Clinical trial NCT02842567: Hydroxytyrosol and Vitamin E in Pediatric NASH
Official title: Hydroxytyrosol and Vitamin E in the Treatment of Children With Biopsy-proven NASH
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: NAFLD
Lead sponsor: Bambino Gesù Hospital and Research Institute
Sponsor class: OTHER
First posted: 2016-07-25
Enrollment: 80
Sex: ALL
Minimum age (years): 4
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Improvement of laboratory markers of inflammation and oxidative stress, such as concentrations of TNF-alpha, lipopolysaccharide (LPS), adiponectin, catepsin D, cytokeratin-18.
timeFrame: 4 months
measure: Improvement of laboratory parameters of metabolic syndrome, such as lipids and gluco-insulinemic profile, transaminases serum levels
timeFrame: 4 months
Secondary outcomes:
measure: Improvement of echographic score of hepatic steatosis (echographic scale)
timeFrame: 4 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE
timeFrame: 4 months
measure: Analysis of fecal gut microbiome of patients before and after treatment with hydroxytyrosol and vitamin E
timeFrame: 4 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Hepatometabolic Department, Bambino Gesù Children's Hospital
Study officials:
References:
citation: 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.