NASH Fitness Intervention in Thrombosis Trial (NASHFit)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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NASH Fitness Intervention in Thrombosis Trial (NASHFit)

Conditions
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Liver Diseases, Blood Disorder, Digestive System Disease

Intervention / Treatment
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* Behavioral: Aerobic Exercise


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: Standard of care Aerobic exercise
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care<br>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<br>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<br>* 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.<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, NASH