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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Active Comparator | Metformin, 500 mg, twice daily |
|
| 2 | Active Comparator | Vitamin E, 400 IU, twice daily |
|
| 3 | Placebo Comparator | Matching placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | 500 mg, twice daily |
| |
| Vitamin E |
| 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 |
| 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). |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Diego | San Diego | California | 92103 | United States | ||
| University of California, San Francisco |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25714579 | Derived | Corey KE, Vuppalanchi R, Vos M, Kohli R, Molleston JP, Wilson L, Unalp-Arida A, Cummings OW, Lavine JE, Chalasani N; Nonalcoholic Steatohepatitis Clinical Research Network. Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2015 Mar;60(3):360-7. doi: 10.1097/MPG.0000000000000584. | |
| 22338037 |
| Label | URL |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases | View source |
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Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin | Metformin, 500 mg, twice daily |
| FG001 | Vitamin E | Vitamin E, 400 IU, twice daily |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Dietary Supplement |
400 IU, twice daily |
|
|
| Matching placebo | Drug | Twice daily |
|
| 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 |
| San Francisco |
| California |
| 94143 |
| United States |
| Children's National Medical Center | Washington D.C. | District of Columbia | 20010 | United States |
| Indiana University | Indianapolis | Indiana | 46202 | United States |
| Johns Hopkins University | Baltimore | Maryland | 21205 | United States |
| St. Louis University | St Louis | Missouri | 63110 | United States |
| Case Western Reserve University | Cleveland | Ohio | 44109 | United States |
| Texas Children's Hospital | Houston | Texas | 77030 | United States |
| Virginia Commonwealth University | Richmond | Virginia | 23298 | United States |
| University of Washington | Seattle | Washington | 98195 | United States |
| Derived |
| Guerrerio AL, Colvin RM, Schwartz AK, Molleston JP, Murray KF, Diehl A, Mohan P, Schwimmer JB, Lavine JE, Torbenson MS, Scheimann AO. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease. Am J Clin Nutr. 2012 Apr;95(4):892-900. doi: 10.3945/ajcn.111.020156. Epub 2012 Feb 15. |
| 21521847 | Derived | Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011 Apr 27;305(16):1659-68. doi: 10.1001/jama.2011.520. |
| 19761871 | Derived | Lavine JE, Schwimmer JB, Molleston JP, Scheimann AO, Murray KF, Abrams SH, Rosenthal P, Sanyal AJ, Robuck PR, Brunt EM, Unalp A, Tonascia J; Nonalcoholic Steatohepatitis Clinical Research Network Research Group. Treatment of nonalcoholic fatty liver disease in children: TONIC trial design. Contemp Clin Trials. 2010 Jan;31(1):62-70. doi: 10.1016/j.cct.2009.09.001. Epub 2009 Sep 15. |
| FG002 |
| Placebo |
Matching placebo |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Metformin | Metformin, 500 mg, twice daily |
| BG001 | Vitamin E | Vitamin E, 400 IU, twice daily |
| BG002 | Placebo | Matching placebo |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||
| NAFLD activity score | Total nonalcoholic fatty liver disease (NAFLD) activity was assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2). | Mean | Standard Deviation | scores on a scale |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Number | participants | baseline and 96 weeks |
|
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| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change in Serum Aspartate Aminotransferase (AST) | Posted | Mean | 95% Confidence Interval | IU/L | baseline and 96 weeks |
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). | Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies. | Posted | Mean | 95% Confidence Interval | units on a scale | baseline and 96 weeks |
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies. | Posted | Number | participants | baseline and 96 weeks |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies. | Posted | Number | participants | baseline and 96 weeks |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies. | Posted | Number | participants | baseline and 96 weeks |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies. | Posted | Number | participants | baseline and 96 weeks |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change in Body Mass Index | Posted | Mean | 95% Confidence Interval | kg/m-squared | baseline and 96 weeks |
|
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| Secondary | Change in Serum Vitamin E Levels | Change in alpha-Tocopherol | Posted | Mean | 95% Confidence Interval | mg/L | baseline and 96 weeks |
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Posted | Mean | 95% Confidence Interval | units on a scale | baseline and 96 weeks |
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| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Posted | Mean | 95% Confidence Interval | units on a scale | baseline and 96 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Metformin | Metformin, 500 mg, twice daily | 7 | 57 | 17 | 57 | ||
| EG001 | Vitamin E | Vitamin E, 400 IU, twice daily | 6 | 58 | 17 | 58 | ||
| EG002 | Placebo | Matching placebo | 14 | 58 | 18 | 58 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Airway constriction/bronchospasm | Respiratory, thoracic and mediastinal disorders |
| |||
| Appendicitis | Gastrointestinal disorders |
| |||
| Cholecystitis | Gastrointestinal disorders |
| |||
| Constipation | General disorders |
| |||
| Diabetes | Endocrine disorders |
| |||
| Elevated serum glucose | Endocrine disorders |
| |||
| Hepatobiliary/pancreas | Hepatobiliary disorders |
| |||
| Hepatotoxicity | Hepatobiliary disorders |
| |||
| Pain | General disorders |
| |||
| Syncope | Cardiac disorders |
| |||
| General disorders |
| ||||
| Depression | General disorders |
| |||
| Suicide | General disorders |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Unspecified- Mild | General disorders |
| |||
| Unspecified- Moderate | General disorders |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joel E. Lavine, MD, PhD | Columbia University Medical Center | jl3553@columbia.edu |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D065626 | Non-alcoholic Fatty Liver Disease |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D014810 | Vitamin E |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Male |
|
| 0.83 |
Since two primary comparisons are planned, a P-value of 0.025 will be considered significant, applying a Bonferroni correction for multiple comparisons. |
| 95 |
| No |
| Superiority or Other |
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