Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

Study Overview
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Brief Summary
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The purpose of this study is to determine if therapeutic modification of insulin resistance or oxidative stress leads to improvement in serum or histologic indicators of liver injury or quality of life.

Official Title
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Clinical Research Network in Nonalcoholic Steatohepatitis: Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

Conditions
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Fatty Liver

Intervention / Treatment
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* Drug: Metformin
* Dietary Supplement: Vitamin E
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Age 8-17 years at first screening visit Histologic evidence of Nonalcoholic Fatty Liver Disease (NAFLD) - biopsy cannot be older than 6 months as of randomization ALT level >60 U/L at time of screening and on one previous occasion determined at least one month but no greater than 6 months prior to screening ALT Consent

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Metformin, 500 mg, twice daily | Drug: Metformin<br>* 500 mg, twice daily<br>|
| Active Comparator: 2<br>Vitamin E, 400 IU, twice daily | Dietary Supplement: Vitamin E<br>* 400 IU, twice daily<br>* Other names: Nature Made;|
| Placebo Comparator: 3<br>Matching placebo | Drug: Matching placebo<br>* Twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L | The primary outcome was sustained reduction in ALT level, defined as 50% or less of the baseline level or 40 IU/L or less at each visit from 48 to 96 weeks of treatment. | baseline and 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Aspartate Aminotransferase (AST) |  | baseline and 96 weeks | 
| Change in Nonalcoholic Fatty Liver Disease (NAFLD) Score (Histologic Feature Scores Determined by Standardized Scoring of Liver Biopsies) From Baseline at 96 Weeks of Treatment | Histological activity was assessed using the NAFLD activity score on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (0-3), lobular inflammation (0-3), and hepatocellular ballooning (0-2). | baseline and 96 weeks | 
| Number of Participants With Improvement in Liver Fibrosis Score | Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis. This secondary outcome measure is the number of participants that experienced a decrease in fibrosis score at 96 weeks compared to baseline, which indicates improvement in fibrosis. | baseline and 96 weeks | 
| Number of Participants With Improvement in Steatosis Score | Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis. This secondary outcome measure is the number of participants that experienced a decrease in steatosis score at 96 weeks compared to baseline, which indicates improvement in steatosis. | baseline and 96 weeks | 
| Number of Participants With Improvement in Lobular Inflammation Score | Lobular inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe lobular inflammation. This secondary outcome measure is the number of participants that experienced a decrease in lobular inflammation score at 96 weeks compared to baseline, which indicates improvement in lobular inflammation. | baseline and 96 weeks | 
| Number of Participants With Improvement in Ballooning Degradation Score | Ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe ballooning. This secondary outcome measure is the number of participants that experienced a decrease in ballooning score at 96 weeks compared to baseline, which indicates improvement in ballooning. | baseline and 96 weeks | 
| Change in Body Mass Index |  | baseline and 96 weeks | 
| Change in Serum Vitamin E Levels | Change in alpha-Tocopherol | baseline and 96 weeks | 
| Change in Quality of Life (QOL) Scores- Physical Health | Change in self-reported QOL physical health Pediatric Quality of Life Inventory (version 4.0) scores were recorded to range from 0 to 100 with increasing scores indicating better quality of life. | baseline and 96 weeks | 
| Change in QOL- Psychosocial Health | Change in self-reported QOL physical health Pediatric Quality of Life Inventory (version 4.0) scores were recorded to range from 0 to 100 with increasing scores indicating better quality of life. | baseline and 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non alcoholic fatty liver disease