Delay in patient enrolment

This is a 28-week, multi-center, randomized, double-blind, placebo-controlled trial to study a potential synergistic effect of Dapagliflozin plus Exenatide once-weekly in combination with high-dose intensive insulin therapy compared to Placebo in obese insulin-resistant patients with Type 2 Diabetes mellitus (T2DM) and inadequate glycemic control (HbA1c≥8.0% and ≤ 11.0%).

In this proof-of-concept study the potential of treatment with Dapagliflozin plus Exenatide added to high-dose intensive insulin therapy compared to Placebo added to high-dose intensive insulin with active insulin up-titration for change in HbA1c from baseline to week 28 shall be explored and generate initial data on the primary outcome. We hypothesize that SGLT-2 inhibition and GLP-1 receptor agonism may be a rational combination therapy that addresses a broad range of pathophysiological defects associated with T2DM in obesity and may reduce HbA1c levels in patients with severe insulin resistance. In a third treatment arm, patients will be treated with Exenatide monotherapy added to high-dose intensive Insulin therapy to study additive effects of Dapagliflozin and Exenatide.

For inclusion in the study patients should fulfill the following key criteria:

1. Informed Consent can be obtained prior to any study procedures.

2. Patient is able to read, understand and sign the Informed Consent.

3. HbA1c ≥ 8.0% and ≤ 11.0% based on laboratory results

4. Currently treated with a stable TDID ≥ 80 U at least 3 months prior to enrolment

5. Patients who are receiving metformin must be on a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment

6. BMI of ≥ 30 kg/m2 at enrolment

7. Male or female and ≥18 and ≤75 years old at time of informed consent

8. For female patients:

   • Not breastfeeding.
   • Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at Visit 0 (Screening) and Visit 1 (randomization) -not applicable to hysterectomized and post-menopausal females.
   • If of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year), must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, ie, less than 1% per year, when used consistently and correctly, such as implants, injectables, hormonal contraceptives [pills, vaginal rings, or patches], some intrauterine contraceptive devices [levonorgestrel-releasing or copper-T], tubal ligation or occlusion, or a vasectomized partner) during the entire duration of the study. As applicable, all methods must be in effect prior to receiving the first dose of study medication.
   • Must practice appropriate birth control as stated above for 10 weeks after the last dose of study medication.

9. Patients who are receiving the following medications must be on a stable treatment regimen for a minimum of 2 months prior to Visit 0 (Screening):

   • Antihypertensive agents
   • Thyroid replacement therapy
   • Antidepressant agents

Exclusion Criteria:

1. Diagnosis of Type 1 Diabetes

2. History of diabetic ketoacidosis, hyperosmolar coma or corticosteroid-induced Type 2 diabetes

3. Patients with significant thyroid disease

4. Patients with history of acute or chronic pancreatitis

5. Clinically significant cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularization procedure

6. Presence of history of severe congestive heart failure (NYHA III and IV)

7. Creatinin-Clearance of < 60 ml/min based on local laboratory results

8. Concomitant medication with loop diuretics

9. Patients who, as judged by the investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety (including e.g. patients with a history of Diabetes insipidus)

10. Pregnant women

11. Administration of any other antidiabetic therapy, other than insulin (see inclusion criterion no.4 and 5) and metformin with a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment

12. History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥ 700 mg/dL (≥ 7.98 mmol/L) at Visit 0 (Screening).

13. History or presence of inflammatory bowel disease or other severe GI diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis.

14. History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study. Current use of gastric balloons is also excluded.

15. Significant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or total bilirubin (TB) >2 mg/dL (>34.2 μmol/L) (patients with TB >2 mg/dL [>34.2 μmol/L] and documented Gilbert's syndrome will be allowed to participate).

16. Known history of hepatotoxicity with any medication

17. Known history of severe hepatobiliary disease.

18. Positive serological test for hepatitis B or hepatitis C.

19. Known or suspected human immunodeficiency virus (HIV) infection.

20. History of organ transplantation.

21. Presence or history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2) OR a family history of medullary thyroid carcinoma or MEN 2.

22. Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 0 (Screening).

23. Hemoglobinopathy, hemolytic anemia, or chronic anemia (haemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) or any other condition known to interfere with the HbA1c methodology.

24. Patients with abnormal test results of hematocrit (hematocrit > 50% for men; hematocrit > 47% for women)

25. Has donated blood or had a significant blood loss within 2 months of first dose of study medication or is planning to donate blood during the study.

26. Has donated plasma within 7 days prior to first dose of study medication.

27. Any exposure to Exenatide (including BYETTA®, BYDUREON, or exenatide suspension).

28. Any exposure to Dapagliflozin or any SGLT-2 inhibitor.

29. Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following treatment excluded medications:

    • Any DPP-4 inhibitor within 3 months prior to Visit 0 (Screening).
    • Any GLP-1 analog within 1 year prior to Visit 0 (Screening).
    • Systemic corticosteroids within 3 months prior to Visit 0 (Screening) by oral, intravenous, intra-articular, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR) steroids known to have a high rate of systemic absorption. For examples of excluded steroids, refer to Section 7.7.
    • Prescription or over-the-counter weight loss medications within 3 months prior to Visit 0 (Screening).