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

Obesity Clinical Trial

Official title:

A 28-week, Multi-center Randomized, Double-blind, Placebo-controlled Study to Evaluate the Potential of Dapagliflozin Plus Exenatide in Combination With High-dose Intensive Insulin Therapy Compared to Placebo in Obese Insulin-resistant Patients With Type 2 Diabetes Mellitus (Proof-of-concept Study)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03419624
• Other study ID #: UKE-DapEx-001
• Status: Terminated
• Phase: Phase 3
• Start date: February 19, 2018
• Est. completion date: August 5, 2019

Study information

• Verified date: March 2020
• Source: Universitätsklinikum Hamburg-Eppendorf
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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%).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: August 5, 2019
• Est. primary completion date: April 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 [ßhCG]) 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).

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Obesity

Intervention

Drug:
• Dapagliflozin 10mg
Dapagliflozin 10 mg tablet once daily
• Exenatide 2 mg [Bydureon]
Exenatide 2 mg injection once weekly
• Placebo Oral Tablet
Placebo oral tablet once daily
• Placebo injection
Placebo injection once weekly
• Insulin
daily Insulin injections
• Metformin, if taken before
If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Locations

Country	Name	City	State
Germany	Diabetologische Schwerpunktpraxis Harburg	Hamburg
Germany	Gemeinschaftspraxis für Innere Medizin und Diabetologie	Hamburg
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	Diabeteszentrum Oldenburg	Oldenburg	Lower Saxony

Sponsors (2)

Lead Sponsor	Collaborator
Universitätsklinikum Hamburg-Eppendorf	AstraZeneca

Country where clinical trial is conducted

Germany, 

References & Publications (19)

2012. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus n.d. ema.europa.eu.

Anderson SL. Dapagliflozin efficacy and safety: a perspective review. Ther Adv Drug Saf. 2014 Dec;5(6):242-54. doi: 10.1177/2042098614551938. Review. — View Citation

Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, Trautmann M, Porter L. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011 May;96(5):1301-10. doi: 10.1210/jc.2010-2081. Epub 2011 Feb 9. — View Citation

Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, Trautmann M. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010 Jun 26;375(9733):2234-43. doi: 10.1016/S0140-6736(10)60406-0. — View Citation

Dixon JB, O'Brien PE. Health outcomes of severely obese type 2 diabetic subjects 1 year after laparoscopic adjustable gastric banding. Diabetes Care. 2002 Feb;25(2):358-63. — View Citation

EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes 2016. www.ema.europe.eu.

FDA Approves Bydureon Pen. 2014 n.d. drugs.com.

FDA approves Farxiga to treat type 2 diabetes. 2014 n.d. fda.gov.

Finkelstein EA, Khavjou OA, Thompson H, Trogdon JG, Pan L, Sherry B, Dietz W. Obesity and severe obesity forecasts through 2030. Am J Prev Med. 2012 Jun;42(6):563-70. doi: 10.1016/j.amepre.2011.10.026. — View Citation

Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016 Dec;4(12):1004-1016. doi: 10.1016/S2213-8587(16)30267-4. Epub 2016 Sep 16. Erratum in: Lancet Diabetes Endocrinol. 2017 Dec;5(12 ):e8. — View Citation

Holman R. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ Annu Diabetol Hotel Dieu. 2007:13-20. — View Citation

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012 Jun;55(6):1577-96. doi: 10.1007/s00125-012-2534-0. Epub 2012 Apr 20. Erratum in: Diabetologia. 2013 Mar;56(3):680. — View Citation

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364-79. doi: 10.2337/dc12-0413. Epub 2012 Apr 19. Review. Erratum in: Diabetes Care. 2013 Feb;36(2):490. — View Citation

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008 Jan;31(1):173-5. doi: 10.2337/dc08-9016. — View Citation

Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015 Jul 9;4:212283. doi: 10.7573/dic.212283. eCollection 2015. Review. — View Citation

Sharma S, Jain S. Prevalence of Obesity among Type-2 Diabetics. J Hum Ecol 2009;25:31-5.

Tatarkiewicz K, Polizzi C, Villescaz C, D'Souza LJ, Wang Y, Janssen S, Parkes DG. Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice. Diabetes Obes Metab. 2014 Apr;16(4):376-80. doi: 10.1111/dom.12237. Epub 2013 Dec 9. — View Citation

Wangnoo SK, Sethi B, Sahay RK, John M, Ghosal S, Sharma SK. Treat-to-target trials in diabetes. Indian J Endocrinol Metab. 2014 Mar;18(2):166-74. doi: 10.4103/2230-8210.129106. Review. — View Citation

Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012 Mar 20;156(6):405-15. doi: 10.7326/0003-4819-156-6-201203200-00003. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in HbA1c from baseline (week 0) to week 28	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	28 weeks
Secondary	Change in HbA1c from baseline (week 0) to week 14	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	14 weeks
Secondary	Change in total body weight from baseline (week 0) to week 14 and 28	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	28 weeks
Secondary	Change in BMI from baseline (week 0) to week 14 and 28	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	28 weeks
Secondary	Change in FPG from baseline (week 0) to week 14 and 28	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	28 weeks
Secondary	Change in TDID from baseline (week 0) to week 14 and 28	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	28 weeks
Secondary	Proportion of patients achieving HbA1c of = 7% at week 28 compared to baseline	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	28 weeks