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Improving Insulin Resistance To Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study

Primary Purpose

Non-alcoholic Fatty Liver Disease (NAFLD)

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Metformin
Lifestyle modifications
Fibroscan device (Echosens)
Sponsored by
Northwell Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-alcoholic Fatty Liver Disease (NAFLD)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • subjects between ages 18-80
  • diagnosed with NAFLD by alanine aminotransferase
  • (ALT) levels >1.5x the upper limit of normal with an otherwise nondiagnostic hepatic serology workup, ultrasound evidence, and/or histologically confirmed NAFLD within the past 1 year.
  • The upper limit of normal for ALT will be defined as 35 U/L in males and 19 U/L in females

Exclusion Criteria:

  • A prior history of diabetes
  • Failure to meet criteria for HbA1C screening
  • Evidence of hepatic disorders
  • Use of insulin or oral hypoglycemic agents
  • eGFR <30
  • Blood transfusion within past 3 months
  • Steroid use in the past 6 months
  • Excessive alcohol use (more than 20g per day in women and more than 30g per day in men)
  • Acute or unstable congestive heart failure
  • Age >80 years old
  • Lactic acidosis
  • Inability to consent due to cognitive impairment.
  • Pregnancy

Sites / Locations

  • North Shore Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Metformin

Lifestyle modification

Arm Description

Metformin is being compared to exercise and diet modifications. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe

The researchers are interested in learning if the addition of metformin to lifestyle modifications is more helpful in treating participants condition or disorder. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe

Outcomes

Primary Outcome Measures

Improvement in NAFLD as measured by ALT levels
The primary endpoint variable is the improvement in NAFLD after 12 months of treatment, as measured by the change in ALT levels from baseline to the end of a one year follow-up. A decrease of at least 25% from baseline will be considered a clinically relevant response.

Secondary Outcome Measures

Incidence of metabolic syndrome (insulin resistance)
The study will be using measurements of BMI, waist circumference, blood pressure, lipids and fasting blood glucose levels to assess insulin resistance.
Incidence of NAFLD fibrosis scores after 12 months of treatment as measured by Fibroscan
A NAFLD Fibrosis Score (28), a noninvasive scoring system for liver fibrosis in patients with NAFLD, can be calculated and potentially used to assess for histologic improvement with metformin, which thus far has never been assessed.

Full Information

First Posted
May 14, 2015
Last Updated
July 26, 2017
Sponsor
Northwell Health
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1. Study Identification

Unique Protocol Identification Number
NCT02457286
Brief Title
Improving Insulin Resistance To Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study
Official Title
Improving Insulin Resistance to Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Withdrawn
Why Stopped
patients do not want to participate
Study Start Date
June 2015 (Actual)
Primary Completion Date
July 2017 (Actual)
Study Completion Date
July 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwell Health

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Metformin is being compared to exercise and diet modifications. The researchers are interested in learning if the addition of metformin to lifestyle modifications is more helpful in treating the condition or disorder. Although metformin is FDA approved to treat type 2 diabetes, it is not FDA approved for the treatment of Non-alcoholic fatty liver (NAFLD) and is considered investigational for the purpose of this study.
Detailed Description
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and a common cause of unexplained mildly elevated serum aminotransferase levels. NAFLD, initially felt to be benign, is now known to potentially progress to cirrhosis and its complications, including the development of liver cancer. NAFLD is strongly correlated with Type 2 Diabetes, insulin resistance, and the metabolic syndrome (1-6). It is hypothesized that the pathogenesis of hepatic injury in NAFLD is due to insulin resistance and the oxidative stress associated with obesity and metabolic syndrome (7). No adequate medical treatment has been shown to be effective for the treatment of NAFLD. Several studies (8-22) have evaluated the effect of metformin in patients with NAFLD in relation to insulin resistance, Homeostatic Model Assessment Insulin Resistance Index (HOMA-IR) values, aminotransferase levels, liver morphology, and histological improvement with treatment. These studies however have shown discrepant results with relation to aminotransferase levels and only a few studies have been able to evaluate histological improvement with follow-up biopsies. There have been no studies focusing specifically on the pre-diabetic population. These patients who are at an increased risk of progressing to diabetes may exhibit a different response to treatment with metformin than non-diabetic or diabetic patients. All the studies support the fact that metformin has a beneficial effect on improving insulin resistance and decreasing the incidence of metabolic syndrome, but there is no consensus thus far on its influence on NAFLD. The majority of published studies were limited by small sample size. Randomized controlled trials with adequate sample size and of longer duration are needed as well as studies assessing endpoints such as liver morphology and histology. The results of this pilot study are significant in that metformin may be a relatively safe and inexpensive way, in addition to lifestyle modifications, to treat NAFLD. The results of this pilot study will pave the way for the larger power, longer duration study required to answer this question.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Fatty Liver Disease (NAFLD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
Metformin is being compared to exercise and diet modifications. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe
Arm Title
Lifestyle modification
Arm Type
Experimental
Arm Description
The researchers are interested in learning if the addition of metformin to lifestyle modifications is more helpful in treating participants condition or disorder. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Intervention Description
Although metformin is FDA approved to treat type 2 diabetes, it is not FDA approved for the treatment of NAFLD and is considered investigational for the purpose of this study.
Intervention Type
Behavioral
Intervention Name(s)
Lifestyle modifications
Intervention Description
Recommendations for lifestyle modification will be based on the Diabetes Prevention Program 2002 (26) and will include recommendations for greater than 150 minutes of physical activity weekly, referrals to group and/or individualized sessions with nutritionists and/or lifestyle coaches as well as educational materials
Intervention Type
Device
Intervention Name(s)
Fibroscan device (Echosens)
Intervention Description
This study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity.
Primary Outcome Measure Information:
Title
Improvement in NAFLD as measured by ALT levels
Description
The primary endpoint variable is the improvement in NAFLD after 12 months of treatment, as measured by the change in ALT levels from baseline to the end of a one year follow-up. A decrease of at least 25% from baseline will be considered a clinically relevant response.
Time Frame
12 Months
Secondary Outcome Measure Information:
Title
Incidence of metabolic syndrome (insulin resistance)
Description
The study will be using measurements of BMI, waist circumference, blood pressure, lipids and fasting blood glucose levels to assess insulin resistance.
Time Frame
12 months
Title
Incidence of NAFLD fibrosis scores after 12 months of treatment as measured by Fibroscan
Description
A NAFLD Fibrosis Score (28), a noninvasive scoring system for liver fibrosis in patients with NAFLD, can be calculated and potentially used to assess for histologic improvement with metformin, which thus far has never been assessed.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: subjects between ages 18-80 diagnosed with NAFLD by alanine aminotransferase (ALT) levels >1.5x the upper limit of normal with an otherwise nondiagnostic hepatic serology workup, ultrasound evidence, and/or histologically confirmed NAFLD within the past 1 year. The upper limit of normal for ALT will be defined as 35 U/L in males and 19 U/L in females Exclusion Criteria: A prior history of diabetes Failure to meet criteria for HbA1C screening Evidence of hepatic disorders Use of insulin or oral hypoglycemic agents eGFR <30 Blood transfusion within past 3 months Steroid use in the past 6 months Excessive alcohol use (more than 20g per day in women and more than 30g per day in men) Acute or unstable congestive heart failure Age >80 years old Lactic acidosis Inability to consent due to cognitive impairment. Pregnancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Bernstein, MD
Organizational Affiliation
Northwell Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
North Shore Hospital
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22374640
Citation
Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, Hardies J, Cusi K. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care. 2012 Apr;35(4):873-8. doi: 10.2337/dc11-1849. Epub 2012 Feb 28.
Results Reference
result
PubMed Identifier
19533014
Citation
Arase Y, Suzuki F, Ikeda K, Kumada H, Tsuji H, Kobayashi T. Multivariate analysis of risk factors for the development of type 2 diabetes in nonalcoholic fatty liver disease. J Gastroenterol. 2009;44(10):1064-70. doi: 10.1007/s00535-009-0091-1. Epub 2009 Jun 17.
Results Reference
result
PubMed Identifier
15895401
Citation
Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005 Jul;42(1):44-52. doi: 10.1002/hep.20734.
Results Reference
result
PubMed Identifier
19293782
Citation
Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009 Apr;104(4):861-7. doi: 10.1038/ajg.2009.67. Epub 2009 Mar 17.
Results Reference
result
PubMed Identifier
18839053
Citation
Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol. 2009 Jun;46(2):113-8. doi: 10.1007/s00592-008-0067-2. Epub 2008 Oct 7.
Results Reference
result
PubMed Identifier
18366995
Citation
Lidofsky SD. Nonalcoholic fatty liver disease: diagnosis and relation to metabolic syndrome and approach to treatment. Curr Diab Rep. 2008 Feb;8(1):25-30. doi: 10.1007/s11892-008-0006-1.
Results Reference
result

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Improving Insulin Resistance To Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study

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