NAFLD: Role of Exenatide in NASH-a Pilot Study

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00650546
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 8
• Locations: 3
• Arm: 1
• Duration (Months): 48
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Fatty Liver Disease	Drug: Exenatide	Phase 2/Phase 3

Detailed Description

Eight adult patients with known type 2 DM(Diabetic) and biopsy-proven NAFLD were treated with 5-10 mcg subcutaneous exenatide for 28 weeks. Liver histology was assessed using the NAFLD Activity Score (NAS) prior to therapy and after 28 weeks of therapy. We used the following criteria to define our primary outcome: (i) no worsening of fibrosis score, (ii) improved score by at least one point in hepatocyte ballooning, (iii) either (a) improvement in NAS by 2 or more points spread across at least two of the three NAS components, or (b) post-treatment NAS equal or greater than 3.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Role of Exenatide in Treatment of NASH-a Pilot Study
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A pre treatment NAS score liver biopsy score pre treatment with exenatide 5 micrograms SQ (sub-cutaneous) twice a day titrated to 10 mcg SQ twice a day as tolerated	Drug: Exenatide; 5 mcg twice a day titrated to 10 mcg twice a day; Other Names: Byetta

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Improvement in Liver Histology After Treatment With Exenatide [between baseline and 24-28 weeks after initiating treatment]

   Number of patients with liver histology improved with exenatide. The improvement of liver histology was defined as (1) no worsening of the fibrosis score, (11) improved score by at least one point in hepatocyte ballooning, and (111) either (a) improvement in NAS (NAFLD Activity Score) by two points spread across as least two of the three NAS components, or by (B)post-treatment NAS<3.

2. Change in NAS [Between baseline and 28 weeks of treatment with exenatide, sub q, 5-10 mcq.]

   The NAFLD Activity Score (NAS) is an underweight sum of steatosis (score 0-3), inflammation (score 0-3), ballooning scores (0-2). The NAS can range from 0-8 with the higher score indicating more aggressive disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University	Indianapolis	Indiana	United States	46202
2	Kansas City VA Medical Center	Kansas City	Missouri	United States
3	Fort Sam Houston	San Antonio	Texas	United States

Sponsors and Collaborators

• Indiana University
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Naga Chalasani, MD, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT00650546
• Other Study ID Numbers: DK61737; U01DK061737
• First Posted: Apr 1, 2008
• Last Update Posted: Apr 11, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Indiana University: Non-alcoholic steatohepatitis; NASH
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Exenatide

Study Results

Participant Flow

Recruitment Details	2 recruitment sites: Department of Gastroenterology, San Antonio Uniformed Services Health Consortium, San Antonio, Texas, USA. Indiana University School of Medicine, Indianapolis, IN, USA
Pre-assignment Detail	This was a single arm, open label study. Only study group received exenatide treatment. Eight adult patients with known type 2 DM and biopsy-proven NAFLD were treated with 5-10mcg subcutaneous exenatide for 28 week.All eight patients were started on exenatide 5 mcg injections twice a day and the dose was increased to 10 mcg injections twice a day

Arm/Group Title	Exenatide Group
Arm/Group Description	Exenatide 5 micrograms SQ twice a day titrated to 10 mcg SQ twice a day as tolerated Exenatide : 5 mcg twice a day titrated to 10 mcg twice a day
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Open-labeled Prospective Case Series
Arm/Group Description	Exenatide 5 micrograms SQ twice a day titrated to 10 mcg SQ twice a day as tolerated Exenatide: 5 mcg twice a day titrated to 10 mcg twice a day
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	4 50%
Male	4 50%
Number of participants who had NAFLD Activity Score (NAS) pre/post 24-28 wks. after treatment (participants) [Number]
Number [participants]	8 100%
NAS score (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	4

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Improvement in Liver Histology After Treatment With Exenatide
Description	Number of patients with liver histology improved with exenatide. The improvement of liver histology was defined as (1) no worsening of the fibrosis score, (11) improved score by at least one point in hepatocyte ballooning, and (111) either (a) improvement in NAS (NAFLD Activity Score) by two points spread across as least two of the three NAS components, or by (B)post-treatment NAS<3.
Time Frame	between baseline and 24-28 weeks after initiating treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment With Exenatide
Arm/Group Description	eight adult patients with known type 2 DM and biopsy proven NAFLD
Measure Participants	8
Number [participants]	8 100%

2. Primary Outcome

Title	Change in NAS
Description	The NAFLD Activity Score (NAS) is an underweight sum of steatosis (score 0-3), inflammation (score 0-3), ballooning scores (0-2). The NAS can range from 0-8 with the higher score indicating more aggressive disease.
Time Frame	Between baseline and 28 weeks of treatment with exenatide, sub q, 5-10 mcq.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individuals Who Recieved Treatment With Exenatide
Arm/Group Description	change of NAS score in eight adult patients with known type 2 DM and biopsy proven NAFLD after treatment with exenatide
Measure Participants	8
Mean (Standard Deviation) [units on a scale]	-1.5 (1.66)

Adverse Events

Time Frame	28 weeks
Arm/Group Title	Exenatide Group
Arm/Group Description	Exenatide 5 micrograms SQ twice a day titrated to 10 mcg SQ twice a day as tolerated Exenatide : 5 mcg twice a day titrated to 10 mcg twice a day
All Cause Mortality
	Exenatide Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Exenatide Group
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Exenatide Group
	Affected / at Risk (%)	# Events
Total	2/8 (25%)
Gastrointestinal disorders
abdominal pain along with nausea	2/8 (25%)	2

Limitations/Caveats

As a case series our findings are limited by a control group and a small number of subjects enrolled. These limitations are tempered by the single expert hepatologist and the stringent definitions for histological improvement, ((primary end point)..

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.