Feasibility of VIIT in Adults With NASH
Condition: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver; Nonalcoholic Steatohepatitis; Liver Diseases
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      The purpose of this study is to determine whether patients with stage 1-3 NASH-related
      fibrosis are able to complete a single vigorous-intensity interval training (VIIT) session on
      an indoor rowing machine and provide blood samples before and afterwards. The results of this
      study will provide the foundation for future research on the role of VIIT in treating NASH.
    

Detailed description: 
      Background & Significance:

      The increasing prevalence of obesity and diabetes has prompted a global epidemic of
      nonalcoholic fatty liver disease affecting 15-30% of the general population. Of those with
      nonalcoholic fatty liver disease, 25% develop NASH and are at increased risk for progressive
      hepatic fibrosis and cirrhosis. NASH-related cirrhosis is now the second leading indication
      of liver transplantation in the United States. For the treatment of NASH, life-style
      modification with diet and exercise is mandatory. Diet and exercise-induced weight loss >5%
      total body weight improves NASH and reverses hepatic fibrosis, the primary determinant of
      liver related morbidity and mortality. While weight loss has remained fundamental to disease
      management it is mistaken as the only assessment for exercise-mediated improvements in NASH.
      Exercise alone has been shown to improve NASH irrespective of weight loss; however, how
      exercise works is unclear. Defining an understanding of how exercise effectively treats NASH
      is an urgent and unmet need that will optimize exercise prescriptions and facilitate
      identifying candidate therapeutic targets that mimic exercise response for those patients
      unable to sustain life-style modifications.

      One potential mechanism for exercise improving NASH is through skeletal muscles' signaling
      proteins, known collectively as myokines. During exercise, myokines are released from
      skeletal muscle into the circulation where they communicate with several organs, including
      the liver. Emerging evidence suggests that myokines - particularly myokine interleukin 6
      (IL-6) -directly regulates liver interleukin (IL)-8.

      Our preliminary data demonstrates that in NASH patients, serum IL-8 is independently
      associated with hepatic fibrosis and differentially expressed by fibrotic stage. Whether
      exercise-mediated myokine IL-6 improves NASH-related fibrosis through reductions in IL-8
      remains a gap in knowledge.

      Myokine IL-6 release into the circulation has been shown to be dependent on the amount of
      skeletal muscle involved during exercise and level of exercise intensity. Thus, full-body
      movements performed at high-intensity may release the greatest amounts of myokine IL-6.
      Vigorous-intensity interval training (VIIT) has not been tested in patients with NASH.
      Additionally, VIIT in NAFLD has been traditionally performed on a cycle ergometer or
      treadmill, which greatly limits maximal skeletal muscle utilization during exercise. Since
      myokine release from skeletal muscle is hypothesized as a critical mechanism of
      exercise-mediated benefits in NAFLD, the investigators are proposing conducting a feasibility
      study of a single VIIT session in patients with NASH using an indoor rower. To measure IL-6
      myokine response and subsequent changes in serum IL-8 the investigators will collect blood
      samples prior, immediately after, and 2-hours following a single VIIT session.

      Design & Procedures:

      12 adults, 18-59 yrs. of age, with NASH-related fibrosis (stage 1-3) will undergo a single
      VIIT session where blood will be collected prior, immediately following, and 2-hours after
      exercise:

        -  Visit 1: The initial visit will take place at the Duke Hepatology Clinic by Dr. Oliver
           Glass, PhD and Dr. Manal Abdelmalek MD MPH, and will last approximately 30 minutes. We
           will explain the study and consent form in detail and on an individual basis, and
           participants will have the opportunity to take the consent home and consider it. If a
           potential subject decides to consent during this visit, participants will be scheduled
           for visits 2 and 3. If a potential subject needs more time to consider the consent,
           participants will have a phone number to call to let study staff know that they wish to
           move forward with visits 2 and 3, and participants will be consented in person at visit
           2 before any study activities take place.

        -  Visit 2: This 1-hour visit will take place at the Duke Integrative Medicine.
           Participants will be instructed on proper form and biomechanics of exercising on an
           indoor rowing machine. This session will ensure subjects are able to perform indoor
           rowing properly and safely.

        -  Visit 3: Subjects will be fitted with a heart rate monitor around the chest and a
           baseline 4ml blood sample will be drawn. Vigorous intensity interval training will
           correspond to heart rate (HR) range of 80-90% of heart rate at age-predicted heart rate
           maximum (220-age). After approximately 5 minutes of warmup subjects will perform 10
           intervals of VIIT: 30 seconds of vigorous intensity exercise followed by 60 seconds of
           rest. Rated Perceived Exertion (RPE) will be rated by 15-point Borg scale; should
           correspond to HR/10 at end of each interval. The subject will self-adjust the intensity
           of the exercise bouts and will be encouraged by the researcher to achieve the desired
           intensity. The exercise session will finish with a short cool-down period and will last
           no more than 25 minutes in total. A 4ml blood sample will be drawn immediately following
           the exercise session and 2-hours after exercise cessation.

      Participants may opt-in/opt-out of the option to have their blood samples stored for future
      research on whether acute exercise alters other myokines besides IL-6 and IL-8. Additionally,
      future research would evaluate whether acute exercise changes other immune-inflammatory blood
      biomarkers.
    

Intervention name(s): Vigorous-intensity interval training (VIIT)
Intervention type(s): Behavioral
Intervention description(s): Subjects will be fitted with a heart rate monitor around the chest and a baseline 4ml blood sample will be drawn. Vigorous intensity interval training will correspond to heart rate (HR) range of 80-90% of heart rate at age-predicted heart rate maximum (220-age). After approximately 5 minutes of warmup subjects will perform 10 intervals of VIIT: 30 seconds of vigorous intensity exercise followed by 60 seconds of rest. Rated Perceived Exertion (RPE) will be rated by 15-point Borg scale; should correspond to HR/10 at end of each interval. The subject will self-adjust the intensity of the exercise bouts and will be encouraged by the researcher to achieve the desired intensity. The exercise session will finish with a short cool-down period and will last no more than 25 minutes in total. A 4ml blood sample will be drawn immediately following the exercise session and 2-hours after exercise cessation.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other