Clinical trial NCT03518294: NASH Fitness Intervention in Thrombosis Trial (NASHFit)
Official title: NASH Fitness Intervention in Thrombosis Trial (NASHFit)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Liver Diseases
Blood Disorder
Digestive System Disease
Keywords: NAFLD
NASH
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
First posted: 2018-05-08
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Standard of care Aerobic exercise
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: PAI-1 Level
timeFrame: 5 months
Secondary outcomes:
measure: Change in Von Williebrand Factor (vWF)
timeFrame: 5 months
measure: Change in Protein S
timeFrame: 5 months
measure: Change in Factor VIII
timeFrame: 5 months
measure: Change in Fibrinogen
timeFrame: 5 months
measure: Change in Antithrombin
timeFrame: 5 months
measure: Change in Protein C
timeFrame: 5 months
measure: Change in Adiponectin
timeFrame: 5 months
measure: Patatin Like Phospholipase-3 (PNPLA3) rs738409 Polymorphism
timeFrame: 5 months
measure: Change in PAI-1 Stratified by Fibrosis Stage
timeFrame: 5 months
measure: Change in % Hepatic Fat
timeFrame: 5 months
measure: Health Related Quality of Life (HRQOL) Change
timeFrame: 5 months (20 weeks)
Other outcomes:
Locations:
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
Study officials:
affiliation: Milton S. Hershey Medical Center
name: Jonathan Stine, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.