Role of Exenatide in NASH-a Pilot Study

Nonalcoholic Fatty Liver Disease Clinical Trial

— NAFLD  

Official title:

Role of Exenatide in Treatment of NASH-a Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00650546
• Other study ID #: DK61737
• Secondary ID: U01DK061737
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: March 28, 2008
• Last updated: May 9, 2013
• Start date: August 2006
• Est. completion date: August 2010

Study information

• Verified date: May 2013
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

We hypothesize that exenatide (Byetta), a GLP-1 agonist administered subcutaneously for 24-28 weeks improves liver histology in diabetic patients with biopsy-proven NASH.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: August 2010
• Est. primary completion date: August 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Well documented NASH based on clinical and histological criteria. Liver biopsy must have been obtained within 12-months prior to initiation of the study.

• Subjects must have known diabetes (either diet controlled or only on Metformin or sulfonylureas such as glyburide or glipizide).

• Subjects must be 18 year or older.

Exclusion Criteria:

• Co-existing etiologies for chronic liver disease (hepatitis B or C, autoimmune or hemochromatosis, etc.).

• Clinical or histological evidence of cirrhosis.

• Alanine aminotransferase or aspartate aminotransferase > 300 IU/L.

• Uncontrolled diabetes (hemoglobin A1C greater than or equal to 9%).

• Insulin or TZD dependant DM.

• Known human immunodeficiency virus infection.

• Current or history of significant alcohol consumption within past 5 years. Significant alcohol consumption is defined as >20 grm/day in females and >30 grms/day in males or if alcohol consumption cannot satisfactorily be quantified.

• Serum creatinine of greater than or equal to 2 mg/dl.

• Active, serious medical disease (cardiac, renal, pulmonary, dermatologic, psychiatric illness) with likely life expectancy less 5 years.

• Current or previous malignancy with expected life expectancy less than 5-years (other than basal cell cancer of the skin).

• Use of drugs historically associated with NASH.

• Histological evidence of malignancy, 4+ iron deposition, or any other type of liver disease.

• Active substance abuse, such as alcohol,inhaled or injection drugs with the previous one year.

• Known intolerance or allergy to exenatide (Byetta).

• History of neuroglycopenia.

• Women of childbearing potential must have had a negative pregnancy test prior to starting the study and should be willing to avoid pregnancy during the study period.

• Women must not be nursing.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• (NAFLD)
• Fatty Liver
• Liver Diseases
• Nonalcoholic Fatty Liver Disease

Intervention

Drug:
• Exenatide
5 mcg twice a day titrated to 10 mcg twice a day

Locations

Country	Name	City	State
United States	Indiana University	Indianapolis	Indiana
United States	Kansas City VA Medical Center	Kansas City	Missouri
United States	Fort Sam Houston	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Indiana University	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (10)

Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005 Jul;129(1):113-21. — View Citation

Chen YE, Drucker DJ. Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem. 1997 Feb 14;272(7):4108-15. — View Citation

Eng J, Andrews PC, Kleinman WA, Singh L, Raufman JP. Purification and structure of exendin-3, a new pancreatic secretagogue isolated from Heloderma horridum venom. J Biol Chem. 1990 Nov 25;265(33):20259-62. — View Citation

Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992 Apr 15;267(11):7402-5. — View Citation

Greig NH, Holloway HW, De Ore KA, Jani D, Wang Y, Zhou J, Garant MJ, Egan JM. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia. 1999 Jan;42(1):45-50. — View Citation

Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, Taylor K, Kim D, Aisporna M, Wang Y, Baron AD. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003 Jul;88(7):3082-9. — View Citation

Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003 Oct;38(4):1008-17. — View Citation

Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004 Jan;39(1):188-96. — View Citation

Shadid S, Jensen MD. Effect of pioglitazone on biochemical indices of non-alcoholic fatty liver disease in upper body obesity. Clin Gastroenterol Hepatol. 2003 Sep;1(5):384-7. — View Citation

Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004 Mar;2(3):262-5. Erratum in: Clin Gastroenterol Hepatol. 2004 Jun;2(6):522. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement in hepatic histology after 24 weeks of treatment as determined by liver biopsies pre and post-treatment		24-28 weeks	Yes
Secondary	Changes in anthropometric measures such as weight, BMI, WHR		24-28 weeks	Yes
Secondary	Change in NAS from baseline to post-treatment		24-28 weeks	Yes
Secondary	Changes in fibrosis, steatosis, lobular inflammation, cellular ballooning and other specific changes from the histologic scoring from baseline to post-treatment		24-28 weeks	Yes
Secondary	Changes in serum aminotransferase levels		24-28 weeks	Yes
Secondary	Changes in selected cytokines and adipokine levels		24-28 weeks	Yes
Secondary	Changes in insulin resistance as measure by HOMA-IR		24-28 weeks	Yes
Secondary	Changes in systemic lipid peroxidation and malondialdehyde		24-28 weeks	Yes