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| ID | Type | Description | Link |
|---|---|---|---|
| H80-MC-X006 | Other Identifier | UC Davis |
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Lack of recruitment
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| Name | Class |
|---|---|
| Amylin Pharmaceuticals, LLC. | INDUSTRY |
| Eli Lilly and Company | INDUSTRY |
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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common complications of type 2 diabetes and leading causes of liver disease in the US and Europe. The prevalence of NAFLD and NASH are expected to become a major cause of liver disease related deaths and liver transplantation. Currently, there are no specific therapies that alter the natural history of NAFLD.Preliminary evidence suggests that exenatide (Byetta®) may have several beneficial direct and indirect effects on NAFLD and liver lipid metabolism.
Preliminary evidence suggests that exenatide (Byetta®) may have several beneficial direct and indirect effects on NAFLD and liver lipid metabolism. Ad hoc analysis of phase III studies has shown that exenatide treatment is associated with improvement and normalization of alanine aminotransferase (ALT), a marker of liver injury, and that this effect is most pronounced in those with the greatest weight loss. In addition, treatment of leptin deficient ob/ob mice with exenatide reduced weight, liver lipid content, serum ALT and liver lipid peroxidation. Additional evidence suggests that the effects of exenatide on the liver are not simply a result of weight loss, but rather due to direct effects on the liver. Hepatocytes express GLP-1 receptors that are responsive to both GLP-1 and exenatide. Furthermore, exenatide treatment of ob/ob mice or isolated hepatocytes reduces mRNA for stearoyl-CoA desaturase-1 (SCD-1) and SREBP-1c, which would be expected to reduce DNL.
Based upon this data, we hypothesize that exenatide treatment of diabetic patients with NAFLD and NASH will reduce liver injury through multiple mechanisms including weight reduction associated with exenatide, improved lipid metabolism by decreased expression of hepatic genes involved in DNL and reduction of adipokines and cytokines associated with severe NASH. This study is aimed to address the potential safety and efficacy of exenatide in the treatment of NAFLD and test these hypotheses.
This will be an open label, single-arm, non-comparative trial of 20 patients with type 2 diabetes and NAFLD treated with exenatide for 6 months with the following specific aims to be assessed:
Determine the safety and efficacy of 24 weeks of exenatide treatment in diabetic patients with Non-Alcoholic Fatty Liver Disease (NAFLD) Efficacy will be measured by changes in serum ALT (primary endpoint) and liver histology.
Characterize the effects of exenatide on serum levels of adipokines and inflammatory cytokines including adiponectin, leptin and TNF- in NAFLD patients.
Compare the hepatic expression of SCD1, SREBP-1c and PPAR- mRNA in NAFLD patients pre- and post-treatment with exenatide.
Establish the effects of exenatide on post-prandial lipid metabolism.
Determine the effects of exenatide on liver fibrosis in NAFLD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exenatide | Experimental | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| exenatide | Drug | Subjects meeting the inclusion criteria will be treated with exenatide 5 µg BID s.c. for 3-7 days, followed by 10 µg BID s.c. daily to week 24 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy | 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis | Steatosis was grades on a scale of 0 (< 5%); 1 (5%- 33%); 2 (> 33% - 66%); and 3 (> 66%). Inflammation was graded on a scale of 0 (No foci); 1 (< 2 foci per 200 X field); 2 (2-4 foci per 200 X field); and 3 (>4 foci per 200 X field) Fibrosis was graded on a scale of 0 (None); 1 (Mild periportal or perisinusoidal); 2 (Moderate periportal or perisinusoidal); 3 (Bridging fibrosis); and 4 (cirrhosis) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christopher L Bowlus, MD | University of California, Davis | Principal Investigator |
| Lars Berglund, MD, PhD | University of California, Davis | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Davis Medical Center | Sacramento | California | 95817 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17379054 | Background | Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG, Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007 Jan;29(1):139-53. doi: 10.1016/j.clinthera.2007.01.015. |
| Label | URL |
|---|---|
| American Liver Foundation | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Exenatide | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 exenatide: Subjects meeting the inclusion criteria will be treated with exenatide 5 µg BID s.c. for 3-7 days, followed by 10 µg BID s.c. daily to week 24 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Exenatide | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 exenatide: Subjects meeting the inclusion criteria will be treated with exenatide 5 µg BID s.c. for 3-7 days, followed by 10 µg BID s.c. daily to week 24 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy | Posted | Number | IU | 24 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Exenatide | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 exenatide: Subjects meeting the inclusion criteria will be treated with exenatide 5 µg BID s.c. for 3-7 days, followed by 10 µg BID s.c. daily to week 24 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christopher L. Bowlus, MD | University of California Davis Medical Center | 916-734-8986 | chris.bowlus@ucdmc.ucdavis.edu |
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| ID | Term |
|---|---|
| D048909 | Diabetes Complications |
| D005234 | Fatty Liver |
| D065626 | Non-alcoholic Fatty Liver Disease |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D004700 | Endocrine System Diseases |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D044882 | Glucose Metabolism Disorders |
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| ID | Term |
|---|---|
| D000077270 | Exenatide |
| ID | Term |
|---|---|
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D014688 | Venoms |
| D045424 | Complex Mixtures |
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|
| 24 weeks |
| Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes | 24 weeks |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Alanine aminotransferase | Mean | Full Range | IU |
|
| Glucose | Mean | Full Range | mg/dL |
|
| Cholesterol | Mean | Full Range | mg/dL |
|
| HDL | Mean | Full Range | mg/dL |
|
| Triglyceride | Mean | Full Range | mg/dL |
|
| hsCRP | Mean | Full Range | mg/L |
|
| Weight | Mean | Full Range | kg |
|
| HbA1c | Mean | Full Range | % |
|
|
| Secondary | Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis | Steatosis was grades on a scale of 0 (< 5%); 1 (5%- 33%); 2 (> 33% - 66%); and 3 (> 66%). Inflammation was graded on a scale of 0 (No foci); 1 (< 2 foci per 200 X field); 2 (2-4 foci per 200 X field); and 3 (>4 foci per 200 X field) Fibrosis was graded on a scale of 0 (None); 1 (Mild periportal or perisinusoidal); 2 (Moderate periportal or perisinusoidal); 3 (Bridging fibrosis); and 4 (cirrhosis) | Posted | Number | units on a scale | 24 weeks |
|
|
|
| Secondary | Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes | Posted | Number | adverse events | 24 weeks |
|
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| 0 |
| 1 |
| 0 |
| 1 |
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| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D014118 |
| Toxins, Biological |
| D001685 | Biological Factors |
| Title | Measurements |
|---|---|
|