NCT00063232

Brief Summary

Nonalcoholic Steatohepatitis (NASH) is associated with progressive liver disease, fibrosis, and cirrhosis. Although the cause of NASH is unknown, it is often associated with obesity, type 2 diabetes, and insulin resistance. At present, there are no approved treatments for NASH patients, but an experimental approach has focused on improving their insulin sensitivity. Metformin is one of the most commonly used medications for the treatment of diabetes. The purpose of this study is to determine whether the medical problems of NASH patients, specifically liver damage, improves when their insulin sensitivity is enhanced with metformin. The study will last 3 to 5 years and will enroll up to 30 patients. Participants will undergo a complete medical examination, a series of lab tests, and a liver biopsy. They will then start taking a single 500-mg tablet of metformin once a day for 2 weeks, then the same dosage twice a day for 2 more weeks, if they tolerate the first dosage. The dosage will increase to 1,000 mg twice a day for the remaining 44 weeks of the study. After 1 year, participants will undergo a repeat medical examination and liver biopsy.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
28

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Jun 2003

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

June 1, 2003

Completed
22 days until next milestone

First Submitted

Initial submission to the registry

June 23, 2003

Completed
1 day until next milestone

First Posted

Study publicly available on registry

June 24, 2003

Completed
4.7 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 1, 2008

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 1, 2008

Completed
3.4 years until next milestone

Results Posted

Study results publicly available

July 20, 2011

Completed
Last Updated

July 20, 2011

Status Verified

June 1, 2011

Enrollment Period

4.8 years

First QC Date

June 23, 2003

Results QC Date

March 14, 2011

Last Update Submit

June 21, 2011

Conditions

Hepatitis

Keywords

InsulinObesityFatty LiverDiabetesCirrhosisMetforminInsulin ResistanceNonalcoholic SteatohepatitisHepatitisNASH

Outcome Measures

Primary Outcomes (1)

  • Change in the Histological NASH Activity Index at 48 Weeks Compared With Baseline (Number of Participants in Each Change Category)

    Patients under went liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint is a three point improvement in the histological NASH activity index with a decrease in at least two of the component scores and no worsening of fibrosis or increase in Mallory bodies.

    from baseline to 48 Weeks

Secondary Outcomes (2)

  • Change in Serum Alanine Aminotransferase (ALT) Levels From Baseline (Number of Participants in Each Change Category)

    from baseline to 48 weeks

  • Change in Insulin Sensitivity (Glucose Tolerance, Homeostatic Model Assessment of Insulin Resistence (HOMA-IR)) From Baseline

    from baseline to 48 weeks

Interventions

MetforminDRUG

After complete medical evaluation and liver biopsy, patients who qualified for therapy were started on metformin in an initial dose of 500 mg once daily. After 2 weeks, the dose was increased to 500 mg twice daily and after 4 weeks to the full dose of 1000 mg twice daily. Subsequent dose reductions were carried out based on tolerance, with particular attention to gastrointestinal upset and abdominal bloating. Patients were seen in the out-patient clinic, had a brief medical history and examination and routine blood tests at 2 and 4 weeks after enrolment and every 4 weeks thereafter. The oral and intravenous glucose tolerance tests were repeated after 40 and 44 weeks respectively and liver biopsy and imaging tests at 48 weeks. Metformin was discontinued after 48 weeks in patients without diabetes on the pre-treatment evaluation.

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Age at entry at least 18 years.
  • Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above the upper limits of normal.
  • Evidence of steatohepatitis on liver biopsy done within the previous 12 months with a NASH activity score of at least 4 (of a total possible score of 16) including a score of at least 1 each for steatosis, hepatocellular injury and parenchymal inflammation. Histological criteria of steatohepatitis include: (1) macrovesicular steatosis, (2) acinar zone 3 hepatocellular injury (ballooning degeneration), (3) parenchymal and (4) portal inflammation. Additionally helpful, but not required, features include the presence of (5) Mallory's hyaline and (6) pericellular and/or sinusoidal fibrosis that predominantly involves zone 3.
  • Written informed consent.

You may not qualify if:

  • Evidence of another form of liver disease.
  • Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).
  • Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.
  • Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy.
  • Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis.
  • Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease.
  • Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency.
  • Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.
  • Drug-induced liver disease as defined on the basis of typical exposure and history.
  • Bile duct obstruction as shown by imaging studies.
  • History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1drink per day: 7 drinks per week) in the previous one year.
  • Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or prothrombin time greater than 16 seconds.
  • Decompensated liver disease, Child-Pugh score greater than or equal to 7 points.
  • History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
  • Presence of diabetes mellitus as defined by: fasting plasma glucose of greater than or equal to 126 mg/dl on two separate occasion, or diabetic symptoms with a random plasma glucose of greater than or equal to 200 mg/dl (34).
  • +9 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

  • Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999 Mar;29(3):664-9. doi: 10.1002/hep.510290347.

    PMID: 10051466BACKGROUND

  • Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009 Jan;29(2):172-82. doi: 10.1111/j.1365-2036.2008.03869.x. Epub 2008 Oct 9.

    PMID: 18945255DERIVED

MeSH Terms

Conditions

HepatitisInsulin ResistanceObesityFatty LiverDiabetes MellitusFibrosisNon-alcoholic Fatty Liver Disease

Interventions

Metformin

Condition Hierarchy (Ancestors)

Liver DiseasesDigestive System DiseasesHyperinsulinismGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesOverweightOvernutritionNutrition DisordersBody WeightSigns and SymptomsPathological Conditions, Signs and SymptomsEndocrine System DiseasesPathologic Processes

Intervention Hierarchy (Ancestors)

BiguanidesGuanidinesAmidinesOrganic Chemicals

Results Point of Contact

Title
Jay Hoofnagle, M.D.
Organization
National Institute of Diabetes and Digestive and Kidney Diseases
hoofnaglej@extra.niddk.nih.gov
3014961333

Publication Agreements

PI is Sponsor Employee
Yes
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Masking
NONE
Purpose
TREATMENT
Sponsor Type
NIH

Study Record Dates

First Submitted

June 23, 2003

First Posted

June 24, 2003

Study Start

June 1, 2003

Primary Completion

March 1, 2008

Study Completion

March 1, 2008

Last Updated

July 20, 2011

Results First Posted

July 20, 2011

Record last verified: 2011-06

Locations

US(1)