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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care | No Intervention | 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. | |
| Aerobic Exercise | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aerobic Exercise | Behavioral | 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. |
| 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 |
| 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. |
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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
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan Stine, MD | Milton S. Hershey Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Penn State Hershey Medical Center | Hershey | Pennsylvania | 17033 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40900364 | Derived | Channapragada T, Batra S, Hummer BL, Chinchilli VM, Huang D, Loomba R, Schreibman IR, Stine JG. Aerobic Exercise Training Leads to MASH Resolution as Defined by the MASH Resolution Index. Dig Dis Sci. 2026 Feb;71(2):628-635. doi: 10.1007/s10620-025-09361-9. Epub 2025 Sep 3. | |
| 38847589 | Derived | Cuthbertson DJ, Keating SE, Pugh CJA, Owen PJ, Kemp GJ, Umpleby M, Geyer NG, Chinchilli VM, Stine JG. Exercise improves surrogate measures of liver histological response in metabolic dysfunction-associated steatotic liver disease. Liver Int. 2024 Sep;44(9):2368-2381. doi: 10.1111/liv.15947. Epub 2024 Jun 7. |
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31 patients were screened for this study. Three were excluded after screening (two declined and one was excluded because they were actively smoking)
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | ng/mL | 5 months |
|
up to 5 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Partial Knee Replacement | Surgical and medical procedures | Non-systematic Assessment | A standard of care control subject elected to have knee surgery to treat longstanding osteoarthritis. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| AEs | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
Possible limitations include the sample size, lack of allocation concealment, study population largely of early-stage NASH that was also predominantly non-Hispanic white, lack of histologic endpoint, lack of long-term clinical outcomes and inability to show global changes in hemostasis with TEG.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jonathan Stine | The Penn State College of Medicine | 7175311017 | jstine@pennstatehealth.psu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 1, 2021 | Jan 6, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D006402 | Hematologic Diseases |
| D004066 | Digestive System Diseases |
| D065626 | Non-alcoholic Fatty Liver Disease |
| ID | Term |
|---|---|
| D006425 | Hemic and Lymphatic Diseases |
| D005234 | Fatty Liver |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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Standard of care Aerobic exercise
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|
| 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) |
| 38014619 | Derived | Harris SJ, Smith N, Hummer B, Schreibman IR, Faust AJ, Geyer NR, Chinchilli VM, Sciamanna C, Loomba R, Stine JG. Exercise training improves serum biomarkers of liver fibroinflammation in patients with metabolic dysfunction-associated steatohepatitis. Liver Int. 2024 Feb;44(2):532-540. doi: 10.1111/liv.15769. Epub 2023 Nov 28. |
| 34402795 | Derived | 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. |
| BG001 | 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. 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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. 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. |
|
|
| Secondary | Change in Von Williebrand Factor (vWF) | Change in vWF was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | International Units/Liter | 5 months |
|
|
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| Secondary | Change in Protein S | Change in protein S was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | IU/dL | 5 months |
|
|
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| Secondary | Change in Factor VIII | Change in factor VIII was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | International Units/Liter | 5 months |
|
|
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| Secondary | Change in Fibrinogen | Change in fibrinogen was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | mg/dL | 5 months |
|
|
|
| Secondary | Change in Antithrombin | Change in antithrombin was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | percentage of protein | 5 months |
|
|
|
| Secondary | Change in Protein C | Change in protein C was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | IU/dL | 5 months |
|
|
|
| Secondary | Change in Adiponectin | Change in adipontin was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | ng/mL | 5 months |
|
|
|
| Secondary | Patatin Like Phospholipase-3 (PNPLA3) rs738409 Polymorphism | Patatin like phospholipase-3 (PNPLA3) rs738409 polymorphism genotyping subjects (GG, GC and CC genotypes) | Posted | Count of Participants | Participants | 5 months |
|
|
|
| Secondary | Change in PAI-1 Stratified by Fibrosis Stage | Change is the difference between measurements at baseline and 5 months | The intended analysis was not performed for both groups, and instead this subset analyzed exercise group participants only. | Posted | Mean | Standard Deviation | ng/mL | 5 months |
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| Secondary | Change in % Hepatic Fat | Change in % hepatic fat was calculated by taking the difference of measurements at baseline and 5 months. | Posted | Mean | Standard Deviation | percentage of liver | 5 months |
|
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| Secondary | 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. | ITT | Posted | Mean | Standard Deviation | T-score | 5 months (20 weeks) |
|
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|
| 0 |
| 10 |
| 1 |
| 10 |
| 1 |
| 10 |
| EG001 | 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. 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. | 0 | 18 | 0 | 18 | 6 | 18 |
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| GG |
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| Social support |
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