Multicentric Cross-over Trial to Assess the Glycemic Profiles on 8 Weeks of Vildagliptin and Sitagliptin Treatment, Each, in Type-2 Diabetic Patients With a Pre-existing Cardiovascular Disease Pre-treated With Insulin, Using a PROBE-design
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2
研究概览
简要总结
Vildagliptin and Sitagliptin both belong to the class of DPP-4 inhibitors, but differ in their pharmacokinetic profile as well as in their approved application (Vildagliptin, 2x 50 mg daily, Sitagliptin, 1x 100 mg daily). This leads to distinct results regarding postprandial blood-glucose normalization as well as protective properties regarding hypoglycemic episodes - especially during the night. Additionally, in type 1 diabetic patients a correlation has been described between hypoglycemia and abnormal heart function (QTc-elongation), which can have severe consequences for the patients. This study aims for the evaluation of the potency of both drugs to prevent and/or reduce hypoglycemic events in insulin-dependent type-2 diabetics and furthermore to evaluate the correlation of hypoglycemic episodes with changes in heart-function measured by Holter-ECG.
The hypothesis is tested, if vildagliptin leads to a more favourable glycemic profile than sitagliptin and is more potent in protecting from nocturnal abnormalities in heart-function caused by undetected hypoglycemic episodes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Ability to comply with all study requirements.
- •Patients with Type 2 diabetes treated with stable, once or twice daily doses (minimal dose of 0.3 unit/kg/day) of basal long-acting or intermediate-acting insulin alone or in pre-mixed combination with rapid-acting or short-acting insulin for at least 12 weeks prior to Visit
- •Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks.
- •Patients receiving metformin must be on a stable dose of metformin (at least 1500 mg daily or a maximally tolerated dose) for at least 12 weeks prior to Visit
- •HbA1c ≥7.5 to ≤ 9,0% at Visit 1
- •Known CV disease based on a documented history of one or more of pre-defined criteria
- •Age: ≥40 to ≤80 years at Visit 1
排除标准
- •FPG ≥ 270 mg/dL (15 mmol/L) at Visit
- •Use of any of the following medications as assessed at Visit 1:
- •rapid or short acting insulin except in pre-mixed formulations with intermediate or long-acting insulin; insulin administration more frequently than twice-daily, or total insulin dose < 0.3 unit/kg/day for the past 12 weeks
- •use of any oral antidiabetic medication or GLP-1 analogues within the last 12 weeks, except metformin
- •use of weight control products including weight-loss medications in the last 12 weeks.
- •use of oral (≥7 consecutive days) or chronic parenteral or intra-articular corticosteroid treatment within the last 8 weeks. Inhaled or topical steroids without systemic effects will be allowed.
- •treatment with growth hormone within the previous 6 months.
- •treatment with any drug of known and frequent toxicity to a major organ, or that may interfere with the interpretation of the efficacy and safety data during the study.
- •a history or evidence of any of the following at Visit 1:
- •acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state (including precoma and coma) within the past 6 months.
- •current diagnosis of congestive heart failure (NYHA III or IV).
- •myocardial infarction within the past 6 months.
- •coronary artery bypass surgery or percutaneous coronary intervention within the past 6 months.
- •Stroke, transient ischemic attack, or reversible ischemic neurologic deficit within the past 6 months.
- •unstable angina within the past 6 months.
- •sustained and clinically relevant ventricular arrhythmia (patients with premature ventricular contractions if deemed not clinically significant may be enrolled).
- •Patients with permanent atrial fibrillation or pacemaker.
- •active substance abuse, alcohol abuse and history of alcohol-related diseases within the past 2 years.
- •type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing's syndrome or acromegaly-associated diabetes).
- •malignancy of an organ system (other than localized basal cell carcinoma of the skin) treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
- •hepatic disorder defined as:
- •acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal hypertension.
- •history of imaging abnormalities that suggest liver disease (except hepatic steatosis), such as portal hypertension, capsule scalloping, cirrhosis.
- •acute infections which may affect blood glucose control within the past 4 weeks.
- •any of the following significant laboratory abnormalities as assessed at Visit 1:
- •clinically significant increase or reduction in thyroid stimulating hormone (TSH) outside of the normal range.
- •clinically significant renal dysfunction: glomerular filtration rate (GFR) <50 mL/min/1.73m2 (via MDRD formula).
- •Patients on metformin with a GFR <60 mL/min/1.73m2 (via MDRD formula).
- •alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) at Visit 1, confirmed by repeated measurements within 3 working days.
- •total bilirubin > 2 x ULN and/or direct bilirubin > 1 x ULN confirmed by repeated measurements within 3 working days.
- •positive Hepatitis B surface antigen (HBsAg).
- •positive Hepatitis C virus (HCV) antibody test (anti-HCV).
- •elevated fasting triglycerides (TGs) > 500mg/dL (5.65mmol/L), confirmed by a repeated measurements within 3 working days.
- •clinically significant laboratory abnormalities which, in the opinion of the investigator, cause the patient to be considered inappropriate for inclusion in the study.
- •any of the following electrocardiographic abnormalities at Visit 1:
- •second or third degree atrio-ventricular block.
- •A QTc of > 440 ms.
- •clinically significant electrocardiogram (ECG) abnormalities which, in the opinion of the investigator, may cause the patient to be considered inappropriate for inclusion in the study
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Vildagliptin followed by Sitagliptin
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks
干预措施: Vildagliptin (Drug)
Vildagliptin followed by Sitagliptin
Period 1: vildagliptin 50mg BID for 8 weeks; followed by Washout then Period 2: sitagliptin 100mg QD for 8 weeks
干预措施: Sitagliptin (Drug)
Sitagliptin followed by Vildagliptin
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks
干预措施: Vildagliptin (Drug)
Sitagliptin followed by Vildagliptin
Period 1: sitagliptin 100mg QD for 8 weeks; followed by Washout then Period 2: vildagliptin 50mg BID for 8 weeks
干预措施: Sitagliptin (Drug)
结局指标
主要结局
Hypoglycemic Profile of Vildagliptin Compared to Sitagliptin Over 4 Days After 8 Weeks of Treatment in Period 1 & 2
时间窗: baseline and 0-24 hours post-dose on Days 2 to 5
The hypoglycemic profile is defined as the area under the curve glucose-time profile obtained by continuous glucose monitoring Interstitial glucose values below 3.9 mmol/L (averaged over 5 minutes) were considered relevant for the estimation of the interstitial glucose AUC in the hypoglycemic range These AUC\<3.9mmol/L/5min. values were summed up over 4 days (unit: mmol/L/4d) or over 24 hours at measurement Days 2, 3, 4, and 5 (unit: mmol/L/24h). Lower values for AUC reflect less intense hypoglycemia.
次要结局
- Number of Occurrence of Pre-defined ECG Findings During 4 Days of Continuous ECG Monitoring at Baseline and in the 8th Week of Periods 1 and 2(after 8 weeks Period 1 & Period 2)
- Glucose Fluctuations During the Day Under Vildagliptin Treatment Compared to Sitagliptin Treatment on Day 2 After 8 Weeks of Treatment Period 1 & Period 2(Day 2 after 8 weeks of treatment Period 1 & Period 2)
- Number of Participants With ECG Abnormalities Depending on Hypoglycemic Events After 8 Weeks of Treatment Period 1 & Period 2(after 8 weeks of treatment Period 1 & Period 2)
- Number of Severe Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment After 8 Weeks of Treatment in Period 1 and Period 2(after 8 weeks Period 1 & Period 2)
- Change From Baseline of Inflammatory Biomarkers Interleukin 6 (IL-6) After 8 Weeks of Treatment in Period 1 & Period 2(Baseline, after 8 weeks Period 1 & Period 2)
- Percentage Change From Baseline of Pro-insulin/C-peptide Ratios After 8 Weeks of Treatment Period 1 & Period 2(Baseline, after 8 weeks Period 1 & Period 2)
- Mean Amplitudes of Hypoglycemic Events (mmol/L) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2(after 8 weeks Period 1 & Period 2)
- Number of Hypoglycemic Events During Vildagliptin Treatment Compared to Sitagliptin Treatment.(after 8 weeks period 1 and Period 2)
- Mean Duration of Hypoglycemic Events (Min.) Measured With Continuous Glucose Monitoring (CGM) Over 4 Days After 8 Weeks of Treatment for Period 1 & Period 2(after 8 weeks for Period 1 & Period 2)
- Change From Baseline of Inflammatory Biomarkers High Sensitivity C-reactive Protein (hsCRP) After 8 Weeks of Treatment in Period 1 & Period 2(Baseline, after 8 weeks Period 1 & Period 2)