The Potential of Dapagliflozin Plus Exenatide in Obese Insulin-resistant Patients
- Conditions
- ObesityDiabetes Mellitus, Type 2
- Interventions
- Drug: Placebo Oral TabletDrug: Placebo injectionDrug: 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 13
Not provided
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Diagnosis of Type 1 Diabetes
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History of diabetic ketoacidosis, hyperosmolar coma or corticosteroid-induced Type 2 diabetes
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Patients with significant thyroid disease
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Patients with history of acute or chronic pancreatitis
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Clinically significant cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularization procedure
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Presence of history of severe congestive heart failure (NYHA III and IV)
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Creatinin-Clearance of < 60 ml/min based on local laboratory results
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Concomitant medication with loop diuretics
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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)
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Pregnant women
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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
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History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥ 700 mg/dL (≥ 7.98 mmol/L) at Visit 0 (Screening).
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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.
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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.
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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).
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Known history of hepatotoxicity with any medication
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Known history of severe hepatobiliary disease.
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Positive serological test for hepatitis B or hepatitis C.
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Known or suspected human immunodeficiency virus (HIV) infection.
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History of organ transplantation.
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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.
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Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 0 (Screening).
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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.
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Patients with abnormal test results of hematocrit (hematocrit > 50% for men; hematocrit > 47% for women)
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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.
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Has donated plasma within 7 days prior to first dose of study medication.
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Any exposure to Exenatide (including BYETTA®, BYDUREON, or exenatide suspension).
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Any exposure to Dapagliflozin or any SGLT-2 inhibitor.
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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