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

NCT03419624 | Terminated Phase 3 DMC

• 1 other identifier: UKE-DapEx-001
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 4

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%).

Conditions

Obesity; Diabetes Mellitus, Type 2

Keywords

Dapagliflozin; Exenatide; high-dose insulin therapy; SGLT-2 inhibitor; GLP-1 receptor agonist

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Change in HbA1c from baseline (week 0) to week 14

  14 weeks

• Change in total body weight from baseline (week 0) to week 14 and 28

  28 weeks

• Change in BMI from baseline (week 0) to week 14 and 28

  28 weeks

• Change in FPG from baseline (week 0) to week 14 and 28

  28 weeks

• Change in TDID from baseline (week 0) to week 14 and 28

  28 weeks

Study Arms (3)

Dapagliflozin plus Exenatide

EXPERIMENTAL

Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy

Drug: Dapagliflozin 10mg; Drug: Exenatide 2 mg [Bydureon]; Drug: Insulin; Drug: Metformin, if taken before

Placebo plus Placebo

PLACEBO COMPARATOR

Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy

Drug: Placebo Oral Tablet; Drug: Placebo injection; Drug: Insulin; Drug: Metformin, if taken before

Placebo plus Exenatide

ACTIVE COMPARATOR

Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy

Drug: Exenatide 2 mg [Bydureon]; Drug: Placebo Oral Tablet; Drug: Insulin; Drug: Metformin, if taken before

Interventions

Dapagliflozin 10mg DRUG

Dapagliflozin 10 mg tablet once daily

Dapagliflozin plus Exenatide

Exenatide 2 mg [Bydureon] DRUG

Exenatide 2 mg injection once weekly

Dapagliflozin plus Exenatide; Placebo plus Exenatide

Placebo Oral Tablet DRUG

Placebo oral tablet once daily

Placebo plus Exenatide; Placebo plus Placebo

Placebo injection DRUG

Placebo injection once weekly

Placebo plus Placebo

Insulin DRUG

daily Insulin injections

Dapagliflozin plus Exenatide; Placebo plus Exenatide; Placebo plus Placebo

Metformin, if taken before DRUG

If the Patient has taken Metformin prior to enrollment, he or she will continue to take it.

Dapagliflozin plus Exenatide; Placebo plus Exenatide; Placebo plus Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Diagnosis of Type 1 Diabetes
• History of diabetic ketoacidosis, hyperosmolar coma or corticosteroid-induced Type 2 diabetes
• Patients with significant thyroid disease
• Patients with history of acute or chronic pancreatitis
• Clinically significant cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularization procedure
• Presence of history of severe congestive heart failure (NYHA III and IV)
• Creatinin-Clearance of \< 60 ml/min based on local laboratory results
• Concomitant medication with loop diuretics
• 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)
• Pregnant women
• History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥ 700 mg/dL (≥ 7.98 mmol/L) at Visit 0 (Screening).
• 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.
• 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.
• 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).
• Known history of hepatotoxicity with any medication

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead
• AstraZeneca: collaborator

Study Sites (4)

Diabeteszentrum Oldenburg

Oldenburg, Lower Saxony, 23758, Germany

Location

University Medical Center Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Diabetologische Schwerpunktpraxis Harburg

Hamburg, 21073, Germany

Location

Gemeinschaftspraxis für Innere Medizin und Diabetologie

Hamburg, 22607, Germany

Location

Related Publications (19)

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  PMID: 26213556 BACKGROUND

• 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.

  PMID: 22431673 BACKGROUND

• 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.

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• 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. No abstract available.

  PMID: 22517736 BACKGROUND

• 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. No abstract available.

  PMID: 22526604 BACKGROUND

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  PMID: 21307137 BACKGROUND

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  BACKGROUND

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  BACKGROUND

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

  PMID: 25436106 BACKGROUND

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

  BACKGROUND

• Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman 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.

  PMID: 27651331 BACKGROUND

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  BACKGROUND

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  BACKGROUND

MeSH Terms

Conditions

Obesity; Diabetes Mellitus, Type 2

Interventions

dapagliflozin; Exenatide; Insulin; Metformin

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Jens Aberle, MD

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2018
• First Posted: February 5, 2018
• Study Start: February 19, 2018
• Primary Completion: April 1, 2019
• Study Completion: August 5, 2019
• Last Updated: March 31, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

DE (4)