Efficacy of a Natural Components Mixture in the Treatment of Non Alcoholic Fatty Liver Disease (NAFLD)
Condition: Non-alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      The objective of this study is to provide clinical data to support the effectiveness of a
      mixture of ingredients of natural origin, suitably selected and packaged, in the protection
      from liver damage, in subjects with NAFLD.

      Study design: double-blind, randomized, multicentre trial, placebo-controlled on two parallel
      groups.

      The study participants are healthy volunteers, since they do not have nor had any
      liver-related clinical symptom, but simply laboratory (plasma levels greater than normal for
      at least one of the liver parameters -aspartate aminotransferase AST, alanine
      aminotransferase ALT or γ -glutamyltranspeptidase γ-GT) or instrumental (ultrasonographic
      abnormalities of steatosic liver) tests altered as compared to normal ranges.

      Three months treatment with the nutraceutical mixture or placebo. Outcomes tested before and
      at the end of treatment - 3 months).
    

Detailed description: 
      A correct hepatic function is highly relevant from the epidemiological point of view. In
      Italy, Non Alcoholic Fatty Liver Disease - NAFLD - has a prevalence of 20-25% in the adult
      population, with peaks of 50-70% within obese and type-2 diabetes populations: it is the most
      frequent cause of hematic changes in cytonecrosis enzymes, and can explain about 90% of
      asymptomatic high levels of transaminases. NAFLD natural history is associated with an
      increase of cerebro and cardiovascular risk, in both healthy subjects and diabetic patients.

      Its prevention and treatment are of great interest, in particular dietary and nutraceutical
      interventions are the object of innovative research. It is also known that about 65% of
      subjects with hepatic dysfunction consume plant extracts, like silymarin from Cardo marianum.
      A recent trial showed an improvement of the hepatic function in subjects with NAFLD treated
      with silybin, combined with phosphatidylcholine and vitamin E. These findings provide
      valuable information on new therapeutic strategies, but warrant further investigation. For no
      natural substance a health claim related to liver function was in fact approved by the
      European Food Safety Authority (EFSA). The only exception is constituted by the food sources
      of choline, for which the maintenance of normal hepatic function has been claimed.

      The objective of this study is to provide clinical data to support the effectiveness of a
      mixture of ingredients of natural origin, suitably selected and packaged, in the protection
      from liver damage, in subjects with NAFLD.

      Treatment: subjects will be randomized to receive the nutraceutical formulation or placebo
      for three months, in the amount of two capsules (about 800 mg each) a day, at one time.

      All subjects, after signing a written informed consent to participation in the study, will
      receive appropriate recomendations about diet and physical exercise.

      A clinic visit, with collection of the patient clinical and pharmacological history and
      recording of any adverse event, liver ultrasound, measurement of weight and height and
      calculation of BMI, measure of arterial blood pressure, collection of a sample of venous
      blood, under fasting conditions, for hematochemical tests, will be made at the baseline (T0);
      all examinations and tests (except liver ultrasound) will be repeated after three months of
      treatment (T1).

      Primary end-points of the study: hematic levels of hepatic enzymes: ALT, AST and γ-GT.

      Secondary end-points of the study:

        1. Hepatic function: direct and indirect bilirubin;

        2. Inflammation markers: C Reactive Protein (CRP), interleukin (IL)-6, IL-1β, IL-8, IL-10,
           Receptor for Advanced Glycation End Products (RAGE), Advanced Glycation End Products
           (AGE), insulin-like growth factor-1 (IGF-1)

        3. Haemostatic function: Factor VII, fibrinogen, thrombin generation with and without
           thrombomodulin, antithrombin (AT), tissue-type Plasminogen Activator (t-PA), Plasminogen
           Activator Inhibitor-1(PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI) and
           activated TAFI (TAFIa), plasmin-antiplasmin complex, plasma fibrinolytic capacity;

        4. Metabolic syndrome parameters: glycemia, triglycerides, HDL cholesterol, insulin e
           insulin-resistance (HOMA-IR homeostasis model assessment-estimated insulin resistance),
           adiponectin;

        5. Apoptosis parameters: total cytokeratin-18 (M65 antigene), M30 and M65/M65ED, soluble
           fas and soluble fas ligand.

      A weekly food diary will be administered to each subject before and at the end of the
      treatment, to highlight any possible change of dietary habits during the study.

      In addition, for all subjects the NAFLD Fibrosis Score (NFS), a composite score of prognostic
      value for the conversion of NAFDL into fibrotic hepatitis and for the disease severity, will
      be calculated. This score includes age, body mass index, platelet count, albumin,
      relationship between AST and ALT, and presence of diabetes. A sub-analysis will be done to
      evaluate the efficacy of the treatment with the synergistic blend of ingredients in subjects
      with high, as compared to those with low NFS.

      Sample size calculation: Establishing Alpha = 0.05 and Β = 80%, the number of 150 people (75
      per treatment arm) will evaluate differences between the two groups (T1 to T0) equal to 46%
      of the standard deviation of the mean of the two liver function parameters selected (primary
      end-points), in particular, differences over 11.5 for ALT (17% of the average), 7.1 for AST
      (17% of the average) or 13.8 for γ-GT (19% of the average). This calculation also includes a
      drop-out of 10% of the sample enrolled in the study.

      Compliance to treatment will be monitored by counting the capsules returned in the box at the
      end of treatment.
    

Intervention name(s): nutraceutical mixture; placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Lifestyle counseling, administration of a nutraceutical mixture: fish oil 70% DHA (docosahexaenoic acid), phosphatidylcholine concentrated in sunflower oil, silymarin, choline bitartrate, curcumin, D-α-tocopherol; choline (82,5 mg, corresponding to 15% of the average intake of 550 mg per day in an adult man); Lifestyle counseling, administration of a placebo, containing only choline, at the same low concentration of the active mixture
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: NAFLD; nutraceutical mixture