E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients suffering of both Type 2 diabetes mellitus and coronary artery disease |
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E.1.1.1 | Medical condition in easily understood language |
Patients with both coronary heart disease and diabetes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011079 |
E.1.2 | Term | Coronary artery disease NOS |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Main Objective of the Trial
To investigate whether glucagon-like peptide-1 (GLP-1) analogue combined with metformin therapy compared to metformin monotherapy
a) improves betacell function
b) improves left ventricular ejection fraction (LVEF) during stress test
in newly diagnosed type-2 diabetes mellitus (T2D) patients, who exhibit stable coronary artery disease (CAD)
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E.2.2 | Secondary objectives of the trial |
Secondary Objective of the Trial
To investigate whether glucagon-like peptide-1 (GLP-1) analogue combined with metformin therapy compared to metformin monotherapy
a) improves insulin sensitivity and food induced glucagon response
b) improves prognostic markers of cardiovascular disease,including 24 h heart rate variability (HRV) and diurnal blood pressure
in newly diagnosed type-2 diabetes mellitus (T2D) patients, who exhibit stable coronary artery disease (CAD)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Stable CAD documented by either;
a) previous MI (a minimum of 6 weeks after acute MI)
b) previous coronary revascularization
c) CAD confirmed by an abnormal coronary arteriograph (CAG) or CT-angiography showing stenosis > 50% of any major coronary arteries.
Body mass index (BMI) >/= 25,0 kg/m2
Age from 18 to 85 years of age
Type 2 diabetes diagnosed either as:
a) HbA1c >/= 6.5% but </= 8.5%
b) HbA1c <6.5 % and fasting plasma glucose >/= 7.0 mmol/l (confirmed)
c) HbA1c <6.5 % and a 2 h plasma glucose value during OGTT >/= 11.1 mmol/l
The data for glucose metabolism are accepted provided that they have been obtained within 20 weeks before screening of the patient. The glucose metabolic categories are defined by ADA and WHO criteria
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E.4 | Principal exclusion criteria |
Type 1 diabetes mellitus defined as C-peptide < 450 pM
Previously diagnosed diabetes mellitus before screening by OGTT except from previous gestational diabetes
Previous use of antidiabetic medication except from use during previous gestational diabetes. It is accepted that the patient has been treated with oral anti diabetic drugs (OAD) after diagnosis of T2D as long as the patient pause OAD at least 4 weeks before baseline measurements in this trial
Significant heart disease (NYHA > 2; Ejection Fraction < 40%, unstable angina pectoris, atrial fibrillation)
Liver disease (transaminases > x2 greater than upper normal level)
Renal diseases (eGFR < 50)
Any chronic medical condition to unduly increase risk for the potential enrollee as judge by study investigators
Anemia (<85% of lower normal limit), leucopenia (<85% of lower normal limit), or thrombocytopenia (< 85% of lower normal limit)
Pregnancy or failure to comply with contraceptional planning within two years, or breastfeeding
Abuse of alcohol or drugs, or any other co-existing condition that would make patients unsuitable to participate in the study, as deemed by the investigators
Use of immunosuppressive therapy in the preceding 12 months
Chronic pancreatitis / previous acute pancreatitis
Known or suspected hypersensitivity to trial product(s) or related products
Treatment with oral glucocorticoids, calcineurin inhibitors, or dipeptidyl peptidase 4 (DPP4) inhibitors, or other GLP-1 mimetics (Exenatide), which in the Investigator’s opinion could interfere with glucose metabolism
Cancer (except basal cell skin cancer or squamous cell skin cancer) or any other clinically significant disorder, which in the Investigator’s opinion could interfere with the results of the trail
Inflammatory bowel disease
Previous bowel resection
Clinical signs of diabetic gastroparesis
The receipt of any investigational product 90 days prior to this trial
Screening calcitonin ≥ 50 ng/l
Subjects with personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia type 2
Refusal to sign informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
Endocrine:
1) Beta-cell function (disposition index) as measures during an intravenous glucose tolerance test (By Bergman Minimal Model)
Cardiovascular:
1) Dobutamine (stress) induced changes in Left ventricular ejection fraction (LVEF)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoints will be evaluated at baseline (week 0), after week 12, after week 14 (following 2 weeks of wash-out) and finallty after week 26 |
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E.5.2 | Secondary end point(s) |
Endocrine/metabolic:
a) Glucagon, incretin, glucose, NEFA, insulin and C-peptide response during meal test
b) Insulin sensitivity (Si), acute insulin and C-peptide response to intravenous glucose (AIRg, ACRg), glucose clearance (Kg), glucose effectiveness (Sg) and hepatic extraction of insulin (HEXi) derived from a standard frequent sampling intravenous glucose tolerance test (FSIGT, Minimal model)
c) CRP, TNFα and IL-6 in plasma and gene expression of IL6 and TNFa in sc. fat
d) NEFA during FSIGT by use of NEFA minimal model
Cardiovascular:
a) Heart rate variability in particular SDNN, i.e. the standard deviation of all normal RR interval assessed during HOLTER monitoring)
b) Maximal velocity of the myocardium in systole (s´) and in diastole (e´) during the dobutamine stress test
c) Changes in exercise tolerance test variables: Total exercise duration (sec), time to limiting angina (sec) and time to 1 mm ST-segment depression (sec)
d) ST-depression and ectopic activity assessed during 24h HOLTER monitoring
e) Diurnal blood pressure
f) Diastolic heart function (E/E*) in rest and during stress
g) The liraglutide effect on LVEF during the dobutamine stress test is supposed to be most prominent in those patients with remaining ischemic components of the heart, i.e. those with significant stenosis where fully revascularization has not been obtained.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The endpoints will be evaluated at baseline (week 0), after week 12, after week 14 (following 2 weeks of wash-out) and finallty after week 26 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Anticipated to be November 2013 but will be possible to extend this date another 6 months |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |