Vitamin E Versus Placebo for the Treatment of Non Diabetic Patients With Nonalcoholic Steatohepatitis

Study Overview
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Brief Summary
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VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in non diabetic adults with NASH compared to treatment with placebo in China.

Official Title
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VENS is a Multicenter, Randomized, Double-masked, Placebo Parallel Controlled Trial to Evaluate the Efficacy and Safety of Treatment With Vitamin E Softgel in Non Diabetic Adults With NASH Compared to Treatment With Placebo in China

Conditions
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NASH (Non-Alcoholic Steatohepatitis)

Intervention / Treatment
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* Drug: Vitamin E softgel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 -75, no limitation for ethnic and gender Body Mass Index(BMI) < 35 kg/m2 Patients with nonalcoholic steatohepatitis (NASH) based on liver biopsy obtained within 6 months before randomization. The histological evidence of NASH was defined as Non - alcoholic fatty liver disease activity score（NAS）≥ 4 (according to Nonalcoholic Steatohepatitis Clinical Research Network, NASH CRN) with a minimum 1 score for steatosis, lobular inflammation, and hepatocyte ballooning respectively. Fibrosis stage 0-3 according to nonalcoholic steatohepatitis clinical research network（NASH CRN). Without history of significant alcohol consumption for a period of more than 3 months within 5 years (<10 g/day for female and < 20 g/day for male). The lab test results should meet the requirements: ① Alanine aminotransferase （ALT） < 5 times of normal upper limit ② Creatinine (Cr)< normal upper limit ③ Albumin （ALB）> 3.5g/L ④ International normalized ratio（INR）= 0.8-1.3 ⑤ Fasting plasma glucose(FPG) < 126mg/dL（7mmol/L） and/or 2h postprandial plasma glucose (PPG) < 200mg/dL（11.1mmol/L）and/ or HbA1C < 6.5 % If a participant with hypertension, he/she was required a stable antihypertensive drug(s) to keep blood pressure stable.(blood pressure < 140/90 mmHg) 3 months prior to randomization. If a participant using a statin or fibrate, he/she was required on a stable dose to keep lipid stable (triglyceride(TG) < 1.7 mmol/L, total cholesterol (TC) < 5.72 mmol/L, LDL-c < 3.64 mmol/L) 3 months prior to randomization. Women of childbearing potential: negative pregnancy test during screening or at randomization or willingness to use an effective form of birth control during the trial(at least include one barrier contraceptive method) and not breast feeding Men must agree to use an effective form of birth control during the trial(at least include one barrier contraceptive method) All participants are needed to sign the informed consent form. Exclusion Criteria: Evidence of other form of acute or chronic liver disease. (Virus hepatitis, Hereditary hemochromatosis, Hepatolenticular degeneration, Alcoholic liver disease, Drug-induced hepatopathy). History of diabetic mellitus or use of antidiabetic drugs. Known heart failure of New York Heart Association class 2, 3, or 4. Wear of cardiac pacemaker. Hypothyroidism (TSH > 2 times of upper normal limit). History of disease affecting drug absorption, distribution, metabolism (inflammatory bowel disease, gastrointestinal surgery, chronic pancreatitis, gluten allergy, vagotomy). Use of anti-NASH drugs within 3 months before randomization (metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon-like peptide-1(GLP-1), sodium glucose contransporter2(SGLT2), S-adenosylmethionine -e(SAM-e), polyene phosphatidyl choline, glycyrrhizin, bicyclol, reduced glutathione, betaine, fish oil, silymarin,oberbic acid/ursodeoxycholic acid (OCA/UDCA), phosphodiesterase (PDE)-inhibitor, gemfibrozil, vitamin E, long term antibiotic (>1 week). Positivity of antibody to Human Immunodeficiency Virus. Inability to safely obtain liver biopsy. Known intolerance to vitamin E Inability to fill out diary card, to manage diet and exercise, poor compliance. Dependence or abuse of alcohol and/or drugs. Any other condition which in the opinion of investigator would impede compliance or hinder completion of the study.

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

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment group<br>Vitamin E softgel,100mg,Tid,orally, 96 weeks. All participants receive standardized recommendations for life-style modification (Diet modification, weight loss, exercise). | Drug: Vitamin E softgel<br>* All participants receive standardized recommendations for life-style modification (Diet modification, weight loss, exercise).<br>|
| Placebo Comparator: placebo group<br>A similar appearing placebo softgel , Vitamin E -Placebo, Tid, orally, 96 weeks, All participants receive standardized recommendations for life-style modification (Diet modification, weight loss, exercise). | Drug: Placebo<br>* All participants receive standardized recommendations for life-style modification (Diet modification, weight loss, exercise). Height and weight, waist-to-hip ratio Review of diet and exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in hepatic histology | Improvement in hepatic histology after 96 weeks of treatment as determined by liver biopsies compared to baseline. (Independent pathological evaluation committee was charged with interpreting of the histological characteristic and that allows for assessment of changes with therapy). The definition of histologic improvement requires all three of the following criteria: ① either improvement in NAS by at least 2 points or post-treatment NAS of 3 points or less, ② at least 1 point improvement in the score for ballooning or lobular inflammation③ no worsening of fibrosis stages. | after 96 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin E, Non Diabetic