NASH AMPK Exercise Dosing (AMPED) Trial (AMPED)

• ClinicalTrials.gov Identifier: NCT04987879
• Recruitment Status: Recruiting
• First Posted: August 3, 2021
• Last Update Posted: November 15, 2022
• Sponsor: Milton S. Hershey Medical Center
• Information provided by (Responsible Party): Jonathan Stine, Milton S. Hershey Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
NAFLD	Behavioral: Exercise	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: NASH AMPK Exercise Dosing (AMPED) Trial
• Actual Study Start Date: August 30, 2022
• Estimated Primary Completion Date: October 1, 2025
• Estimated Study Completion Date: June 1, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Exercise Arm 1; 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; 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).; Other Name: Physical activity
Experimental: Exercise Arm 2; 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; 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).; Other Name: Physical activity
No Intervention: Standard of Care; 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.

Outcome Measures

Primary Outcome Measures :

1. Change in liver fat [ Time Frame: 16 weeks ]
   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.

Secondary Outcome Measures :

1. Hip/waist circumference [ Time Frame: 16 weeks ]
   change in Hip/waist circumference
2. Body mass index [ Time Frame: 16 weeks ]
   change in body mass index
3. change in body composition [ Time Frame: 16 weeks ]
   change in body composition as measured by Dual-energy X-ray absorptiometry (DXA scan) across different doses of exercise in patients with NASH.
4. Insulin [ Time Frame: 16 weeks ]
   change in insulin
5. Hemoglobin A1c [ Time Frame: 16 weeks ]
   change in Hemoglobin A1c
6. change in cholesterol and triglycerides levels (dyslipidemia) [ Time Frame: 16 weeks ]
   change in cholesterol and triglycerides levels (dyslipidemia) as measured by clinical labs.
7. Interleukin-6 [ Time Frame: 16 weeks ]
   change in Interleukin-6
8. c-reactive protein [ Time Frame: 16 weeks ]
   change in c-reactive protein
9. Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score [ Time Frame: 16 weeks ]

   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

10. Enhance liver fibrosis (ELF) test [ Time Frame: 16 weeks ]
    change in Enhance liver fibrosis (ELF) test
11. TIMP-1 [ Time Frame: 16 weeks ]
    change in TIMP-1
12. ProC3 [ Time Frame: 16 weeks ]
    change in ProC3
13. Adiponectin [ Time Frame: 16 weeks ]
    change in Adiponectin
14. Fibroblast Growth Factor (FGF) 21 [ Time Frame: 16 weeks ]
    change in Fibroblast Growth Factor (FGF) 21
15. Change in stiffness of the liver [ Time Frame: 16 weeks ]
    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. Liver glycogen [ Time Frame: 16 weeks ]
    change in liver glycogen

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 69 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age 18-69 years
• Sedentary [<90 min/wk of exercise identified by the Get Active Questionnaire (GAQ)
• BMI >30kg/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.

Contacts and Locations

Contacts

Contact: Gloriany Rivas, BA; 7175310003 ext 320223; grivas@pennstatehealth.psu.edu

Locations

United States, Pennsylvania

Penn State Hershey Medical Center; Recruiting

Hershey, Pennsylvania, United States, 17033

Contact: Gloriany Rivas, MPH 717-531-0003 ext 320223 grivas@pennstatehealth.psu.edu

Principal Investigator: Jonathan G Stine, MD

Sponsors and Collaborators

Milton S. Hershey Medical Center

Investigators

• Principal Investigator: Jonathan G Stine; Milton S. Hershey Medical Center

More Information

• Responsible Party: Jonathan Stine, Director of Research, Penn State Liver Center, Assosiate Professor of Medicine and Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT04987879
• Other Study ID Numbers: STUDY00018280
• First Posted: August 3, 2021
• Last Update Posted: November 15, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No