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)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 4
- 主要终点
- Change in HbA1c from baseline (week 0) to week 28
研究概览
简要总结
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%).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •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
- •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
- •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
- •Known history of severe hepatobiliary disease.
- •Positive serological test for hepatitis B or hepatitis C.
- •Known or suspected human immunodeficiency virus (HIV) infection.
- •History of organ transplantation.
- •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
- •Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 0 (Screening).
- •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.
- •Patients with abnormal test results of hematocrit (hematocrit > 50% for men; hematocrit > 47% for women)
- •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.
- •Has donated plasma within 7 days prior to first dose of study medication.
- •Any exposure to Exenatide (including BYETTA®, BYDUREON, or exenatide suspension).
- •Any exposure to Dapagliflozin or any SGLT-2 inhibitor.
- •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.
- •Prescription or over-the-counter weight loss medications within 3 months prior to Visit 0 (Screening).
研究组 & 干预措施
Dapagliflozin plus Exenatide
Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Dapagliflozin 10mg (Drug)
Dapagliflozin plus Exenatide
Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Exenatide 2 mg [Bydureon] (Drug)
Dapagliflozin plus Exenatide
Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Insulin (Drug)
Dapagliflozin plus Exenatide
Dapagliflozin (10mg orally once daily) plus Exenatide (2mg subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Metformin, if taken before (Drug)
Placebo plus Placebo
Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Placebo Oral Tablet (Drug)
Placebo plus Placebo
Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Placebo injection (Drug)
Placebo plus Placebo
Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Insulin (Drug)
Placebo plus Placebo
Placebo (film-coated tablet once daily) plus Placebo (subcutaneous once-weekly injection) as add-on to high-dose intensive insulin therapy
干预措施: Metformin, if taken before (Drug)
Placebo plus Exenatide
Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
干预措施: Exenatide 2 mg [Bydureon] (Drug)
Placebo plus Exenatide
Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
干预措施: Placebo Oral Tablet (Drug)
Placebo plus Exenatide
Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
干预措施: Insulin (Drug)
Placebo plus Exenatide
Placebo (film-coated tablet once daily) plus Exenatide (2mg subcutaneous once- weekly injection) as add-on to high dose intensive insulin therapy
干预措施: Metformin, if taken before (Drug)
结局指标
主要结局
Change in HbA1c from baseline (week 0) to week 28
时间窗: 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
次要结局
- 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)
- Proportion of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline(28 weeks)