Clinical Trials Using HepatoKeeper Herbal Essentials to Treat Non-alcoholic Fatty Liver Disease and Metabolic Factors

Not Applicable

Completed

• Conditions: Liver Fibrosis; Non-alcoholic Fatty Liver Disease; Liver Injury
• Interventions: Drug: Ganwei; Drug: Placebo; Drug: Metformin

• Registration Number: NCT06244550
• Lead Sponsor: Taipei City Hospital

Brief Summary

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease globally, with an estimated prevalence of approximately 15 to 30%. The incidence of NAFLD is even higher, reaching up to 58%, in individuals who are overweight or obese. The pathogenesis of NAFLD is complex and not fully understood. The metabolism of carbohydrates contributes to the development of NAFLD, as it increases the enzymatic activity of lipid synthesis in the liver, depleting adenosine triphosphate (ATP) rapidly and causing stress on mitochondria and endoplasmic reticulum. The multifunctional protein Glycine N-methyltransferase (GNMT) plays a regulatory role in liver carbohydrate metabolism, and its expression is downregulated in the liver tissues of NAFLD.

While weight loss and lifestyle adjustments are helpful in controlling NAFLD, effective pharmacological or healthcare interventions for NAFLD patients are currently lacking. Insulin resistance is crucial in the pathogenesis of NAFLD, suggesting that drugs improving insulin sensitivity, such as metformin, might have therapeutic effects. However, recent large-scale clinical trial results have not supported this hypothesis. Investigators propose that the mitochondrial inhibitory effects of metformin may be related to this discrepancy, and the negative effects may be reversed through food containing substances promoting GNMT gene expression, such as Ganwei (as know as "HepatoKeeper"). Preliminary animal experiments also show that the combined use of metformin and GNMT enhancers effectively eliminates liver lipid droplet accumulation and improves liver inflammation in a NAFLD mouse model, surpassing the effects of either drug used alone.

Based on these findings, our team designed the medication treatment group for this clinical trial, aiming to investigate whether the combination of Ganwei and metformin produces a synergistic effect in humans. Ganwei compound herbal extract capsules contain extracts from natural foods such as Schisandra chinensis, Paeonia lactiflora, and Punica granatum. Among them, Paeonia lactiflora is known to contain components that enhance GNMT expression. Animal and cell experiments have demonstrated its potential for repairing liver damage and inflammation. This trial aims to assess the impact of orally administering Ganwei compound herbal extract capsules on participants and evaluate its effects on fatty liver, liver fibrosis, and metabolic indicators.

Detailed Description

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease globally, with an estimated prevalence of approximately 15 to 30%. The incidence of NAFLD is even higher, reaching up to 58%, in individuals who are overweight or obese (Schwenger, 2014). With the Westernization of diets and insufficient physical activity, the prevalence of obesity, diabetes, and hyperlipidemia has been increasing in Taiwan in recent years, contributing to the gradual rise in the prevalence of NAFLD. NAFLD is strongly associated with metabolic syndrome, cardiovascular diseases, insulin resistance, and may progress to hepatitis, liver fibrosis, and even cirrhosis (Fazel, 2016; Amr, 2020).

The pathogenesis of NAFLD is complex and not fully understood. Current understanding suggests that environmental factors such as diet, exercise, obesity, gut microbiota, and genetics play a role in the development of NAFLD. The liver, responsible for metabolizing major substances including carbohydrates and fatty acids, becomes overwhelmed, leading to the production of toxic lipids. Disruptions in lipid metabolism, inhibition of mitochondrial function, and impaired export of triglycerides from liver cells contribute to the accumulation of lipids within the liver. Insulin resistance further exacerbates this process. Additionally, lipid alterations in liver cells increase oxidative stress and activate cell signaling, triggering immune responses that damage liver cells and contribute to the development of fatty liver inflammation, fibrosis, and potentially liver cancer (Fazel, 2016; Amr, 2020).

The metabolism of carbohydrates also contributes to NAFLD, as it increases the enzymatic activity of lipid synthesis in the liver, depleting adenosine triphosphate (ATP) rapidly and causing stress on mitochondria and endoplasmic reticulum. This results in liver cell necrosis, contributing to the development of NAFLD. The multifunctional protein Glycine N-methyltransferase (GNMT) plays a regulatory role in liver carbohydrate metabolism, and its expression is downregulated in the liver tissues of NAFLD (Liao, 2012).

While weight loss and lifestyle adjustments are helpful in controlling NAFLD, effective pharmacological or healthcare interventions for NAFLD patients are currently lacking (Julien et al., 2019; Mary et al., 2020). Insulin resistance is crucial in the pathogenesis of NAFLD, suggesting that drugs improving insulin sensitivity, such as metformin, might have therapeutic effects. However, recent large-scale clinical trial results have not supported this hypothesis. Investigators propose that the mitochondrial inhibitory effects of metformin may be related to this discrepancy, and the negative effects may be reversed through food containing substances promoting GNMT gene expression, such as Ganwei (as know as "HepatoKeeper"). Preliminary animal experiments also show that the combined use of metformin and GNMT enhancers effectively eliminates liver lipid droplet accumulation and improves liver inflammation in a NAFLD mouse model, surpassing the effects of either drug used alone.

Based on these findings, our team designed the medication treatment group for this clinical trial, aiming to investigate whether the combination of Ganwei and metformin produces a synergistic effect in humans. Ganwei compound herbal extract capsules contain extracts from natural foods such as Schisandra chinensis, Paeonia lactiflora, and Punica granatum. Among them, Paeonia lactiflora is known to contain components that enhance GNMT expression (Kyu-Han et al., 2020; Rajni et al., 2019). Animal and cell experiments have demonstrated its potential for repairing liver damage and inflammation. This trial aims to assess the impact of orally administering Ganwei compound herbal extract capsules on participants and evaluate its effects on fatty liver, liver fibrosis, and metabolic indicators.

Study Timeline

• Study Start: 2021-09-22
• Primary Completion: 2023-03-14
• Study Completion: 2023-06-13
• Status Verified: 2024-01
• Study First Submitted: 2024-01-29
• Study First Submitted QC: 2024-01-29
• Study First Posted: 2024-02-06
• Last Update Submitted: 2024-02-16
• Last Update Posted: 2024-02-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Must be willing to participate in the study and provide written informed consent.

• Male and female adults ≥20 and <80 years of age.

• Suspected or confirmed diagnosis of NAFLD:

  • Fibroscan with CAP ≥220 dB/m
  • Criteria for diagnosing fatty liver: Abdominal ultrasound reveals differences in liver and kidney parenchyma due to wave reflection, liver parenchymal ultrasound attenuation, and blurred imaging of liver vessels and diaphragm, indicating fatty liver.

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Exclusion Criteria

• Female patients who are pregnant or breastfeeding.
• Diabetic patients undergoing medication treatment.
• Patients clinically diagnosed with alcoholic hepatitis, autoimmune hepatitis, or biliary liver disease.
• Excessive alcohol consumption (more than 15 grams/day for females, more than 30 grams/day for males).
• Users of weight-loss products and vitamin E supplements.
• Individuals with an estimated Glomerular Filtration Rate (eGFR) less than 60 mL/min/1.73m².

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Ganwei + metformin	Ganwei	Double blinded: Ganwei + metformin Ganwei 500mg/15 kg of body weight, daily metformin 1500mg daily
Placebo	Placebo	Double blinded: matching placebo Placebo daily
Placebo + metformin	Placebo	Double blinded: matching placebo + metformin Placebo daily metformin 1500mg daily
Ganwei	Ganwei	Double blinded: Ganwei Ganwei 500mg/15 kg of body weight, daily
Placebo + metformin	Metformin	Double blinded: matching placebo + metformin Placebo daily metformin 1500mg daily
Ganwei + metformin	Metformin	Double blinded: Ganwei + metformin Ganwei 500mg/15 kg of body weight, daily metformin 1500mg daily

Primary Outcome Measures

Name	Time	Method
Liver fibrosis severity: the change of kPa by Fibroscan	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in kPa by FibroScan
Liver steatosis severity: the change of CAP (dB/m) by Fibroscan	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Controlled Attenuation Parameter(CAP) by FibroScan

Secondary Outcome Measures

Name	Time	Method
General health	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in General health by 36-Item Short Form Health Survey (SF-36)
C-reactive protein (CRP)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in C-reactive protein (CRP)
Triglyceride (TG)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Triglyceride (TG)
Social functioning	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Social functioning by 36-Item Short Form Health Survey (SF-36)
estimated Glomerular filtration rate (eGFR)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in estimated Glomerular filtration rate (eGFR)
Bodily pain	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Pain by 36-Item Short Form Health Survey (SF-36)
Aspartate Transaminase (AST)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Aspartate Transaminase (AST)
Alanine amino Transferase (ALT)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Alanine amino Transferase (ALT)
Glycated Hemoglobin (HbA1c)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Glycated Hemoglobin (HbA1c)
Body mass index (BMI)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Body mass index (BMI)
White blood cell (WBC)	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in White blood cell (WBC)
Physical functioning	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Physical functioning by 36-Item Short Form Health Survey (SF-36)
Role limitations due to physical health	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Role limitations due to physical health by 36-Item Short Form Health Survey (SF-36)
Role limitations due to emotional problems	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Role limitations due to emotional problems by 36-Item Short Form Health Survey (SF-36)
Energy/fatigue	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Energy/fatigue by 36-Item Short Form Health Survey (SF-36)
Emotional well-being	Week 24	The effect of once daily, oral administration of 500 mg/15 kg of body weight Ganwei and/or 1500 mg metformin 24 weeks treatment versus before on the change in Emotional well-being by 36-Item Short Form Health Survey (SF-36)

Trial Locations

Locations (1)

Taipei City Hospital; 🇨🇳 Taipei, Taiwan