Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of berberine treatment on Non-alcoholic Steatohepatitis.

Detailed Description
-----------------
This is a multicenter, double-blinded, randomized, placebo-controlled clinical trial to investigate the efficacy and safety of berberine on subjects with Non-alcoholic Steatohepatitis.Patients with biopsy-proven non-alcoholic steatohepatitis (NASH) from 18-65 years of age were enrolled. Patients should had no excessive alcohol intake or use of any hepatoprotective or hepatotoxicity medication within 3 months before enrollment.Patients will have an screening period 12 weeks, and a 48-week double-blinded treatment period.

Official Title
-----------------
Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis: a Multicentre, Randomised, Placebo-controlled Trial

Conditions
-----------------
Non-alcoholic Steatohepatitis

Intervention / Treatment
-----------------
* Behavioral: Lifestyle intervention
* Drug: Placebo
* Drug: Berberine


Participation Criteria
=================
Eligibility Criteria
-----------------
The inclusion criteria are as follows: 18-75 years old, no limitation for ethnicity and gender. BMI is no more than 40 kg/m2. Patients with NASH based on liver biopsy obtained within 24 weeks before randomization. The histological evidence of NASH is defined as NAS ≥5 [] or NAS ≥4 with a minimum score of 1 for all of three components (steatosis, hepatocyte ballooning, and lobular inflammation), the diagnosis of NASH for EASYBEinNASH eligibility is based on reviews by three pathologists. If there are controversial pathologic diagnosis, at least 2 of the 3 pathologists are consistent with the pathologic diagnosis, which will be the final pathological diagnosis. If there are three different pathological diagnoses, it needs to be discussed and make a judgment by the chief pathologist to form the final pathology report. For patients with impaired glucose metabolism, one of the three following conditions needs to be met. ① For patients diagnosed as impaired glucose regulation, they will be treated with lifestyle intervention without hypoglycemic drugs; ② For patients diagnosed as diabetes and treated with hypoglycemic drugs, the treatment regimen should not be changed and the dosage should remain stable for more than 2 months before randomization; ③ For patients diagnosed as diabetes and treated with lifestyle intervention without hypoglycemic drugs, the treatment regimen should not be changed before randomization. All participants agree to sign the informed consent form. Exclusion criteria Excessive alcohol intake ( > 140 g per week for men and >70 g per week for women within 6 months before enrollment); Liver enzymes (ALT or aspartate aminotransferase(AST) is 5 times higher than the upper limit of normal range; Liver diseases caused by other reasons, such as alcohol abuse, viral hepatitis, drugs, auto-immune hepatitis, hereditary liver disease, liver cirrhosis, liver cancer, etc; Biliary tract diseases, biliary obstructive disease, etc; Other diseases that affect glucose and lipid metabolism, such as hypothyroidism, hyperthyroidism, hypercortisolism, etc; Diabetic patients with poor blood glucose control: HbA1c >9.5%; Use of drugs that may affect the outcome measures of this study 3 months before enrollment, including pioglitazone, GLP-1 receptor agonist, DPP-4 inhibitor, insulin, and glycyrrhizic acid preparation, etc; Chronic kidney disease or severe renal impairment, defined as serum creatinine greater than 2.0mg/dL (176.8umol/L); Life expectancy is no more than 5 years; Pregnant or planning to become pregnant within the next 64 weeks for female participant; Any situation that may affect the implementation or results of the study; Continuous use of drugs that may affect steatohepatitis 3 months before enrollment, such as glucocorticoids, methotrexate, etc; Subjects participated in other clinical trials in the past 4 weeks; The researchers did not think they were suitable for the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berberine<br>Berberine was taken orally 0.5g three times per day for 48 weeks, based on lifestyle intervention. | Behavioral: Lifestyle intervention<br>* Lifestyle intervention is consisted of diet control and aerobic exercise. calorie restriction: to subtract 500 kcal from daily calorie intake aerobic exercise: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate.<br>Drug: Berberine<br>* Berberine tablets 0.5 tid, 30 minutes before each meal, for 48weeks<br>|
| Placebo Comparator: Placebo<br>Placebo was taken orally 0.5g three times per day for 48 weeks, based on lifestyle intervention. | Behavioral: Lifestyle intervention<br>* Lifestyle intervention is consisted of diet control and aerobic exercise. calorie restriction: to subtract 500 kcal from daily calorie intake aerobic exercise: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate.<br>Drug: Placebo<br>* placebo tablets 0.5 tid, 30 minutes before each meal, for 48weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in histologic features of nonalcoholic steatohepatitis by NAFLD activity score (NAS) | A separate system of scoring the histological features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was used. An improvement in histologic findings require an improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in the composites of NAFLD activity scores for steatosis, lobular inflammation, hepatocellular ballooning | NAFLD activity score (NAS) is composed of steatosis (scale of 0 to 3), lobular inflammation (scale of 0 to 3), hepatocellular ballooning (scale of 0 to 2). Alteration in each component of NAS is measured. | 48 weeks | 
| Improvement in liver histological fibrosis staging | Fibrosis staging was measured as following criteria: 0=none, 1=perisinusoidal or periportal fibrosis, 2=perisinusoidal and portal/periportal fibrosis, 3=bridging fibrosis, and 4=cirrhosis.the definition of fibrosis stages improvement requires at least one stage. | 48 weeks | 
| Resolution of NASH | Resolution of NASH was defined as a diagnosis of no steatohepatitis at 48 weeks among those with possible or definite NASH at baseline. | 48 weeks | 
| Change in anthropometric measures | including BMI etc | 48 weeks | 
| Change in blood biochemistry | including serum aminotransferase levels etc | 48 weeks | 
| Change in liver fat content | liver fat content determined by 1H MRS (in part of clinical centers) | 48 weeks | 
| Change in serum cytokeratin 18 (CK-18) in U/L | serum cytokeratin 18 (CK-18) in U/L | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-alcoholic steatohepatitis