Proof of Concept ELectro-Stimulation of Muscles to resolVe Insulin Resistance in NASH
Condition: NASH - Nonalcoholic Steatohepatitis; Insulin Sensitivity
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance
Study type: Interventional

Summary: 
      Non-alcoholic steato-hepatitis (NASH) affects up to 3% of the population and leads to liver
      cirrhosis, hepatocellular carcinoma (HCC) and death. The only known treatment is weight loss
      and exercise. Many patients cannot or will not achieve this with conventional means. The
      pathogenic process of the disease is insulin resistance which can be reversed relatively
      quickly with intense exercise or electrical stimulation of muscle. Most patients cannot
      achieve or sustain the level of aerobic exercise required; resistance exercise is more
      sustainable and similarly effective. The aim of this pilot study is to investigate whether
      electro-muscle stimulation, designed to emulate resistance exercise, resolves NASH in
      patients and moves them to a less dangerous metabolic steady state which should be easier to
      maintain.
    

Detailed description: 
      This is a pilot study which will determine if muscle stimulation by using electro-stimulation
      can mimic resistance exercise and improve insulin resistance and hepatitis steatosis. We aim
      to recruit up to 20 patients into the study, needing a minimum of 12 subjects suitable for
      per protocol analysis. The participants will self-administer EMS for 8 -12 weeks. An interim
      analysis of change in insulin resistance at 8 weeks of study will be undertaken in the first
      4 patients, if this shows a clear effect the study period will be shortened to 8 weeks.

      Patients with biopsy proven NASH will be approached by their clinician at their routine liver
      outpatient clinic and provided with study information alongside the contact details of study
      staff. Patients will be given adequate time (over 24 hours) to consider the study and will be
      asked to contact research staff by email or telephone supplied on the PIS if they then wish
      to participate in the study or require further information. An appointment will be arranged
      to attend for study screening convenient to the patient where a full in-depth discussion will
      take place prior to consent or any study procedures undertaken.

      Study participants will then follow the study pathway as shown in the flow chart, (section
      3.2) Study Matrix (3.3) and as described in the study assessments schedule (section 6).

      Electro Muscle Stimulation (EMS) will commence at baseline visit, which will take place in
      the Institute of Motion Analysis & Research centre, Ninewells hospital, 6 sessions per week
      self-administered at home, of up to 35 minutes duration for up to a total of 12 weeks.
      Participants will self-administer muscle stimulation via the Neurotrac Myoplus 2/4 device.
      Manufactured by: Verity Medical Ltd, in compliance with the European Union Medical Device
      Directive MDD93/42/EEC under the supervision of SGS, Notified Body number 0120. CE 0120.

      Custom STIM (stimulation) mode settings will be utilised and locked for safety. Each
      participant's own tolerance for the settings within regulated parameters will be used to
      ensure patient comfort but also allow for optimum muscle activity. 4 channels on the device
      will be used with 2 sets of skin electrodes attached to the medial and lateral aspects of the
      quadriceps muscles of each leg.

      Assessments of Insulin Sensitivity. This will be based around frequently sampled oral Glucose
      Tolerance test (fsOGTT) which will be performed in the Clinical Research Centre at baseline,
      week 4, 8 and 12. The fsOGTT will use the 2 hour, seven sample method following glucose
      administration (22).

      Samples will be analysed for glucose, insulin, c-peptide and non-esterified fatty acids
      (NEFA), using the model described in Man et al (22). For the days leading up to the test
      patients should eat a normal diet without restriction, fast overnight from 10pm (at least 8
      hours), water is allowed. Regular medication may be taken, If any need to be taken with food
      it may be best to take them after the test. Patients are asked to refrain from smoking,
      chewing gum or wearing nicotine patches, during the fasting period until after the test is
      completed. The procedure will last for 2-2½ hours. On the morning of the test patients will
      be asked to sit comfortably. A peripheral venous cannula will be inserted into a vein in the
      hand or arm to allow blood samples to be taken before the glucose drink and at 10, 20, 30,
      60, 90, 120 minutes afterwards. The glucose drink should be drunk over a maximum of 5
      minutes.

      Water is allowed after the glucose drink if the patient is thirsty. After the blood tests are
      complete the cannula will be removed. They will be offered a drink and something to eat at
      the end of the test and the patient is free to leave.

      Assessments of liver steatosis by MRI liver.

      The MRI scanning will take place at the Radiology department, Ninewells hospital. The
      protocol will consist of three sub-sections, namely (i) cardiac MR for studying heart
      structure and function (30 minutes scanning); (ii) abdominal MR for measuring liver lipid and
      iron concentrations, and visceral/sub-cutaneous adipose tissue volumes (20 minutes scanning);
      and (iii) MR elastography for measuring liver fibrosis (30 minutes scanning). For the
      baseline visit, patient volunteers will undergo (i) and (ii), and for the follow-up visit
      patient volunteers will undergo (ii) and (iii). This will ensure that the abdominal MR
      sub-section of the protocol is acquired at both time-points, with a total scan time that will
      not exceed 50 minutes for any given session.
    

Intervention name(s): Electro-muscular stimulation using NeuroTrac MyoPlus 2/4
Intervention type(s): Device
Intervention description(s): In this pilot study we aim to determine if change in the muscle metabolism can resolve insulin resistance in NAFLD through muscle stimulation by using electro-stimulation. We hypothesise that 6x35 minute sessions per week over a 12 week time scale would mimic effects of resistance exercise on metabolic parameters associated with NAFLD and hepatic steatosis. All 20 participants will have the electro-stimulation intervention.
Intervention model: Single Group Assignment
Intervention model description: Proof of concept study.
Masking: None (Open Label)
Primary purpose: Treatment