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CompletedNCT00063635TONICUpdated Sep 27, 2012Results posted

Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

A Phase 3 interventional study of Metformin and Vitamin E in Fatty Liver, sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Completed at 10 sites in United States. Open to participants aged 8 Years to 17 Years. Per ClinicalTrials.gov, last updated 2012-09-27.

Sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
173
Allocation
Randomized
Ages
8 Years to 17 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Fatty Liver

Keywords

  • Non alcoholic fatty liver disease
03

In context

Liver Diseases

2,081 studies on the registry are indexed under Liver Diseases; 390 are open to participants now.

This study's enrollment of 173 is above the median of 50 across 1,323 interventional studies indexed under Liver Diseases.

Browse Liver Diseases studies →

Lead sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is the lead sponsor of 529 studies on the registry; 54 are open to participants now.

Of its 79 completed or terminated interventional studies of FDA-regulated products, 50 (63%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
8 Years to 17 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility 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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
173 participants (actual)

Study arms

  • Active comparator
    1

    Metformin, 500 mg, twice daily

    Drug: Metformin

  • Active comparator
    2

    Vitamin E, 400 IU, twice daily

    Dietary Supplement: Vitamin E

  • Placebo comparator
    3

    Matching placebo

    Drug: Matching placebo

Interventions

  • DrugMetformin

    500 mg, twice daily

  • Dietary supplementVitamin E

    400 IU, twice daily

    Also known as: Nature Made

  • DrugMatching placebo

    Twice daily

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. Change in Serum Aspartate Aminotransferase (AST)

    Time frame: baseline and 96 weeks

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. Change in Body Mass Index

    Time frame: baseline and 96 weeks

  8. Change in Serum Vitamin E Levels

    Change in alpha-Tocopherol

    Time frame: baseline and 96 weeks

  9. 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

  10. 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

07

Results

Posted Sep 27, 2012

Participant flow

Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States.

Participant flow — Overall Study
MilestoneMetforminVitamin EPlacebo
Started575858
Completed515049
Not completed689

Outcome measures

PrimaryNumber 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
Reported as:
Number · participants
Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L
participantsMetforminVitamin EPlacebo
Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L9 (7 to 28)15 (15 to 39)10 (9 to 29)
Statistical analysis
  • Vitamin E vs Placebo · Mantel Haenszel · p = 0.26 (Since two primary comparisons are planned, a P-value of 0.025 will be considered significant, applying a Bonferroni correction for multiple comparisons.)
  • Metformin vs Placebo · Mantel Haenszel · p = 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.)
SecondaryChange in Serum Aspartate Aminotransferase (AST)
Time frame:
baseline and 96 weeks
Reported as:
Mean · IU/L
Change in Serum Aspartate Aminotransferase (AST)
IU/LMetforminVitamin EPlacebo
Change in Serum Aspartate Aminotransferase (AST)-21.5 (-34.6 to -8.4)-22.8 (-33.3 to -12.3)-20.4 (-32.7 to -8.0)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = 0.32
  • Metformin vs Placebo · ANCOVA · p = 0.29
SecondaryChange 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
Reported as:
Mean · units on a scale
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
units on a scaleMetforminVitamin EPlacebo
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 (-1.7 to -0.5)-1.8 (-2.4 to -1.2)-0.7 (-1.3 to -0.2)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = 0.02
  • Metformin vs Placebo · ANCOVA · p = 0.25
SecondaryNumber 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
Reported as:
Number · participants
Number of Participants With Improvement in Liver Fibrosis Score
participantsMetforminVitamin EPlacebo
Number of Participants With Improvement in Liver Fibrosis Score221819
Statistical analysis
  • Vitamin E vs Placebo · Chi-squared · p = 0.71
  • Metformin vs Placebo · Chi-squared · p = 0.72
SecondaryNumber 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
Reported as:
Number · participants
Number of Participants With Improvement in Steatosis Score
participantsMetforminVitamin EPlacebo
Number of Participants With Improvement in Steatosis Score262719
Statistical analysis
  • Vitamin E vs Placebo · Chi-squared · p = 0.18
  • Metformin vs Placebo · Chi-squared · p = 0.25
SecondaryNumber 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
Reported as:
Number · participants
Number of Participants With Improvement in Lobular Inflammation Score
participantsMetforminVitamin EPlacebo
Number of Participants With Improvement in Lobular Inflammation Score232220
Statistical analysis
  • Vitamin E vs Placebo · Chi-squared · p = 0.89
  • Metformin vs Placebo · Chi-squared · p = 0.73
SecondaryNumber 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
Reported as:
Number · participants
Number of Participants With Improvement in Ballooning Degradation Score
participantsMetforminVitamin EPlacebo
Number of Participants With Improvement in Ballooning Degradation Score222210
Statistical analysis
  • Vitamin E vs Placebo · Chi-squared · p = 0.02
  • Metformin vs Placebo · Chi-squared · p = 0.02
SecondaryChange in Body Mass Index
Time frame:
baseline and 96 weeks
Reported as:
Mean · kg/m-squared
Change in Body Mass Index
kg/m-squaredMetforminVitamin EPlacebo
Change in Body Mass Index1.3 (0.6 to 2.0)2.1 (1.2 to 3.0)1.9 (1.1 to 2.7)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = 0.77
  • Metformin vs Placebo · ANCOVA · p = 0.25
SecondaryChange in Serum Vitamin E Levels

Change in alpha-Tocopherol

Time frame:
baseline and 96 weeks
Reported as:
Mean · mg/L
Change in Serum Vitamin E Levels
mg/LMetforminVitamin EPlacebo
Change in Serum Vitamin E Levels-0.5 (-1.1 to 0.2)9.4 (6.2 to 12.6)-0.9 (-2.1 to 0.4)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = <0.001
  • Metformin vs Placebo · ANCOVA · p = 0.44
SecondaryChange 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
Reported as:
Mean · units on a scale
Change in Quality of Life (QOL) Scores- Physical Health
units on a scaleMetforminVitamin EPlacebo
Change in Quality of Life (QOL) Scores- Physical Health5.4 (0.8 to 10.0)7.6 (2.7 to 12.5)5.4 (-0.7 to 11.5)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = 0.08
  • Metformin vs Placebo · ANCOVA · p = 0.63
SecondaryChange 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
Reported as:
Mean · units on a scale
Change in QOL- Psychosocial Health
units on a scaleMetforminVitamin EPlacebo
Change in QOL- Psychosocial Health4.0 (-0.4 to 8.4)6.0 (1.4 to 10.6)5.6 (0.0 to 11.2)
Statistical analysis
  • Vitamin E vs Placebo · ANCOVA · p = 0.15
  • Metformin vs Placebo · ANCOVA · p = 0.96

Adverse events

Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Metformin—7/57 (12.3%)17/57 (29.8%)
Vitamin E—6/58 (10.3%)17/58 (29.3%)
Placebo—14/58 (24.1%)18/58 (31%)
Most frequent serious events
Showing 10 of 13
Most frequent serious events
EventMetforminVitamin EPlacebo
Hepatobiliary/pancreasHepatobiliary disorders0/570/585/58
HepatotoxicityHepatobiliary disorders2/571/580/58
DepressionGeneral disorders1/571/582/58
AppendicitisGastrointestinal disorders1/570/581/58
ConstipationGeneral disorders1/570/580/58
Elevated serum glucoseEndocrine disorders1/571/580/58
PainGeneral disorders1/570/581/58
Airway constriction/bronchospasmRespiratory, thoracic and mediastinal disorders0/571/581/58
CholecystitisGastrointestinal disorders0/570/581/58
DiabetesEndocrine disorders0/570/581/58
Most frequent other events
Most frequent other events
EventMetforminVitamin EPlacebo
Unspecified- ModerateGeneral disorders7/577/5812/58
Unspecified- MildGeneral disorders10/5710/586/58

Baseline characteristics

Age Continuous
Age Continuous(years)MetforminVitamin EPlaceboTotal
Mean13.1 ± 2.413.4 ± 2.312.9 ± 2.613.1 ± 2.4
Sex: Female, Male
Sex: Female, Male(Participants)MetforminVitamin EPlaceboTotal
Female10111233
Male474746140
Region of Enrollment
Region of Enrollment(participants)MetforminVitamin EPlaceboTotal
United States575858173
NAFLD activity score
NAFLD activity score(scores on a scale)MetforminVitamin EPlaceboTotal
Mean4.5 ± 1.24.8 ± 1.64.6 ± 1.34.6 ± 1.4
08

Study locations

10 sites
  • University of California, San Diego
    San Diego, California 92103, United States
  • University of California, San Francisco
    San Francisco, California 94143, United States
  • Children's National Medical Center
    Washington, 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
09

References and documents

Publications

  • 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. PubMed 25714579 ↗
  • 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. PubMed 22338037 ↗
  • 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. PubMed 21521847 ↗
  • 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. PubMed 19761871 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 27, 2012, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00063635
Lead sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Responsible party
Sponsor
First posted
Jul 3, 2003
Start date
Sep 2005
Primary completion
Sep 2009
Completion
Feb 2010
Results posted
Sep 27, 2012
Last update
Sep 27, 2012

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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