Safety and tolerability study of Cotadutide in Japanese obese subjects with type 2 diabetes melitus

Exclusion Criteria

• 1. Subjects with any of the following results at screening and run-in visit
• 2. 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 and/or any subject unable or unwilling to follow study procedures.
• 3. Acute pancreatitis at screening or history of chronic pancreatitis or serum triglyceride levels > 11 mmol/L (1000 mg/dL) at screening.
• 4. Significant inflammatory bowel disease, gastroparesis or other severe disease or surgery affecting the upper GI tract (including weight-reducing surgery and procedures), which may affect gastric emptying or could affect the interpretation of safety and tolerability data.
• 5. Significant hepatic disease (except for NASH or non-alcoholic fatty liver disease without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening or run-in visit.
• - Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
• - Alanine transaminase (ALT) ≥ 3 × ULN
• - Total bilirubin (TBL) ≥ 2 × ULN
• 6. Impaired renal function defined as estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73m2 at screening or run-in visit (GFR estimated according to Modification of Diet in Renal Disease [MDRD] using MDRD Study Equation IDMS-traceable [International System of Units (SI)]).
• 7. Poorly controlled hypertension defined as,
• For age ≤ 55 years;
• Systolic BP > 140 mmHg
• Diastolic BP ≥ 90 mmHg
• For age > 55 years;
• Systolic BP > 150 mmHg
• Diastolic BP ≥ 90 mmHg
• After 10 minutes of supine rest and confirmed by repeated measurement at screening or run-in visit. Subjects who fail BP screening criteria may be considered for 24-hour or day time ABPM at the discretion of the investigator. Subjects who maintain a mean 24-hour BP < 130/80 mmHg with a preserved nocturnal dip of > 15% or day time BP < 135/85 mmHg will be considered eligible
• 8. Resting heart rate is ≥ 80 bpm at screening or run-in visit.
• 9. Any clinically important abnormalities in rhythm, conduction, or morphology of the 12-lead ECG or any abnormalities that may interfere with the interpretation of serial ECG changes, including QTc interval changes at screening, as judged by the investigator.
• 10. Prolonged QT intervals corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec, or family history of long QT-segment at screening or run-in visit.
• 11. PR (PQ) interval prolongation (> 220 msec), intermittent second (Wenckebach block while asleep is not exclusive), or third-degree atrioventricular (AV) block, or AV dissociation at screening or run-in visit.
• 12. Persistent or intermittent complete bundle branch block. A QRS duration < 120 msec is acceptable if there is no evidence of ventricular hypertrophy or preexcitation at screening or run-in visit.
• 13. Abnormal findings during the exercise stress test, such as chest pain, dyspnoea, presyncope, arrhytmias, signs of cardiac ischemia on ECG as judged by the investigator.
• 14. History of, unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke, or subjects who have undergone percutaneous coronary intervention or a coronary artery bypass graft or who are due to undergo these procedures at the time of screening.
• 15. Severe congestive heart failure (New York Heart Association Class III or IV).
• 16. Basal calcitonin level > 50 ng/L at screening, or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia.
• 17. Hemoglobinopathy, hemolytic anemia or chronic anemia (hemoglobin, < 11.5 g/dL [115 g/L]) for males, < 10.5 g/dL (105 g/L) for females) at screening or run-in visit, or any other condition known to interfere with the interpretation of HbA1c measurement.
• 18. 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.
• 19. Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and human HIV antibody.
• 20. History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as an average weekly intake of > 21 alcoholic drinks for men or > 10 alcoholic drinks for women) within 3 years prior to screening and/or a positive screen for drugs of abuse or alcohol at screening or run-in visit. Subjects who use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study.
• 21. Symptoms of depression or any other psychiatric disorder requiring treatment with medication (eg, anti-depressants, anti-psychotics) at screening. However, subjects who use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study.
• 22. History of severe allergy/hypersensitivity, including to any component of the investigational product formulation including excipients or other biological agent, any of the proposed study treatments, or ongoing clinically important allergy/hypersensitivity.
• 23. Any subject who has received another investigational product as part of a clinical study or a 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.
• 24. Any subject who has received any of the following medications within the specified timeframe prior to the start of the study.
• - Herbal preparations within one week prior to the start of screening or drugs licensed for control of body weight or appetite within 30 days (or 5 half-lives of the drug) prior to the start of screening
• - Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying and within 2 weeks prior to the start of dosing
• - Antimicrobials within the quinolone, macrolide or azole class within 2 weeks prior to the start of dosing
• - Any change in antihypertensive medication within 3 months prior to screening
• - Any change in thyroid replacement therapy within 2 months prior to screening
• - Aspirin at a total daily dose of greater than 150 mg
• - Paracetamol or paracetamol-containing preparations at a total daily dose of greater than 3000 mg
• - Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg
• 25. Concurrent participation in another study of any kind and repeat randomization in this study.
• 26. Received Cotadutide in another clinical study prior to enrolment in this study.