• Change in hepatic fat [ Time Frame: Basaeline - Week 19 ]
  Percent change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo
• Change in hepatic fat [ Time Frame: Baseline - Week 19 ]
  Absolute change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo
• Change in liver volume [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in: liver fat volume assessed by MRI compared with placebo
• Change in liver fat volume [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in: liver fat volume assessed by MRI compared with placebo
• Change in visceral adipose tissue [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in visceral adipose tissue assessed by MRI compared with placebo
• Change in subcutaneous adipose tissue [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in subcutaneous adipose tissue assessed by MRI compared with placebo
• Change in liver diffusion [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in liver diffusion assessed by MRI compared with placebo
• Change in abdominal sagittal diameter (image based) [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in abdominal sagittal diameter (image based)assessed by MRI compared with placebo.
• Change in abdominal transversal diameter (image based) [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in abdominal transversal diameter (image based)assessed by MRI compared with placebo
• Change in circulating markers of hepatic inflammation [ Time Frame: Basaeline - Week 19 ]
  Changes from baseline to Week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT)
• To assess the effect of MEDI0382 on BMI [ Time Frame: Baseline - Week 19 ]
  Change and percent change from baseline to week 19 on BMI.
• To assess the dose response of MEDI0382 on HFF by MRI-PDFF [ Time Frame: Baseline - Week 19 ]
  Absolute change from baseline in HFF from baseline to week 19.
• To assess the dose response of MEDI0382 on body weight [ Time Frame: Baseline - Week 19 ]
  Change from baseline to week 19 on body weight.
• To assess the dose response of MEDI0382 on hepatic safety [ Time Frame: Baseline - Week 19 ]
  Measured by the incidences of treatment emergent adverse events and serious adverse events through the end of the follow up period.
• To assess the dose response of MEDI0382 on imaging parameters. [ Time Frame: Baseline - Week 19 ]
  Measured by the change in baseline to week 19 on: Liver fat volume visceral adipose tissue subcutaneous adipose tissue liver diffusion liver sagittal diameter liver transversal diameter
• To assess the dose response of MEDI0382 on circulating biomarkers of hepatic inflammation [ Time Frame: Baseline - Week 19 ]
  Measured by the change in baseline to week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT).
• Immunogenicity profile defined by presence of anti-drug antibodies (ADA) [ Time Frame: Day 1 - Day 161 ]
  Development of ADA and titer (if confirmed positive) during treatment and follow up

• Change in hepatic fat [ Time Frame: Basaeline - Week 19 ]
  Percent change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo
• Change in hepatic fat [ Time Frame: Baseline - Week 19 ]
  Absolute change from baseline in hepatic fat fraction (HFF) at Week 19 assessed by MRI-PDFF compared with placebo
• Change in liver fat volume [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in: liver fat volume assessed by MRI compared with placebo
• Change in visceral adipose tissue [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in visceral adipose tissue assessed by MRI compared with placebo
• Change in subcutaneous adipose tissue [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in subcutaneous adipose tissue assessed by MRI compared with placebo
• Change in liver diffusion [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in liver diffusion assessed by MRI compared with placebo
• Change in liver sagittal diameter (image based) [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in liver sagittal diameter (image based)assessed by MRI compared with placebo.
• Change in liver transversal diameter (image based) [ Time Frame: Baseline - Week 19 ]
  Changes from baseline to Week 19 in liver transversal diameter (image based)assessed by MRI compared with placebo
• Change in circulating markers of hepatic inflammation [ Time Frame: Basaeline - Week 19 ]
  Changes from baseline to Week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT)
• To assess the dose response of MEDI0382 on HFF by MRI-PDFF [ Time Frame: Baseline - Week 19 ]
  Absolute change from baseline in HFF from baseline to week 19.
• To assess the dose response of MEDI0382 on hepatic safety [ Time Frame: Baseline - Week 19 ]
  Measured by the incidences of treatment emergent adverse events and serious adverse events through the end of the follow up period.
• To assess the dose response of MEDI0382 on imaging parameters. [ Time Frame: Baseline - Week 19 ]
  Measured by the change in baseline to week 19 on: Liver fat volume visceral adipose tissue subcutaneous adipose tissue liver diffusion liver sagittal diameter liver transversal diameter
• To assess the dose response of MEDI0382 on circulating biomarkers of hepatic inflammation [ Time Frame: Baseline - Week 19 ]
  Measured by the change in baseline to week 19 in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT).
• Immunogenicity profile defined by presence of anti-drug antibodies (ADA) [ Time Frame: Day 1 - Day 161 ]
  Development of ADA and titer (if confirmed positive) during treatment and follow up

• Non-alcoholic Fatty Liver Disease (NAFLD)
• Non-alcoholic Steatohepatitis (NASH)

• Drug: MEDI0382 high dose
  MEDI0382 high dose administered subcutaneously
  Other Name: Cotadutide high dose
• Drug: Placebo for MEDI0382 high dose
  Placebo for MEDI0382 high dose administered subcutaneously
  Other Name: Placebo high dose
• Drug: MEDI0382 low dose
  MEDI0382 low dose administered subcutaneously
  Other Name: Cotadutide low dose
• Drug: Placebo for MEDI0382 low dose
  Placebo for MEDI0382 low dose administered subcutaneously
  Other Name: Placebo low dose

• Experimental: MEDI0382 high dose
  MEDI0382 high dose administered subcutaneously
  Intervention: Drug: MEDI0382 high dose
• Placebo Comparator: Placebo for MEDI0382 high dose
  Placebo for MEDI0382 high dose administered subcutaneously
  Intervention: Drug: Placebo for MEDI0382 high dose
• Experimental: MEDI0382 low dose
  MEDI0382 low dose administered subcutaneoously
  Intervention: Drug: MEDI0382 low dose
• Placebo Comparator: Placebo for MEDI0382 low dose
  Placebo for MEDI0382 low dose administered subcutaneously
  Intervention: Drug: Placebo for MEDI0382 low dose

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.