A Phase 3b, Randomized, Active Comparator, Open-label, Multicenter Study to Compare the Efficacy, Safety, and Tolerability of ITCA 650 to Empagliflozin and to Glimepiride as Add-on Therapy to Metformin in Patients with Type 2 Diabetes

1. Understanding of the study procedures and conditions of the protocol
and agreement to participate in the study by providing a signed and
dated informed consent prior to any study-specific procedures.
2. Male or female patients 18 to 80 years old, inclusive.
3. Diagnosis of T2D >= 3 months prior to the Screening Visit.
4. Body mass index (BMI) between >= 25 to <= 45 kg/m2 at the Screening
Visit.
5. Stable body weight (not varying by >10%) >= 3 months prior to the
Screening Visit.
6. Glycosylated hemoglobin A1c (HbA1c) >=7.5 and <=10.5%. One re-test
of this parameter is allowed prior to Visit 2.
7. Calcitonin <50 ng/L (50 pg/mL) at the Screening Visit.
8. On a stable (>= 3 months prior to the Screening Visit) treatment
regimen of metformin monotherapy of >=1500 mg/day.
9. Agreement to maintain the same dose of background metformin from
the Screening Visit to the end of the study (unless a change is clinically
indicated).
10. Women may be enrolled if all of the following criteria (in addition to
other criteria) are met: they are not pregnant; they are not breast
feeding; and they do not plan on becoming pregnant during the study.
11. Women of childbearing potential (WOCBP) must have a negative
pregnancy test at the Screening Visit. Women are considered to be of
childbearing potential unless they meet one of the following criteria as
documented by the Investigator:
• They have had a hysterectomy or tubal ligation prior to signing the
informed consent form (ICF); or
• They are post-menopausal, defined for women <= 50 years old as >= 2
years since their last menstrual period and for women >50 years old as
>= 1 year since their last menstrual period.
12. WOCBP must agree to use an adequate method of contraception
during the study and for 1 additional menstrual cycle after the Follow-up
visit. Women practicing abstinence or whose partner(s) is (are) sterile
should be considered to be of childbearing potential. Adequate methods
of contraception for WOCBP include: oral, implanted or injectable
contraceptive hormones; mechanical products (intrauterine device); or
barrier methods (diaphragm, condoms, cervical cap) with spermicide.
The patient's understanding of this requirement must be documented by
the Investigator.

Diabetes Therapy or History
1. History of type 1 diabetes, diabetes that is the result of pancreatic
injury, or secondary forms of diabetes, (eg, Cushing's syndrome) and/or
acute metabolic complications such as diabetic ketoacidosis or
hyperosmolar state (coma)
2. Participation in a clinical study involving ITCA 650
3. Treatment with any GLP-1 receptor agonist within 6 months prior to
Screening or at any time in the past if therapy was discontinued due to
gastrointestinal intolerance. This includes treatment during participation
in a clinical study
4. Treatment with any of the following antidiabetic agents within 3
months prior to Screening: sodium-glucose cotransporter-2 inhibitors,
sulfonylureas, dipeptidyl peptidase-4 inhibitors, alpha glucosidase
inhibitors, meglitinides, thiazolidinediones, bile acid sequestrants (eg,
colesevelam), dopamine receptor agonists (eg, bromocriptine), amylin
analogues (eg, pramlitide), or insulin. NOTE: History of short term (<14
days) use of insulin is allowed as long as the last dose was administered
more than 2 weeks prior to the Screening
5. FPG >270 mg/dL (15 mmol/L). One re-test of this parameter is
allowed prior to randomization
6. Significant symptomatic hyperglycemia: polyuria, polydipsia,
unexplained weight loss
History
7. Any condition, clinically significant laboratory abnormality or therapy,
which might pose a risk to the patient, or interfere with the conduct of
the study or interpretation of the safety and efficacy data
8. Alcohol or substance abuse within 1 year prior to Screening
9. Treatment with an investigational drug within 30 days prior to
screening or 5 half-lives (whichever is longer); participation in a clinical
study involving an investigational product or non-approved use of a drug
or device or concurrently enrolled in any other type of medical research
judged not to be scientifically or medically compatible with this study
10. History of hypersensitivity to exenatide, empagliflozin, or glimepiride
or to one of its excipients
11. Contraindications or warnings according to the specific labels for
metformin, empagliflozin, or glimepiride therapy
Endocrine
12. History of medullary thyroid cancer or a family or personal history of
multiple endocrine neoplasia type 2
13. Presence of a thyroid nodule, detected on a physical examination
that has not been fully evaluated
14. Thyroid-stimulating hormone outside of normal limits at Screening.
One re- test of this parameter is allowed prior to inclusion
15. Thyroid hormone therapy that has not been stable for >=6 weeks prior
to Screening
Cardiovascular
16. History or evidence, within the last 6 months prior to the Screening
Visit, of any of the following: myocardial infarction, coronary
revascularization (coronary artery bypass grafting or percutaneous
coronary intervention), unstable angina, cerebrovascular accident or
stroke
17. Uncontrolled hypertension: sitting systolic blood pressure >=180
mmHg and /or sitting diastolic blood pressure >100 mmHg at Screening
(may be repeated after 15 minutes and exclusion will be based on the
last measurement)
18. Congestive heart failure (Grade III and IV acc. to NYHA
classification)
Renal
19. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at
the Screening
Hepatic/Pancreatic/Gastrointestinal
20. History or evidence of acute or chronic pancreatitis
21. History of weight loss surgery
22. History of current infectious liver disease including hepatitis B or
hepatitis C virus. Patients who have isolated, positive anti-hepatitis B
surface antibody may be included
23. Aspartate aminotransferase (AST), alanine aminotransferase (ALT)
or alkaline phosphatase 3 × above upper limit of normal (ULN) at
Screening
24. Bilirubin 2 × above ULN at Screening
25. Fasting triglycerides >=500 mg/dL at Screening
Oncologic/Neoplastic
26. History of malignancy (not including basal or squamous cell
carcinoma of the skin) within the past 5 years; patients who have been
disease free for 5 years may be included
Immune System
27. History or evidence of immunocompromised status, including but not
limited to individuals who have undergone organ transplantation or who
are known to be positive for the HIV
28. Requires treatment with immunosuppressant therapy. Low dose
methotrexate (<=7.5 mg/week) for the treatment of rheumatoid arthritis
is allowed
Other Medical Conditions
29. Donation of 1 unit (500 mL) or more of blood, significant blood loss
equaling at least 1 unit of blood or transfusion within 30 days prior to
Screening
30. Poor mental function or any other reason to expect patient difficulty
in complying with the study requirements
31. Chronic (>10 consecutive days) treatment with systemic
corticosteroids within 8 weeks prior to screening (intra-nasal, intraarticular,
intra-ocular, inhaled or topical steroids are permitted)
32. Requires treatment with weight-loss medications
33. Requires treatment with medications that affect GI motility