NASH AMPK Exercise Dosing (AMPED) Trial

Study Overview
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Brief Summary
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There is no known cure or regulatory agency approved drug therapy for nonalcoholic fatty liver disease (NAFLD), the leading cause of liver disease worldwide, and its progressive type, NASH. This places increased importance on using exercise to treat NAFLD. While physical activity is recommended for all with NAFLD, how to best prescribe exercise as a specific treatment remains unknown, including what dose of exercise is most effective.

Detailed Description
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The mechanism explaining how exercise training benefits patients with NAFLD and NASH is unclear. The AMPK pathway may be responsible for the benefits seen with exercise training because: 1) AMPK has a liver-specific role in hepatic de novo lipogenesis and fatty acid oxidation, 2) AMPK activity is abnormally low in NAFLD and 3) NAFLD animal models demonstrate exercise changes the liver-specific AMPK pathway, leading to less liver fat accumulation by reducing lipogenesis and increasing fatty acid oxidation (This has not been studied in patients). Importantly, exercise-induced AMPK activation appears to be dose dependent.

Official Title
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NASH AMPK Exercise Dosing (AMPED) Trial

Conditions
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NAFLD

Intervention / Treatment
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* Behavioral: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-69 years Sedentary [<90 min/wk of exercise identified by the Get Active Questionnaire (GAQ) BMI >25kg/m2 Liver biopsy within six months prior to enrollment showing: NASH defined by NASH Clinical Research Network (CRN) histology scoring system (NAS) >4 and MRI-PDFF >5% and; Liver fibrosis stage 1-3 Exclusion Criteria: Active cardiac symptoms Body mass index (BMI) >45kg/m2 Cancer that is active Inability to walk >2 blocks Institutionalized/prisoner Other liver disease Pregnancy Secondary hepatic steatosis Severe comorbidities AUDIT-C questionnaire identified significant alcohol use Substance abuse/active smoking Uncontrolled diabetes (changes in drug dosing over previous three months or A1c >9%) GAQ response indicates exercise may be unsafe.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise Arm 1<br>Aerobic exercise will be completed by walking, jogging or running or by using cardio equipment (e.g., recumbent bike). Each session will begin with a warm-up with walking and dynamic exercises. A 5-min walking cool down will end the session. The training dose for this arm is 750 MET-min/wk for 3-5 days per week, 22-45 minutes per session at a moderate to vigorous intensity. The exercise can be completed in person or virtually. | Behavioral: Exercise<br>* Aerobic exercise can be completed by walking, jogging or running or by using cardio equipment (e.g., recumbent bike). Each session will begin with a warm-up with walking (30-40% target HR for 5-min) and dynamic exercises (knee-to-chest, 10-yd lateral shuffle, bent over twist, calf sweeps, leg swings). A 5-min walking cool down will end the session (30-40% target HR).<br>* Other names: Physical activity;|
| Experimental: Exercise Arm 2<br>Aerobic exercise will be completed by walking, jogging or running or by using cardio equipment (e.g., recumbent bike). Each session will begin with a warm-up with walking and dynamic exercises. A 5-min walking cool down will end the session. The training dose for this arm is 1,000 MET-min/wk for 3-5 days per week, 30-60 minutes per session at a moderate to vigorous intensity. The exercise can be completed in person or virtually. | Behavioral: Exercise<br>* Aerobic exercise can be completed by walking, jogging or running or by using cardio equipment (e.g., recumbent bike). Each session will begin with a warm-up with walking (30-40% target HR for 5-min) and dynamic exercises (knee-to-chest, 10-yd lateral shuffle, bent over twist, calf sweeps, leg swings). A 5-min walking cool down will end the session (30-40% target HR).<br>* Other names: Physical activity;|
| No Intervention: Standard of Care<br>This group will receive best NASH clinical practices counseling at baseline and end-of-trial in accordance with NAFLD clinical practice guidelines and be reinforced by handouts from the American Liver Foundation. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver fat | Degree of liver fat change as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) across different doses of exercise in patients with NASH. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hip/waist circumference | change in Hip/waist circumference | 16 weeks | 
| Body mass index | change in body mass index | 16 weeks | 
| change in body composition | change in body composition as measured by Dual-energy X-ray absorptiometry (DXA scan) across different doses of exercise in patients with NASH. | 16 weeks | 
| Insulin | change in insulin | 16 weeks | 
| Hemoglobin A1c | change in Hemoglobin A1c | 16 weeks | 
| change in cholesterol and triglycerides levels (dyslipidemia) | change in cholesterol and triglycerides levels (dyslipidemia) as measured by clinical labs. | 16 weeks | 
| Interleukin-6 | change in Interleukin-6 | 16 weeks | 
| c-reactive protein | change in c-reactive protein | 16 weeks | 
| Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score | change in NAFLD Fibrosis Score which estimates amount of scarring in the liver based on several laboratory tests. NAFLD Score Correlated Fibrosis Severity < -1.455 F0-F2 -1.455 - 0.675 Indeterminant score > 0.675 F3-F4 Fibrosis Severity Scale F0 = no fibrosis F1 = mild fibrosis F2 = moderate fibrosis F3 = severe fibrosis F4 = cirrhosis | 16 weeks | 
| Enhance liver fibrosis (ELF) test | change in Enhance liver fibrosis (ELF) test | 16 weeks | 
| TIMP-1 | change in TIMP-1 | 16 weeks | 
| ProC3 | change in ProC3 | 16 weeks | 
| Adiponectin | change in Adiponectin | 16 weeks | 
| Fibroblast Growth Factor (FGF) 21 | change in Fibroblast Growth Factor (FGF) 21 | 16 weeks | 
| Change in stiffness of the liver | Change in stiffness of the liver as measured by the technique of transient elastography, a non-invasive test to stage the severity of liver disease. | 16 weeks | 
| Liver glycogen | change in liver glycogen | 16 weeks |