NASH Fitness Intervention in Thrombosis Trial (NASHFit)

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States. The most advanced forms of NAFLD are associated with increased liver-related mortality and lower overall survival. The current standard of care for NAFLD is lifestyle changes through diet and exercise. The human genome and regulation of gene expression is influenced by physical activity. NAFLD is a prothrombotic state with derangements in all three phases of hemostasis leading to clinically important clotting events. Exercise can improve coagulation in healthy persons. In this proposal, we seek to begin a line of work to answer the question "Can lifestyle changes effectively mitigate the increased risk of clotting in patients with NAFLD?" focusing initially on the at-risk population genetically susceptible to advanced disease.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Digestive System Disease; Blood Disorder
• Intervention / Treatment: Behavioral: Aerobic Exercise

Detailed Description

Often comorbid with obesity, nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States affecting 75-100 million adults, of which 15-20 million have the more severe variant nonalcoholic steatohepatitis (NASH). Conservative estimates project a doubling in NASH by 2025.The most advanced forms of NAFLD are associated with increased liver-related mortality and lower overall survival. The most effective treatment for NAFLD remains adopting healthy dietary and exercise patterns, however NAFLD patients are among the least physically active individuals. Predicting exercise behavior on an individual level is highly complex due to differing motivation, physiologic response to and subjective experience of exercise as well as emerging genetic evidence. The human genome and regulation of gene expression is influenced by physical activity. Patatin like phospholipase-3 (PNPLA3) rs738409 polymorphism (GG, GC and CC genotypes) plays a crucial role in the development of NAFLD. The GG genotype is both associated with advanced NAFLD, and predicts response to physical activity. Patients with NASH have extensive extrahepatic disease and are hypercoagulable. NASH is a prothrombotic state with fibrinolytic dysfunction through elevated plasminogen activator inhibitor (PAI-1), an independent risk factor for venous thromboembolism (VTE). Consequently, patients with NASH are predisposed to VTE; the risk of portal vein thrombosis (PVT) in NASH is 210% greater than in other liver disease. NASH patients are also at increased risk for pulmonary embolism (PE) and deep vein thrombosis (DVT).The most advanced forms of NASH have the greatest thrombotic risk. While studies observe that change in diet, weight and physical activity patterns improve NASH, it is not clear whether these lifestyle changes also reduce the elevated clot risk, however, moderate-intensity exercise leads to improved fibrinolysis in healthy persons.The NASHFit study is being done to find out if exercise is beneficial in decreasing the risk of clotting problems in patients with NASH. Exercise has been shown to decrease markers of clotting in healthy individuals as well as in those with cardiovascular disease.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria Adults age >=18 or <70 years Liver biopsy <= 6months prior to enrollment Biopsy proven NASH(79)

Lack of secondary causes of hepatic fat accumulation:

Significant alcohol consumption (<21 drinks/week for men and <14 drinks/week for women) Chronic hepatitis C Wilson disease Lipodystrophy Parenteral nutrition Long-term use of steatogenic medications (mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen, corticosteroids) Monogenic hereditary disorders

Exclusion Criteria >90 minutes/week of at least moderate intensity exercise over the previous three months Pregnancy BMI <18 or >40 kg/m2(16) Uncontrolled diabetes (changes in medication dosing over the previous three months or hemoglobin A1c >9%)(12) Active cardiac symptoms Severe medical comorbidities/psychiatric illness Decompensated cirrhosis (history of esophageal varices, ascites or hepatic encephalopathy) Abdominal hernia Cancer with life expectancy <6 months MRI contraindications (severe claustrophobia, implanted ferrous metal) Other liver disease (positive hepatitis B surface antigen, antinuclear antibody titer >1:160) Active weight-loss program participation or weight-loss supplement use Active substance abuse/smoking Inability to provide informed consent Institutionalized/prisoner Inability to walk > 2 blocks or ¼ mile. Physical Activity Readiness Questionnaire (PAR-Q) score >=1 at the discretion of the study PI

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of Care; Subjects in the control condition will be instructed to continue their medical care at the discretion of their treating medical professional. They will be informed to maintain their current physical activity level. Weekly phone calls will be performed by study personnel to ensure adherence to the protocol (no changes in activity). Subjects will report to Penn State on a monthly basis for anthropometric assessment to confirm their self-reports and study investigators will perform and interim history and physical examination at that time.
Experimental: Aerobic Exercise; Subjects in the aerobic exercise group will be supervised to exercise 30 minutes, 5 times per week at a moderate intensity. Formal exercise instruction and supervision will be provided by ACSM certified fitness professionals at the Penn State University Fitness Center. Aerobic exercise can be completed on either the treadmill, exercise bike, rowing machine or the elliptical machine.	Behavioral: Aerobic Exercise; Subjects in the aerobic exercise group will be supervised to exercise 30 minutes, 5 times per week at a moderate intensity. Formal exercise instruction and supervision will be provided by ACSM certified fitness professionals at the Penn State University Fitness Center. Aerobic exercise can be completed on either the treadmill, exercise bike, rowing machine or the elliptical machine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAI-1 Level	Change in fibrinolysis as indicated by PAI-1 level was calculated by taking the difference of measurements at baseline and 5 months.	5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Von Williebrand Factor (vWF)	Change in vWF was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Protein S	Change in protein S was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Factor VIII	Change in factor VIII was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Fibrinogen	Change in fibrinogen was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Antithrombin	Change in antithrombin was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Protein C	Change in protein C was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Change in Adiponectin	Change in adipontin was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Patatin Like Phospholipase-3 (PNPLA3) rs738409 Polymorphism	Patatin like phospholipase-3 (PNPLA3) rs738409 polymorphism genotyping subjects (GG, GC and CC genotypes)	5 months
Change in PAI-1 Stratified by Fibrosis Stage	Change is the difference between measurements at baseline and 5 months	5 months
Change in % Hepatic Fat	Change in % hepatic fat was calculated by taking the difference of measurements at baseline and 5 months.	5 months
Health Related Quality of Life (HRQOL) Change	Data was collected at baseline and at 5 months to assess changes in domains of health. PROMIS-29 Profile v2.1 (Physical function & pain interference) PROMIS Bank v2.0 - Instrumental Support (Social Support) Scores are reported as standardized T-score metrics derived from population means, with a mean of 50 and standard deviation of 10. The minimum is 0 and the maximum is 90. A higher score for fatigue, pain intensity, pain interference, sleep disturbance, anxiety and depression means a worse outcome. A higher score for physical function and social roles means a better outcome.	5 months (20 weeks)

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Investigators: Principal Investigator: Jonathan Stine, MD, Milton S. Hershey Medical Center

Publications and helpful links

General Publications

• Motz V, Faust A, Dahmus J, Stern B, Soriano C, Stine JG. Utilization of a Directly Supervised Telehealth-Based Exercise Training Program in Patients With Nonalcoholic Steatohepatitis: Feasibility Study. JMIR Form Res. 2021 Aug 17;5(8):e30239. doi: 10.2196/30239.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2018
• Primary Completion (Actual): March 24, 2021
• Study Completion (Actual): March 24, 2021

Study Registration Dates

• First Submitted: April 23, 2018
• First Submitted That Met QC Criteria: May 4, 2018
• First Posted (Actual): May 8, 2018

Study Record Updates

• Last Update Posted (Actual): February 3, 2023
• Last Update Submitted That Met QC Criteria: January 31, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: NAFLD; NASH
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Liver Diseases; Hematologic Diseases; Gastrointestinal Diseases; Digestive System Diseases; Thrombosis
• Other Study ID Numbers: 8507

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No