term safety of vitamin E is also an issue, because doses of 400 IU/day or higher have been associated with increased all-cause mortality. (11) While lifestyle management is often advocated, it is difficult to maintain. (12) Thus, it is important to explore new treatment strategies. In general, NAFLD prevalence is higher in men compared to women. However, the prevalence of NAFLD in women is increasing in women over the past 10 years, (13) especially postmenopausal women who have greater NAFLD risk and higher rates of severe hepatic fibrosis relative to premenopausal women, and older women with NAFLD experience greater mortality than men. (14) A cohort study in Japan reported that women after the age of 70 had a higher prevalence of fatty liver than men (19.4% vs 14.9%). (15) Another cohort showed that gradual age-related increases in NAFLD prevalence were also observed in women (3.9% in the 21-39 age group; 7.6% in the 40-49 age group; 14.0% in the 50-59 age group; 18.9% in 60-69 age group), but not men. (15) NAFLD is more prevalent in overweight and obese individuals; gut microbiota also plays a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. (16) On the other hand, probiotics can strengthen the intestinal wall, reducing its permeability, bacterial translocation, and endotoxemia according to animal and human studies. Recently, it has been reported that NAFLD might be linked to small intestinal bacterial overgrowth (SIBO), which induces liver injury by gut-derived lipopolysaccharides (LPS) and TNF- α production. (17) Probiotics have several anti-inflammatory effects that can contribute to their clinical benefits in NAFLD. (18) The use of probiotics, prebiotics and synbiotics has been considered a potential and promising strategy to regulate the gut microbiota. (19, 20) Some clinical studies have been conducted to investigate the effects of probiotics on liver functions in NAFLD and NASH subjects. In general, the results of the trials (21-28) showed that the use of probiotics can reduce BMI, total fat percentage, total cholesterol, triglycerides, fasting insulin, alanine aminotransferase (ALT), aspartate transaminase (AST), tumour necrosis factor (TNF-α), interleukin (IL-6), liver stiffness et cetera. This is a single-arm, open-label clinical trial for evaluating the efficacy of SIM01 on the reduction of liver biochemistry in 40 female subjects with NAFLD. All subjects will take 2 sachets of SIM01 daily for 3 months with monthly assessment on adverse event observation, and adherence to the study product throughout the study period. The change in CAP scores measured by the fibroscan, BMI, liver function and interleukin-6 will also be evaluated.

Official Title
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A Single-arm, Open-label Clinical Study to Evaluate the Effect of SIM01 in Female Subjects With Non-Alcoholic Fatty Liver Disease (NAFLD)

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Dietary Supplement: SIM01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subjects with NAFLD with CAP ≥ 270 by fibroscan Age ≥ 55 Subjects with or without diabetes or components of metabolic syndrome and having stable medication 3 months prior to enrolment Written informed consent can be obtained Exclusion Criteria: Known history of any secondary causes of NAFLD including alcoholic liver disease, drug-induced liver injury, autoimmune hepatitis, viral hepatitis, cholestatic liver disease and metabolic/genetic liver disease Known diabetes with poor control (HbA1c > 8.5%) within 3 months Significant alcohol consumption (over 10g per day: a half pint or half bottle of beer or a standard-size of a wine glass) Consumption of systemic corticosteroids or methotrexate in the last 6 months Concomitant probiotics or prebiotics one month prior to enrolment Any condition or allergy history for probiotics Subjects who are using antibiotics, insulin and Glucagon-like peptide-1(GLP1) such as dulaglutide, semaglutide Malignancy

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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Female

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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: All study subjects will receive the same study products.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIM01<br>2 sachets daily for 3 months | Dietary Supplement: SIM01<br>* SIM01 consists of a blend of food-grade Bifidobacterium as active probiotics<br>* Other names: G-NiiB Immunity formula;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Controlled Attenuation Parameter (CAP) score by fibroscan after taking SIM01 for 3 months | The change of CAP score measured by fibroscan. CAP score is a measurement of fat accumulation in the liver to further determine the steatosis grade. The CAP score ranges from 100 to 400 decibels per meter (dB/m). The higher the score, the more the steatosis is. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver enzymes (alanine aminotransferase (ALT) and aspartate transaminase (AST)) across the study period. | The change in the level of liver enzymes. | 3 months | 
| Change in fasting lipid and HbA1c across the study period. | The change in the level of lipid profiles | 3 months | 
| Change of body mass index (BMI) across the study period. | The change of body weight and body height | 3 months | 
| Change of body waist circumference across the study period. | The change of waist circumference | 3 months | 
| Change in interleukin-6 (IL-6) across the study period. | The change in the one of the immunity marker | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Alcoholic Fatty Liver Disease, Probiotics