Fatty Liver
Conditions
Keywords
Non alcoholic fatty liver disease
Brief summary
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.
Interventions
DRUGMetformin
500 mg, twice daily
DIETARY_SUPPLEMENTVitamin E
400 IU, twice daily
DRUGMatching placebo
Twice daily
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L | baseline and 96 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | baseline and 96 weeks | 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). |
| Number of Participants With Improvement in Liver Fibrosis Score | baseline and 96 weeks | 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. |
| Number of Participants With Improvement in Steatosis Score | baseline and 96 weeks | 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. |
| Number of Participants With Improvement in Lobular Inflammation Score | baseline and 96 weeks | 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. |
| Change in Serum Aspartate Aminotransferase (AST) | baseline and 96 weeks | — |
| Change in Body Mass Index | baseline and 96 weeks | — |
| Change in Serum Vitamin E Levels | baseline and 96 weeks | Change in alpha-Tocopherol |
| Change in Quality of Life (QOL) Scores- Physical Health | baseline and 96 weeks | 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. |
| Change in QOL- Psychosocial Health | baseline and 96 weeks | 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. |
| Number of Participants With Improvement in Ballooning Degradation Score | baseline and 96 weeks | 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. |
Countries
United States
Participant flow
Recruitment details
Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin, 500 mg, twice daily | 57 |
| Vitamin E Vitamin E, 400 IU, twice daily | 58 |
| Placebo Matching placebo | 58 |
| Total | 173 |
Baseline characteristics
| Characteristic | Metformin | Vitamin E | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 13.1 years STANDARD_DEVIATION 2.4 | 13.4 years STANDARD_DEVIATION 2.3 | 12.9 years STANDARD_DEVIATION 2.6 | 13.1 years STANDARD_DEVIATION 2.4 |
| NAFLD activity score | 4.5 scores on a scale STANDARD_DEVIATION 1.2 | 4.8 scores on a scale STANDARD_DEVIATION 1.6 | 4.6 scores on a scale STANDARD_DEVIATION 1.3 | 4.6 scores on a scale STANDARD_DEVIATION 1.4 |
| Region of Enrollment United States | 57 participants | 58 participants | 58 participants | 173 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 12 Participants | 33 Participants |
| Sex: Female, Male Male | 47 Participants | 47 Participants | 46 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 57 | 17 / 58 | 18 / 58 |
| serious Total, serious adverse events | 7 / 57 | 6 / 58 | 14 / 58 |
Outcome results
Primary
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.
Time frame: baseline and 96 weeks
Population: All enrolled patients were included in analysis of the primary outcome, sustained reduction in ALT level. Patients missing a 96-week ALT measurement were imputed as not achieving a sustained reduction.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L | 9 participants |
| Vitamin E | Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L | 15 participants |
| Placebo | Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L | 10 participants |
p-value: 0.26Mantel Haenszel
p-value: 0.83Mantel Haenszel
Secondary
Change in Body Mass Index
Time frame: baseline and 96 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Body Mass Index | 1.3 kg/m-squared |
| Vitamin E | Change in Body Mass Index | 2.1 kg/m-squared |
| Placebo | Change in Body Mass Index | 1.9 kg/m-squared |
p-value: 0.77ANCOVA
p-value: 0.25ANCOVA
Secondary
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).
Time frame: baseline and 96 weeks
Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | 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 | -1.1 units on a scale |
| Vitamin E | 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 | -1.8 units on a scale |
| Placebo | 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 | -0.7 units on a scale |
p-value: 0.02ANCOVA
p-value: 0.25ANCOVA
Secondary
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.
Time frame: baseline and 96 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in QOL- Psychosocial Health | 4.0 units on a scale |
| Vitamin E | Change in QOL- Psychosocial Health | 6.0 units on a scale |
| Placebo | Change in QOL- Psychosocial Health | 5.6 units on a scale |
p-value: 0.15ANCOVA
p-value: 0.96ANCOVA
Secondary
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.
Time frame: baseline and 96 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Quality of Life (QOL) Scores- Physical Health | 5.4 units on a scale |
| Vitamin E | Change in Quality of Life (QOL) Scores- Physical Health | 7.6 units on a scale |
| Placebo | Change in Quality of Life (QOL) Scores- Physical Health | 5.4 units on a scale |
p-value: 0.08ANCOVA
p-value: 0.63ANCOVA
Secondary
Change in Serum Aspartate Aminotransferase (AST)
Time frame: baseline and 96 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Serum Aspartate Aminotransferase (AST) | -21.5 IU/L |
| Vitamin E | Change in Serum Aspartate Aminotransferase (AST) | -22.8 IU/L |
| Placebo | Change in Serum Aspartate Aminotransferase (AST) | -20.4 IU/L |
p-value: 0.32ANCOVA
p-value: 0.29ANCOVA
Secondary
Change in Serum Vitamin E Levels
Change in alpha-Tocopherol
Time frame: baseline and 96 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Serum Vitamin E Levels | -0.5 mg/L |
| Vitamin E | Change in Serum Vitamin E Levels | 9.4 mg/L |
| Placebo | Change in Serum Vitamin E Levels | -0.9 mg/L |
p-value: <0.001ANCOVA
p-value: 0.44ANCOVA
Secondary
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.
Time frame: baseline and 96 weeks
Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Participants With Improvement in Ballooning Degradation Score | 22 participants |
| Vitamin E | Number of Participants With Improvement in Ballooning Degradation Score | 22 participants |
| Placebo | Number of Participants With Improvement in Ballooning Degradation Score | 10 participants |
p-value: 0.02Chi-squared
p-value: 0.02Chi-squared
Secondary
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.
Time frame: baseline and 96 weeks
Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Participants With Improvement in Liver Fibrosis Score | 22 participants |
| Vitamin E | Number of Participants With Improvement in Liver Fibrosis Score | 18 participants |
| Placebo | Number of Participants With Improvement in Liver Fibrosis Score | 19 participants |
p-value: 0.71Chi-squared
p-value: 0.72Chi-squared
Secondary
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.
Time frame: baseline and 96 weeks
Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Participants With Improvement in Lobular Inflammation Score | 23 participants |
| Vitamin E | Number of Participants With Improvement in Lobular Inflammation Score | 22 participants |
| Placebo | Number of Participants With Improvement in Lobular Inflammation Score | 20 participants |
p-value: 0.89Chi-squared
p-value: 0.73Chi-squared
Secondary
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.
Time frame: baseline and 96 weeks
Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Participants With Improvement in Steatosis Score | 26 participants |
| Vitamin E | Number of Participants With Improvement in Steatosis Score | 27 participants |
| Placebo | Number of Participants With Improvement in Steatosis Score | 19 participants |
p-value: 0.18Chi-squared
p-value: 0.25Chi-squared