A Study to Evaluate Safety and Pharmacodynamic Efficacy of 0382 in Obese Subjects With NAFLD/NASH.
Condition: Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic Steatohepatitis (NASH)
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: MEDI0382 high dose; Placebo for MEDI0382 high dose; MEDI0382 low dose; Placebo for MEDI0382 low dose
Intervention description: MEDI0382 high dose administered subcutaneously; Placebo for MEDI0382 high dose administered subcutaneously; MEDI0382 low dose administered subcutaneously; Placebo for MEDI0382 low dose administered subcutaneously
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 74.0
Sex: All
Minimum age: 18 Years
Maximum age: 101 Years
Healthy volunteers: No
Keywords: Non-alcoholic fatty liver disease; NAFLD; Non-alcoholic steatohepatitis; NASH; 0382

Summary:

      A Phase 2 study with 4 treatment groups of two differing doses and matched placebos designed
      to evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects
      of two dose levels of MEDI0382 in obese subjects with non-alcoholic fatty liver disease
      (NAFLD)/non-alcoholic steatohepatitis (NASH). The subjects will have biopsy-confirmed
      NAFLD/NASH with liver fibrosis stage F1, F2 or F3. Approximately 72 subjects will be
      randomized
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of informed consent (with the exception of consent for future genetic and
             non genetic research) prior to performing any study-specific procedures, including
             screening evaluations.

          2. Subjects aged ≥ 18 years at the time of consent.

          3. Body mass index ≥ 30 kg/m2 at screening.

          4. HbA1c ≤ 9.5% (inclusive) at screening if T2DM present, managed by either diet and/or a
             stable dose of metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors,
             sulphonylureas or acarbose (ie, no major dose adjustments in prior 3 months to
             screening).

          5. Definitive NAFLD / NASH with NASH activity score (NAS) ≥ 4 with ≥ 1 in each component
             (i.e. steatosis, lobular inflammation and ballooning), as diagnosed by liver biopsy
             within 6 months of screening with liver fibrosis stage F1, F2 or F3. The number of
             subjects with F1 will be capped at 25% in the study.

          6. Evidence of hepatic steatosis or liver fat (≥ 10%) by MRI.

          7. Women of childbearing potential:

               1. Who are sexually active with a non-sterilized male partner must have used at
                  least one highly effective method of contraception from screening, and must agree
                  to continue using such precautions through to the end of the study. It is
                  strongly recommended for the male partner of a female subject to also use male
                  condom plus spermicide throughout this period. Cessation of contraception after
                  this point should be discussed with a responsible physician. Periodic abstinence,
                  the rhythm method, and the withdrawal method are not acceptable methods of
                  contraception.

               2. Must have a negative urine pregnancy test within 72 hours prior to the first dose
                  of investigational product; and not be breastfeeding.

        Exclusion Criteria:

          1. History of, or any existing condition that, in the opinion of the investigator, would
             interfere with evaluation of the investigational product, put the subject at risk,
             influence the subject's ability to participate or affect the interpretation of the
             results of the study.

          2. Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral,
             or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis;
             hemochromatosis; alpha 1 antitrypsin deficiency; Wilson's disease) including positive
             results for hepatitis B surface antigen (HBsAg) or hepatitis C antibody tests
             (anti-HCV).

          3. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic
             encephalopathy or variceal bleeding.

          4. Prior or planned liver transplantation.

          5. Alcohol consumption > 21 units of alcohol per week for men and > 14 units per week for
             women on average over a two-year time frame prior to baseline biopsy.

          6. Evidence of alcohol dependence as assessed by the Alcohol Use Disorder Identification
             Test (AUDIT) questionnaire at screening

          7. A history of type 1 diabetes mellitus (T1DM), a history of diabetic ketoacidosis or
             current use of insulin-based therapies.

          8. Clinically significant inflammatory bowel disease or other severe disease or surgery
             affecting the upper GI tract (including bariatric surgery) which may affect gastric
             emptying or could affect the interpretation of safety and tolerability data

          9. Physician-diagnosed diabetic subjects with clinically significant gastroparesis (as
             judged by the investigator) or those treated for gastroparesis within 6 months prior
             to screening

         10. History of > 5 kg weight loss in the last 6 months prior to screening or recent
             (within 3 months of screening) use of drugs approved for weight loss (eg, orlistat,
             bupropion / naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as
             those drugs used off-label.

         11. Clinically significant cardiovascular or cerebrovascular disease within the past 3
             months, including but not limited to, myocardial infarction, acute coronary syndrome
             or stroke, or subjects who have undergone percutaneous coronary intervention or a
             coronary artery bypass graft within the past 6 months or who are due to undergo these
             procedures at the time of screening.

         12. Severe congestive heart failure (New York Heart Association Class IV).

         13. History of neoplastic disease within 5 years prior to screening, except for adequately
             treated basal cell, squamous cell skin cancer, or in situ cervical cancer.

         14. History of substance dependence or a positive screen for drugs of abuse, likely to
             impact subject safety or compliance with study procedures, at the discretion of the
             investigator.

         15. History of psychosis or bipolar disorder. History of major depressive disorder within
             the past year with the subject being clinically unstable, or any history of suicide
             attempt or history of suicidal ideation within the past year.

         16. Recent (within 3 months of baseline biopsy) use of therapies associated with
             development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen,
             amiodarone, or long-term use of tetracyclines).

         17. Recent (within 3 months of baseline biopsy) use of obeticholic acid or other therapy
             under investigation for NASH.

         18. High dose vitamin E (> 400 IU) unless on a stable dose for at least 1 year prior to
             the baseline biopsy, and not initiated after the biopsy was taken.

         19. Recent (within 3 months of baseline biopsy) use of GLP-1 receptor agonist or GLP-1
             receptor agonist containing therapies.

         20. Any subject who has received another investigational product as part of a clinical
             study within the last 30 days or 5 half-lives of the therapy (whichever is longer) at
             the time of screening. Any prior exposure to MEDI0382 is not permitted.

         21. Concurrent participation in another interventional study of any kind or repeat
             randomization in this study.

         22. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.

         23. Contra-indication to MRI: such as subjects with pacemakers, metallic cardiac valves,
             magnetic material such as surgical clips, implanted electronic infusion pumps or other
             conditions that would preclude proximity to a strong magnetic field; subjects with
             history of extreme claustrophobia or subject cannot fit inside the MR scanner cavity.

         24. History of acute pancreatitis or current chronic pancreatitis. Subjects with serum
             triglyceride concentrations above 1000 mg/dL (11 mmol/L) at screening, as this can
             precipitate acute pancreatitis.

         25. Abnormal laboratory values including any of the following:

               1. AST or ALT > 5 × ULN.

               2. Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤
                  30 mL/minute/1.73 m2 at screening (estimated according to chronic kidney disease
                  epidemiology collaboration [CKD-EPI]).

               3. Albumin < 35 g/L.

               4. International normalized ratio (INR) > 1.3.

               5. Total Bilirubin (TBL) > 25 µmol/L in the absence of known Gilbert's disease.

               6. Platelets < 140-150,000/mm3

               7. Any other clinically significant abnormalities in clinical chemistry, hematology,
                  or urinalysis results as judged by the investigator.

         26. Severely uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 180 mm
             Hg and/or diastolic blood pressure (DBP) ≥ 110 mm Hg on the average of 2 seated
             measurements after being at rest for at least 10 minutes at screening or
             randomization.

         27. Basal calcitonin level > 50 ng/L at screening, or history/family history of medullary
             thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2).

         28. Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration < 11.5
             g/dL [115 g/L] for male subjects or < 10.5 g/dL [105 g/L] for female subjects) at
             screening, or any other condition known to interfere with interpretation of HbA1c
             measurements

         29. Any positive results for human immunodeficiency virus (HIV) infection.

         30. Any AstraZeneca, MedImmune, contract research organization (CRO), or study site
             employee, or close relatives of any of the aforementioned employees.

         31. Females who are pregnant or lactating.