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Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) (TONIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00063635
Recruitment Status : Completed
First Posted : July 3, 2003
Results First Posted : September 27, 2012
Last Update Posted : September 27, 2012
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Fatty Liver
Interventions Drug: Metformin
Dietary Supplement: Vitamin E
Drug: Matching placebo
Enrollment 173
Recruitment Details Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States.
Pre-assignment Details  
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description Metformin, 500 mg, twice daily Vitamin E, 400 IU, twice daily Matching placebo
Period Title: Overall Study
Started 57 58 58
Completed 51 50 49
Not Completed 6 8 9
Arm/Group Title Metformin Vitamin E Placebo Total
Hide Arm/Group Description Metformin, 500 mg, twice daily Vitamin E, 400 IU, twice daily Matching placebo Total of all reporting groups
Overall Number of Baseline Participants 57 58 58 173
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 57 participants 58 participants 58 participants 173 participants
13.1  (2.4) 13.4  (2.3) 12.9  (2.6) 13.1  (2.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 57 participants 58 participants 58 participants 173 participants
Female
10
  17.5%
11
  19.0%
12
  20.7%
33
  19.1%
Male
47
  82.5%
47
  81.0%
46
  79.3%
140
  80.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 57 participants 58 participants 58 participants 173 participants
57 58 58 173
NAFLD activity score   [1] 
Mean (Standard Deviation)
Unit of measure:  Scores on a scale
Number Analyzed 57 participants 58 participants 58 participants 173 participants
4.5  (1.2) 4.8  (1.6) 4.6  (1.3) 4.6  (1.4)
[1]
Measure Description: 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).
1.Primary Outcome
Title Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 57 58 58
Measure Type: Number
Unit of Measure: participants
9 15 10
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.26
Comments Since two primary comparisons are planned, a P-value of 0.025 will be considered significant, applying a Bonferroni correction for multiple comparisons.
Method Mantel Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.83
Comments Since two primary comparisons are planned, a P-value of 0.025 will be considered significant, applying a Bonferroni correction for multiple comparisons.
Method Mantel Haenszel
Comments [Not Specified]
2.Secondary Outcome
Title Change in Serum Aspartate Aminotransferase (AST)
Hide Description [Not Specified]
Time Frame baseline and 96 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 51 50 49
Mean (95% Confidence Interval)
Unit of Measure: IU/L
-21.5
(-34.6 to -8.4)
-22.8
(-33.3 to -12.3)
-20.4
(-32.7 to -8.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.29
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
3.Secondary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 50 50 47
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-1.1
(-1.7 to -0.5)
-1.8
(-2.4 to -1.2)
-0.7
(-1.3 to -0.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.25
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants With Improvement in Liver Fibrosis Score
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 50 50 47
Measure Type: Number
Unit of Measure: participants
22 18 19
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.71
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Improvement in Steatosis Score
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 50 50 47
Measure Type: Number
Unit of Measure: participants
26 27 19
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.18
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.25
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants With Improvement in Lobular Inflammation Score
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 50 50 47
Measure Type: Number
Unit of Measure: participants
23 22 20
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.89
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.73
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
7.Secondary Outcome
Title Number of Participants With Improvement in Ballooning Degradation Score
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 50 50 47
Measure Type: Number
Unit of Measure: participants
22 22 10
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
8.Secondary Outcome
Title Change in Body Mass Index
Hide Description [Not Specified]
Time Frame baseline and 96 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 51 50 49
Mean (95% Confidence Interval)
Unit of Measure: kg/m-squared
1.3
(0.6 to 2.0)
2.1
(1.2 to 3.0)
1.9
(1.1 to 2.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.77
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.25
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
9.Secondary Outcome
Title Change in Serum Vitamin E Levels
Hide Description Change in alpha-Tocopherol
Time Frame baseline and 96 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 51 50 49
Mean (95% Confidence Interval)
Unit of Measure: mg/L
-0.5
(-1.1 to 0.2)
9.4
(6.2 to 12.6)
-0.9
(-2.1 to 0.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.44
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
10.Secondary Outcome
Title Change in Quality of Life (QOL) Scores- Physical Health
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 51 50 49
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
5.4
(0.8 to 10.0)
7.6
(2.7 to 12.5)
5.4
(-0.7 to 11.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.08
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.63
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
11.Secondary Outcome
Title Change in QOL- Psychosocial Health
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description:
Metformin, 500 mg, twice daily
Vitamin E, 400 IU, twice daily
Matching placebo
Overall Number of Participants Analyzed 51 50 47
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
4.0
(-0.4 to 8.4)
6.0
(1.4 to 10.6)
5.6
(0.0 to 11.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Vitamin E, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.15
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.96
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Metformin Vitamin E Placebo
Hide Arm/Group Description Metformin, 500 mg, twice daily Vitamin E, 400 IU, twice daily Matching placebo
All-Cause Mortality
Metformin Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Metformin Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/57 (12.28%)   6/58 (10.34%)   14/58 (24.14%) 
Cardiac disorders       
Syncope  0/57 (0.00%)  1/58 (1.72%)  1/58 (1.72%) 
Endocrine disorders       
Diabetes  0/57 (0.00%)  0/58 (0.00%)  1/58 (1.72%) 
Elevated serum glucose  1/57 (1.75%)  1/58 (1.72%)  0/58 (0.00%) 
Gastrointestinal disorders       
Appendicitis  1/57 (1.75%)  0/58 (0.00%)  1/58 (1.72%) 
Cholecystitis  0/57 (0.00%)  0/58 (0.00%)  1/58 (1.72%) 
General disorders       
Constipation  1/57 (1.75%)  0/58 (0.00%)  0/58 (0.00%) 
Pain  1/57 (1.75%)  0/58 (0.00%)  1/58 (1.72%) 
  0/57 (0.00%)  0/58 (0.00%)  1/58 (1.72%) 
Depression  1/57 (1.75%)  1/58 (1.72%)  2/58 (3.45%) 
Suicide  0/57 (0.00%)  1/58 (1.72%)  0/58 (0.00%) 
Hepatobiliary disorders       
Hepatobiliary/pancreas  0/57 (0.00%)  0/58 (0.00%)  5/58 (8.62%) 
Hepatotoxicity  2/57 (3.51%)  1/58 (1.72%)  0/58 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Airway constriction/bronchospasm  0/57 (0.00%)  1/58 (1.72%)  1/58 (1.72%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Metformin Vitamin E Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/57 (29.82%)   17/58 (29.31%)   18/58 (31.03%) 
General disorders       
Unspecified- Mild  10/57 (17.54%)  10/58 (17.24%)  6/58 (10.34%) 
Unspecified- Moderate  7/57 (12.28%)  7/58 (12.07%)  12/58 (20.69%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Joel E. Lavine, MD, PhD
Organization: Columbia University Medical Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00063635     History of Changes
Other Study ID Numbers: NASH - PEDIATRICS (IND)
First Submitted: July 1, 2003
First Posted: July 3, 2003
Results First Submitted: June 26, 2012
Results First Posted: September 27, 2012
Last Update Posted: September 27, 2012