The Potential of Dapagliflozin Plus Exenatide in Obese Insulin-resistant Patients

Phase 3

Terminated

• Conditions: Obesity; Diabetes Mellitus, Type 2
• Interventions: Drug: Dapagliflozin 10mg; Drug: Placebo Oral Tablet; Drug: Exenatide 2 mg [Bydureon]; Drug: Placebo injection; Drug: Insulin; Drug: Metformin, if taken before

• Registration Number: NCT03419624
• Lead Sponsor: Universitätsklinikum Hamburg-Eppendorf

Brief Summary

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%).

Detailed Description

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.

Study Timeline

• Study First Submitted: 2018-01-17
• Study First Submitted QC: 2018-01-26
• Study First Posted: 2018-02-05
• Study Start: 2018-02-19
• Primary Completion: 2019-04-01
• Study Completion: 2019-08-05
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-29
• Last Update Posted: 2020-03-31

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

Not provided

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin plus Exenatide	Exenatide 2 mg [Bydureon]	Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Dapagliflozin plus Exenatide	Dapagliflozin 10mg	Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Exenatide	Insulin	Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
Placebo plus Placebo	Insulin	Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Placebo	Placebo injection	Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Exenatide	Metformin, if taken before	Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
Placebo plus Exenatide	Exenatide 2 mg [Bydureon]	Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
Dapagliflozin plus Exenatide	Insulin	Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Placebo	Placebo Oral Tablet	Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Placebo	Metformin, if taken before	Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Dapagliflozin plus Exenatide	Metformin, if taken before	Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
Placebo plus Exenatide	Placebo Oral Tablet	Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy

Primary Outcome Measures

Name	Time	Method
Change in HbA1c from baseline (week 0) to week 28	28 weeks	To compare the absolute change from baseline in HbA1c at week 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy

Secondary Outcome Measures

Name	Time	Method
Change in HbA1c from baseline (week 0) to week 14	14 weeks	To compare the absolute change in HbA1c from baseline at week 0 to week 14 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in total body weight from baseline (week 0) to week 14 and 28	28 weeks	To compare the change in total body weight from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in BMI from baseline (week 0) to week 14 and 28	28 weeks	To compare the change in BMI from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in FPG from baseline (week 0) to week 14 and 28	28 weeks	To compare the change in fasting plasma glucose (FPG) from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Change in TDID from baseline (week 0) to week 14 and 28	28 weeks	To compare the change in total daily insulin dose (TDID) from baseline at week 0 to week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
Proportion of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline	28 weeks	To compare the number of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline at week 0 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy

Trial Locations

Locations (4)

University Medical Center Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Diabeteszentrum Oldenburg; 🇩🇪 Oldenburg, Lower Saxony, Germany

Diabetologische Schwerpunktpraxis Harburg; 🇩🇪 Hamburg, Germany

Gemeinschaftspraxis für Innere Medizin und Diabetologie; 🇩🇪 Hamburg, Germany