Hydroxytyrosol and Vitamin E in Pediatric NASH

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

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.

Study Overview

• Status: Completed
• Conditions: NAFLD
• Intervention / Treatment: Drug: Hydroxytyrosol plus Vitamin E; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00165
    • Hepatometabolic Department, Bambino Gesù Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 16 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TREATED GROUP; 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; 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; Other Names: Hydroxytyrosol, alpha-tocopherol
PLACEBO_COMPARATOR: PLACEBO GROUP; This group will treated with 2 identical placebo pills daily given orally for 16 weeks.	Drug: Placebo; This group will treated with 2 identical placebo pills daily given orally for 16 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Bambino Gesù Hospital and Research Institute

Publications and helpful links

General Publications

• Mosca A, Crudele A, Smeriglio A, Braghini MR, Panera N, Comparcola D, Alterio A, Sartorelli MR, Tozzi G, Raponi M, Trombetta D, Alisi A. Antioxidant activity of Hydroxytyrosol and Vitamin E reduces systemic inflammation in children with paediatric NAFLD. Dig Liver Dis. 2021 Sep;53(9):1154-1158. doi: 10.1016/j.dld.2020.09.021. Epub 2020 Oct 13.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2017
• Primary Completion (ACTUAL): May 31, 2018
• Study Completion (ACTUAL): May 31, 2018

Study Registration Dates

• First Submitted: July 13, 2016
• First Submitted That Met QC Criteria: July 20, 2016
• First Posted (ESTIMATE): July 25, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 17, 2018
• Last Update Submitted That Met QC Criteria: July 16, 2018
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Platelet Aggregation Inhibitors; Protective Agents; Micronutrients; Vitamins; Antioxidants; Disinfectants; Vitamin E; Tocopherols; alpha-Tocopherol; 3,4-dihydroxyphenylethanol; Phenylethyl Alcohol
• Other Study ID Numbers: 1066_OPBG_2016

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No