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Fatty LiverPhase 3TONICNCT00063635

Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

A Phase 3 study testing Metformin and Vitamin E in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 10 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 8 to 17 years
Conditions the study is for
Fatty Liver
What is being tested?
Metformin and Vitamin E
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
173 participants
Where
10 sitesUnited States
Study dates
Sep 2005to Feb 2010
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 8 to 17 years
  • All sexes
  • No healthy volunteers
  • Child
  • 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

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

United States10 sites

  • Johns Hopkins University

    Baltimore, Maryland, 21205

  • Case Western Reserve University

    Cleveland, Ohio, 44109

  • Texas Children's Hospital

    Houston, Texas, 77030

  • Indiana University

    Indianapolis, Indiana, 46202

  • Virginia Commonwealth University

    Richmond, Virginia, 23298

  • University of California, San Diego

    San Diego, California, 92103

  • University of California, San Francisco

    San Francisco, California, 94143

  • University of Washington

    Seattle, Washington, 98195

  • St. Louis University

    St Louis, Missouri, 63110

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

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

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.

Conditions
Fatty Liver
Being tested
Metformin, Vitamin E, Matching placebo
Keywords
Non alcoholic fatty liver disease
Medical subject headings
Fatty Liver, Non-alcoholic Fatty Liver Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    500 mg, twice daily

  • Vitamin EDietary supplement

    Also called Nature Made

    400 IU, twice daily

  • Matching placeboDrug

    Twice daily

Study groups in NCT00063635
Study groupRoleWhat they receive
1Active comparatorMetformin, 500 mg, twice daily
Receives: Drug: Metformin
2Active comparatorVitamin E, 400 IU, twice daily
Receives: Dietary Supplement: Vitamin E
3Placebo comparatorMatching placebo
Receives: Drug: Matching placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: baseline and 96 weeks

Secondary outcomes (10)

  1. Change in Serum Aspartate Aminotransferase (AST)

    Measured: 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).

    Measured: 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.

    Measured: 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.

    Measured: 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.

    Measured: 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.

    Measured: baseline and 96 weeks

  7. Change in Body Mass Index

    Measured: baseline and 96 weeks

  8. Change in Serum Vitamin E Levels

    Change in alpha-Tocopherol

    Measured: 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.

    Measured: 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.

    Measured: baseline and 96 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jul 2003 (estimated)
  2. Study startSep 2005
  3. Primary completionSep 2009
  4. Study completionFeb 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
173 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00063635
Sponsor's protocol ID
NASH - PEDIATRICS (IND)
Acronym
TONIC
Status last verified
Aug 2012
First submitted
1 Jul 2003
Last updated
27 Sep 2012
Data monitoring committee
Yes

Publications

  • Hakim A, Lin KH, Schwantes-An TH, Abreu M, Tan J, Guo X, Yates KP, Lotta L, Verweij N, Loomba R, Kleiner DE, Schwimmer JB, Rotter JI, Chalasani NP. A comprehensive evaluation of candidate genetic polymorphisms in a large histologically characterized MASLD cohort using a novel framework. Hepatol Commun. 2025 May 29;9(6):e0728. doi: 10.1097/HC9.0000000000000728. eCollection 2025 Jun 1.

    PubMed 40434633

  • 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

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Metformin and Vitamin E in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 10 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Sep 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Sep 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L (time frame: baseline and 96 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00063635, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2012.

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