Hydroxytyrosol and Vitamin E in Pediatric NASH

Study Overview
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Brief Summary
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Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is rapidly becoming the one of most common causes of chronic liver disease in children. The pathogenesis of NAFLD is generally considered the result of a series of liver injuries, commonly referred as multi-hit hypothesis. Several studies suggest that inflammatory pathways and oxidative stress could be responsible of disease progression to non-alcoholic steatohepatitis (NASH). Hydroxytyrosol is a simple phenolic compound naturally occurring in olive and olive oil with antioxidant properties. Some studies have demonstrated that hydroxytyrosol show several anti-inflammatory and anti-atherogenic activities, such as the inhibition of LDL oxidation and platelet aggregation. Alpha tocopherol (Vitamin E) is the most studied anti-oxydant in pediatric NAFLD with conflicting results. It inhibits proinflammatory cytokine production and attenuates the release of profibrogenic agents and liver collagen. The purpose of this interventional study is to evaluate the efficacy and tolerability of Hydroxytyrosol and Vitamin E in the treatment of children with biopsy-proven NASH.

Detailed Description
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80 children and adolescents (4-16 years) with biopsy-proven NASH will be enrolled. They will be randomized to treatment with hydroxytyrosol and vitamin E (n: 40 pts) or an identical placebo (n: 40 pts) given orally for a period of 16 weeks. Patients will undergo a medical evaluation at baseline (enrollment) and after 4 months (end of treatment). Anthropometric measures and laboratory assay, includin liver enzymes, gluco-insulinemic and lipid profiles will be performed at baseline and at the end of the study. Hepatic ultrasound examination will be performed at enrollment and at the end of the study. Serum sample for determination of markers of inflammation and oxidative stress will be collected at enrollment and at the end of the study. A stool sample for analysis of gut microbioma will be collected at enrollment and at the end of the study.

Official Title
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Hydroxytyrosol and Vitamin E in the Treatment of Children With Biopsy-proven NASH

Conditions
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NAFLD

Intervention / Treatment
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* Drug: Hydroxytyrosol plus Vitamin E
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver biopsy consistent with diagnosis of NASH (liver biopsy performed in 3-6 months before enrollment) Hyperechogenicity of liver at ultrasound examination ALT levels range between normal and < 10 UNL INR < 1.3 Albumin > 3 gr/dl. Total bilirubin < 2.5 mg/dl normal renal function normal cells blood count exclusion of other causes of chronic hepatopathies in children Written informed consent to participate in the Protocol by their parents or legal guardians of patients Exclusion Criteria: alcohols or drugs abuse use of drugs known to induce steatosis or to affect body weight or carbohydrate metabolism autoimmune liver diseases, Wilson's disease, alpha-1-antitripsin deficiency, metabolic liver disease every clinical or psychiatric diseases interfering with experimentation according to investigator's evaluation finding of active liver disease due to other causes

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 16 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: TREATED GROUP<br>This group will treated with 2 pills daily, each containing 3.75 mg of hydroxytyrosol plus 5 mg of Vitamin E, given orally for 16 weeks. | Drug: Hydroxytyrosol plus Vitamin E<br>* This group will treated with 2 pills daily, each containing 3.75 mg of hydroxytyrosol plus 5 mg of Vitamin E, given orally for 16 weeks<br>* Other names: Hydroxytyrosol, alpha-tocopherol;|
| Placebo Comparator: PLACEBO GROUP<br>This group will treated with 2 identical placebo pills daily given orally for 16 weeks. | Drug: Placebo<br>* This group will treated with 2 identical placebo pills daily given orally for 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of laboratory markers of inflammation and oxidative stress, such as concentrations of TNF-alpha, lipopolysaccharide (LPS), adiponectin, catepsin D, cytokeratin-18. |  | 4 months | 
| Improvement of laboratory parameters of metabolic syndrome, such as lipids and gluco-insulinemic profile, transaminases serum levels |  | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of echographic score of hepatic steatosis (echographic scale) |  | 4 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE |  | 4 months | 
| Analysis of fecal gut microbiome of patients before and after treatment with hydroxytyrosol and vitamin E |  | 4 months |