A Study to Evaluate the Safety and Tolerability of MEDI0382 in Overweight and Obese Participants With Type 2 Diabetes Mellitus

Inclusion Criteria:

1. Participants aged 18 to 74 years (inclusive) at screening.
2. Provision of signed and dated written informed consent (with the exception of consent for genetic and non-genetic research) prior to any study specific procedures.
3. Body mass index (BMI) between 27 and 35 kg/m^2 (inclusive) at screening.
4. Hemoglobin A1c (HbA1c) range of 6.5% to 8.5% (inclusive) at screening (Note: Participants may be re-tested for the HbA1c entry criterion only once.).
5. Willing and able to self-inject study drug for the duration of the study.
6. Diagnosed with type 2 diabetes mellitus with glucose control managed with metformin monotherapy where no significant dose change (increase or decrease >= 500 mg/day) has occurred in the three months prior to screening.
7. Female participants must have a negative pregnancy test at screening and randomization, and must not be lactating.
8. Female participants of childbearing potential who are sexually active with a male partner must be using at least one highly effective method of contraception from screening and up to 4 weeks after the last dose of study drug.

Exclusion Criteria:

1. History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the study drug, put the participant at risk, influence the participant's ability to participate or affect the interpretation of the results of the study and/or any participant unable or unwilling to follow study procedures during the run-in period.
2. Any participant who has received another study drug as part of a clinical study or a glucagon-like peptide-1 (GLP-1) analogue containing preparation within the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening.
3. Concurrent participation in another study of any kind and repeat randomization in this study is prohibited.

4. Any participant who has received any of the following medications prior to the start of the study:

   • Herbal preparations or drugs licensed for control of body weight or appetite
   • Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying
   • Antimicrobials within the quinolone, macrolide or azole class
   • Any change in antihypertensive medication
   • Aspirin (acetylsalicylic acid)
   • Paracetamol (acetaminophen) or paracetamol-containing preparations
   • Ascorbic acid (vitamin C) supplements
5. Severe allergy/hypersensitivity to any of the proposed study treatments, standardized meals, or excipients.
6. Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis, or if the participant has been treated with daily SC insulin within 90 days prior to screening.
7. Acute pancreatitis, pancreatic amylase, and/or pancreatic lipase > 3 × upper limit of normal range (ULN); history of chronic pancreatitis; or serum triglyceride levels > 11 mmol/L (1000 mg/dL) at screening.
8. Significant inflammatory bowel disease, gastroparesis or other severe disease or surgery affecting the upper gastrointestinal tract (including weight-reducing surgery and procedures), which may affect gastric emptying or could affect the interpretation of safety and tolerability data.

9. Significant hepatic disease (except for nonalcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease without portal hypertension or cirrhosis) and/or participants with any of the following results at screening:

   • Aspartate transaminase (AST) >= 3 × ULN
   • Alanine transaminase (ALT) >= 3 × ULN
   • Total bilirubin (TBL) >= 2 × ULN
10. Impaired renal function defined as estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73m^2 at screening.

11. Poorly controlled hypertension defined as:

    • Systolic blood pressure (BP) > 160 mm Hg
    • Diastolic BP or >= 90 mm Hg
12. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG or any abnormalities that may interfere with the interpretation of serial ECG changes.
13. Prolonged QT intervals corrected for heart rate or family history of long QT-segment at screening.
14. PR (PQ) interval prolongation, intermittent second or third-degree atrioventricular (AV) block, or AV dissociation.
15. Persistent or intermittent complete bundle branch block.
16. Unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke within 3 months prior to screening, or participants 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.
17. Severe congestive heart failure.
18. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia.
19. Hemoglobinopathy, hemolytic anemia or chronic anemia or any other condition known to interfere with the interpretation of HbA1c measurement.
20. 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.
21. Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
22. History of substance dependence, alcohol abuse, or excessive alcohol intake. Participants who use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study.
23. Symptoms of depression or any other psychiatric disorder requiring treatment with medication.
24. History of severe allergy/hypersensitivity, including to any component of the investigational product formulation or other biological agent, or ongoing clinically important allergy/hypersensitivity.
25. Blood/plasma donation within 1 month of screening.