A Phase ll Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis
Condition: Non-alcoholic Steatohepatitis (NASH)
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: IMM-124E; Placebo
Intervention description: IMM-124E; Matched placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 133.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      This study will evaluate the safety and preliminary efficacy of two dose levels of IMM-124E
      in reducing liver fat and/or serum alanine aminotransaminase (ALT) compared with placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years.

          2. Provision of written informed consent.

          3. Diagnosis of NASH, histologically proven within 12 months of Screening with

               -  NASH activity score (NAS) of 4 or more

               -  cytologic ballooning score of at least 1;

               -  10% or more macrovescicular steatosis.

               -  Hematoxylin & Eosin (H&E) stained slides and/or paraffin block available for
                  independent assessment.

          4. HBA1C of <9.0

          5. Agree to the use of effective contraceptive measures if either male or female of child
             bearing potential.

        Exclusion Criteria:

          1. Presence of vascular liver disease or cirrhosis;

          2. Presence of liver disease with other cause (autoimmune, metabolic, medication
             induced);

          3. BMI <25 kg/m^2;

          4. Alcohol use >30 g/day;

          5. Type 1 diabetes;

          6. 6. History of major bariatric surgery (not including balloon / sleeve gastrectomy);

          7. Weight loss or gain of 5kg or more in the past 6 months or >10% change in bodyweight
             in the past 12 months;

          8. Contraindication for MRI;

          9. Inadequate venous access;

         10. Lactating/breastfeeding/pregnant at Screening or Baseline;

         11. HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or Hepatitis C
             virus (HCV)-RNA positive;

         12. Receiving an elemental diet or parenteral nutrition;

         13. Concurrent conditions

               -  Inflammatory bowel disease;

               -  Unstable angina, myocardial infarction, transient ischemic events, or stroke
                  within 24 weeks of Screening;

               -  Ongoing infectious, ongoing multi-systemic immune-mediated and/or concurrent or
                  past malignant disease;

               -  Any other concurrent condition which, in the opinion of the investigator, could
                  impact adversely on the subject participating or on the interpretation of the
                  study data;

         14. Concurrent medications including:

               -  anti-NASH therapy(s) taken for more than 10 continuous days in the last 3 months.
                  These include S-adenosyl methionine (SAM-e), betaine, milk thistle, probiotic
                  supplements (other than yoghurt), vitamin E and gemfibrozil.

                    -  NB: If vitamin E or gemfibrozil are used, the dose must be stable and liver
                       biopsy confirming diagnosis of NASH subsequent to commencing treatment;
                       commencing treatment;

                    -  Wash out for any of the anti-NASH therapies is as follows: under 10 days no
                       washout required, more than 10 days and up to 3 months treatment requires 6
                       weeks washout. Any treatment of over 3 months would require to re-biopsy to
                       ensure histological eligibility

               -  thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors (gliptins) or
                  glucagon-like peptide-1 analogs in the last 6 months. If treatment commenced and
                  is stable for more than 6 month prior to the determinant biopsy and the dose is
                  still stable at time of study entry, subjects will be eligible for recruitment.

               -  Allowable anti-diabetic treatment includes metformin and/or sulfonylureas
                  administered at constant dose for at least 2 months prior to study entry.

               -  Subjects treated with Insulin are eligible if clinically stable on insulin
                  treatment (i.e. no recurrent acute hypo-/hyperglycemic episodes diagnosed
                  clinically and by Glucose serum levels of <50 mg/dL and >200 mg/dL respectively)
                  for at least 2 months prior to study entry.

               -  immune modulatory agents including

                    -  In the last 3 months:

                    -  systemic steroids for more than 7 days.

                    -  daily treatment with multiple non-steroidal anti-inflammatory drugs (such as
                       aspirin >100mg/day, ibuprofen, naproxen, meloxicam, celecoxib) for more than
                       1 month within 3 months prior to study entry;

                    -  In the last 12 months:

                    -  azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNFα
                       therapies (infliximab, adalimumab, etanercept) or anti-integrin therapies
                       (namixilab) ;

               -  more than 10 consecutive days oral or parenteral antibiotics within 4 weeks prior
                  to study entry (Note: such subjects would not be included in the stool and PBMC
                  analysis).

               -  variable dose of antilipidemic agents (3-hydroxy-3-methyl-glutaryl (HMG)-Co-A
                  reductase inhibitors - "statins") in the 3 months prior to study entry.

         15. The following laboratory abnormalities:

               -  Neutrophil count ≤1.0 x 10^9/L

               -  Platelets <100 x 10^9/L

               -  Hemoglobin <10 g/dL

               -  Albumin <3.5 g/dL

               -  International Normalized Ratio (INR) >1.5

               -  Total bilirubin >1.5 x upper limit of reference range (unless Gilbert's syndrome
                  or extrahepatic source as denoted by increased indirect bilirubin fraction)

               -  Either creatinine clearance ≤60 mL/minute calculated by Cockroft Gault or
                  creatinine >1.5x upper limit of reference range.

         16. Known substance abuse, including inhaled or injected drugs in the year prior to
             Screening.

         17. Cow milk allergy, lactose intolerance or any known or suspected hypersensitivity to
             study products.