Study of Exenatide Once-Weekly Suspension in Chinese Patients With Type 2 Diabetes Mellitus

A Phase 1, Open-Label Study to Evaluate Single and Multiple Dose Pharmacokinetics, Safety, and Tolerability of Exenatide Once-Weekly Suspension in Chinese Patients With Type 2 Diabetes Mellitus

The purpose of this study is to evaluate the pharmacokinetics, tolerability, and safety of single and multiple doses of exenatide once-weekly suspension via subcutaneous (SC) injection using a pre-filled, single-dose autoinjector in male and female Chinese with type 2 diabetes.

This is an open-label, single- and multiple-dose, PK study in Chinese subjects with type 2 diabetes mellitus. Up to 30 patients may initially be enrolled to target at least 20 patients completing the study. Up to 10 more patients (ie, 40 in total) may be subsequently recruited to replace patients who discontinue, provided such discontinuations are not due to significant (based on PI and Sponsor judgment) safety or tolerability issues. Eligible patients will receive their first 2.0-mg dose of exenatide once-weekly suspension via subcutaneous (SC) injection using a pre-filled, single-dose autoinjector at Visit 3 (Day 1).Blood samples will be drawn for up to 168 hours after the first dose on Day 1 to assess single-dose PK for exenatide once-weekly suspension. Patients will receive the second dose of the investigational product (IP) at Visit 6 (Day 8). Thereafter, patients will receive weekly (±1 day) doses of IP up to Visit 18 (Week 14). Intensive and extended PK sampling will be conducted after administration of the final dose (Dose 14) to assess multiple-dose PK for exenatide once-weekly suspension. Follow-up observations will be conducted at Visits 22 to 29 (Weeks 15 to 26), with the final follow-up at/after Visit 29 (Week 26 ±2 days). During follow-up period, Blood samples will be collected for PK analyses. Subjects will be monitored closely for adverse events throughout the study.

Inclusion Criteria:

1. Provision of informed consent prior to any study-specific procedures.

2. Male or female patients with T2DM treated with diet modification and exercise alone or in combination with a stable (in PI's opinion) regimen of metformin only for at least two months prior to screening. The T2DM diagnosis will be confirmed clinically by the PI, and should be consistent with the World Health Organization criteria for diagnosis and classification of diabetes

3. Between 20 to 75 years of age inclusive at Visit 1 (Screening)

4. The following criterion applies to females of child-bearing potential (not surgically sterilized and between menarche and 1-year postmenopause) only:

   1. Test negative for pregnancy at the time of screening.
   2. Intend not to become pregnant during the study.
   3. Are sexually inactive or have practiced a reliable method of birth control (for example, use of oral contraceptives or levonorgestrel, diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, intrauterine devices, partner with vasectomy) for at least 6 weeks prior to screening.
   4. Agree to continue to use a reliable method of birth control (as determined by the PI) during the study and until 90 days after last dose.

5. Have a body weight of ≥45 kg and a body mass index (BMI) of 18.5 to 35 kg/m2 inclusive at Visit 1 (Screening).

6. Have clinical laboratory test results within the normal reference range for the population or study site, or with abnormalities deemed clinically insignificant by the PI. Abnormalities of plasma glucose (fasting ≤12.0 mmol/L and anytime≤15.0mmol/L), HbA1c (<10.5%), plasma lipids (TG<5.7 mmol/L), and urinary protein (with a range of trace < 2+ on dipstick) are acceptable.

7. Venous access sufficient to allow blood sampling as per the protocol.

8. Are reliable and willing to be available for the duration of the study and are willing to follow study procedures.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to bothAstraZeneca staff and/or staff at the study site, and direct family members).

2. Previous enrollment in the present study or have previously completed or withdrawn from any other study investigating exenatide.

3. Within 30 days of the initial dose of IP, have received treatment with a drug that has not received regulatory approval for any indication.

4. Known allergy or hypersensitivity to exenatide or any of the excipients contained in these agents (exenatide: sodium acetate buffer, mannitol, metacresol, MCT vehicle).

5. Previous treatment with exenatide or related GLP-1 receptor agonist compounds.

6. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data.

7. Systolic blood pressure (SBP) persistently (on ≥2 separate occasions) >160 mmHg on stable regimen of antihypertensive medication or >180 mmHg regardless of antihypertensive treatment.

8. History of, or currently have angina, revascularization, myocardial infarction, or heart failure.

9. Clinically significant peripheral vascular disease.

10. Evidence of poorly controlled T2DM or evidence of significant diabetes-related complications such as:

    1. Plasma glucose >12 mmol/L (fasting) or >15 mmol/L (anytime) at Visit 1 (Screening)
    2. HbA1c >10.5%
    3. History of hypoglycemic or hyperglycemic coma within 1 year prior to Visit 1 (Screening)
    4. History of active diabetic proliferative retinopathy or macular oedema
    5. Known significant autonomic neuropathy as evidenced by urinary retention, orthostatic hypotension, diabetic diarrhea, or gastroparesis

11. Two or more episodes of major hypoglycemia within 6 months prior to Visit 1 (Screening). See Section 5.2.8.1 for hypoglycemia classification.

12. Impaired renal function (serum creatinine >125 μ/mol/L in women, >132 μ/mol/L in men).

13. Liver disease, acute or chronic hepatitis, alanine aminotransferase (ALT/SGPT), or aspartate aminotransferase (AST) ≥3x upper limit of normal (ULN) of the reference range and total bilirubin level (TBL) ≥2xULN.

14. Evidence of hepatitis B and/or positive hepatitis B surface antigen.

15. Clinical symptoms associated with cholelithiasis (eg, cholecystitis or biliary colic), within 3 years of Visit 1 (Screening).

16. History of, or currently have acute or chronic pancreatitis, or have triglyceride concentrations ≥500 mg/dL at Visit 1 (Screening).

17. Have a serum calcitonin concentration ≥40 pg/mL at Visit 1 (Screening).

18. An abnormality in the 12-lead ECG that, in the opinion of the PI, increases the risks associated with participating in the study.

19. Evidence of significant active neuropsychiatric disease.

20. Evidence of current use of drugs of abuse or history of use within the past year.

21. Women who are lactating and/or breastfeeding.

22. Use of over-the-counter or prescription medication (other than thyroid replacement therapy, metformin, antihypertensive medication, lipid-lowering agents, aspirin, or paracetamol/acetaminophen) 7 and 14 days, respectively prior to dosing. If this situation arises, inclusion of an otherwise suitable patient may occur if permitted by the PI and Sponsor.

23. Significant active hematological disease and/or blood donation of more than 400 mL within the last 6 months.

24. An average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females), or patients unwilling to adhere to study alcohol restrictions (1 unit=360 mL of beer; 150 mL of wine; 45 mL of distilled spirits).

25. A personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B.

26. Currently enrolled in any other clinical study.

27. Determined by the PI to be unsuitable for inclusion in this study.