Vitamin E and DHA-EE on NAFLD - Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial (PUVENAFLD)
Condition: Non-Alcoholic Fatty Liver Disease; Non-Alcoholic Fatty Liver; Non-Alcoholic Steatohepatitis
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Vitamin E [(all-rac)-α-tocopheryl acetate]; Omega-3 fatty acid (DHA EE); Omega-3 fatty acid (DHA EE) & Vitamin E [(all-rac)-α-tocopheryl acetate]; Placebo
Intervention description: Vitamin E (1000 mg) once daily for 6 months (1 capsule) and matching placebos (2 matched capsules) for 6 months; DHA EE (1.89 g) once daily for 6 months (2 capsules) and matching placebo for DHA EE (1 matched capsule for 6 months); DHA EE (1.89 g) once daily for 6 months and Vitamin E (1000 mg) once daily for 6 months; Matching soybean placebo (3 capsules) of all arms daily for 6 months.
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 205.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non-Alcoholic Fatty Liver Disease; Non-Alcoholic Fatty Liver; NAFL; NAFLD; Vitamin E; DHA

Summary:

      Multicenter, randomized, double-blinded, placebo-controlled clinical trial is focused on
      novel treatments for non-alcoholic fatty liver disease (NAFLD), the most common cause of
      chronic liver disease. The primary objective of the study is to determine the clinical
      efficacy and safety of Vitamin E [(all-rac)-α-tocopheryl acetate] and Omega-3 fatty acid (DHA
      EE) compared to placebo on reducing liver fat content in participants with NAFLD. There is
      currently no approved drug treatment for NAFLD or NASH. While several new targets are being
      evaluated, they are not sufficiently powered to provide definitive data. There is, therefore,
      a need for well-designed, appropriately powered efficacy (phase 2) trials to define the
      utility of newer therapies for NAFLD. The combination of Vitamin E and DHA may provide
      optimal benefit for patients with NAFLD due to their associated mechanisms of action, namely
      Vitamin E's antioxidant action, preventing lipid oxidation of long-chain fatty acids such as
      DHA and thus preventing the propagation of free radicals and ROS.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female gender

          -  ≥18 years of age

          -  A new diagnosis or reconfirmation of previously known fatty liver by imaging
             (ultrasound or CT or MRI), or by liver biopsy within ≤ 4 years

          -  Fibroscan CAP score >300db

          -  Hepatic fat fraction ≥12% by MRI PDFF

          -  ALT≥ 40 U/L

          -  eGFR/Creatinine Clearance ≥ 60ml/min

          -  Participants with previously diagnosed Type 2 diabetes (up to 50% of sample): they
             must either be taking anti-diabetic medications, or their fasting (>10 hours) glucose
             must be ≥ 100 mg/dL at the time of screening

          -  Stable weight (±5%) for at least 3 months

          -  Subjects willing and able to give written informed consent and to understand, to
             participant and to comply with the clinical study requirements.

        Exclusion Criteria:

          -  Evidence of alternative causes of hepatic steatosis or other forms of chronic liver
             disease, e.g. Hep.B, Hep.C

          -  Evidence of acute Hepatitis A

          -  Serum ALT or AST ≥ 250 U/L

          -  Serum Alkaline Phosphatase > 2 ULN

          -  Total bilirubin > 2 ULN in the absence of Gilbert's Syndrome [In patients with
             Gilbert's Syndrome, direct bilirubin must not exceed 2 ULN]

          -  HbA1c≥9.5%

          -  Decompensated acute or chronic liver disease

          -  Clinical, imaging or histological evidence of cirrhosis

          -  Use of anti-NASH drugs (e.g. thiazolidinediones) in the 3 months prior to
             randomization

          -  Use of a non-stable dose of statins or fibrates in the 3 months prior to randomization

          -  Use of fish oil, algal oil or Krill oil supplements, drugs or foods fortified with
             omega-3s in the 2 months prior to randomization (>200mg DHA/d and/or >60mg EPA/d by
             FFQ)

          -  Known intolerance to vitamin E or DHA

          -  Malabsorption of Vit E (e.g. due to steatorrhea, chronic pancreatitis, severe
             cholestasis)

          -  Vitamin E supplementation of greater than 100 IU/day in the 3 months prior to
             randomization

          -  History of bariatric surgery (jejunoileal bypass or gastric weight loss surgery) or
             currently undergoing evaluation for bariatric surgery

          -  History of biliary diversion

          -  Known positivity for antibody to Human Immunodeficiency Virus (HIV)

          -  Patients with coagulopathy (PT ≥3 sec.from ULN), thrombocytopenia (<70K)

          -  Contraindication to MRI (implants, metal…)

          -  Active, serious medical disease or disease diagnosis of a life-expectancy less than 5
             years

          -  Ongoing or recent alcohol consumption > 21 drinks (1 drink= 12 oz regular beer, or 5
             oz wine, or 1.5 oz distilled spirits) per week in men and > 14 drinks per week in
             women as per subject self-report as part of medical history.

          -  Active substance abuse, such as oral, inhaled or injected illicit drugs (except
             marijuana), in the year prior to screening

          -  Women of childbearing potential: positive pregnancy test during screening or at
             randomization or unwillingness to use an effective form of birth control during the
             trial

          -  Women who are breastfeeding

          -  Any other condition which, in the opinion of the investigator would impede compliance
             or hinder completion of the study

          -  Subjects who are enrolled in an interventional clinical study or have received an
             investigational new drug or product within the last 30 days prior to screening

          -  Participants diagnosed with type 1 diabetes