| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 |
| 1. To demonstrate the effect of vildagliptin on the incretin mediated enhancement of insulin secretion (75 g oral glucose vs. matched i.v. glucose) in patients with T2DM treated with metformin by testing the hypothesis that the improvement of the incretin effect assessed as C-peptide IAUC(0-4hr) with vildagliptin 100 mg qd is superior to that with placebo after 2 weeks of treatment. |
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| E.2.2 | Secondary objectives of the trial |
1. To demonstrate the effect of vildagliptin on the incretin mediated enhancement of insulin secretion (75 g oral glucose vs. matched i.v. glucose) in patients with T2DM treated with metformin by testing the hypothesis that the improvement of the incretin effect assessed as ‘insulin secretion rate (ISR) relative to glucose (0-2hr)’ (see Section 10.5.1 for details) with vildagliptin 100 mg qd is superior to that with placebo after 2 weeks of treatment.
2. To evaluate the prandial responses to vildagliptin in patients with T2DM treated with metformin by testing the hypothesis that vildagliptin 100 mg qd has favorable effects relative to placebo on postprandial parameters (derived from C-peptide, insulin, glucagon, GLP-1, and GIP) following an oral glucose challenge or “isoglycemic” intravenous glucose infusion after 2 weeks of treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male, non-fertile female or female of childbearing potential using a medically approved birth control method.
A non-fertile female is defined as: post menopausal (12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/m); 6 weeks post bilateral oophorectomy with or without hysterectomy; post hysterectomy; or sterilized by tubal ligation.
• A female of childbearing potential is defined as any woman physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means.
• Medically approved birth control method include: hormonal contraceptives and IUD. Acceptable methods of contraception may include total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Reliable contraception should be maintained throughout the study.
2. Patients with type 2 diabetes who have received metformin for at least 3 months and have been on a stable dose of at least 1500 mg daily for a minimum of 4 weeks prior to visit 1.
3. Agreement to maintain the same dose of metformin throughout the study.
4. Age 30-78 years.
5. Body mass index (BMI) in the range of 22-35 kg/m2 inclusive at visit 1.
6. HbA1c in the range of 6.5 to 9.0 % inclusive at visit 1.
7. FPG < 200 mg/dl (11.1 mmol/L) at visit 1.
8. Agreement to maintain prior diet and exercise habits during the full course of the study.
9. Ability to comply with all study requirements and signed informed consent to participate in the study.
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| E.4 | Principal exclusion criteria |
1. Pregnant or lactating female.
2. A history of:
• Type 1 diabetes, diabetes that is a result of pancreatic injury, or other secondary forms of diabetes, e.g., Cushing’s syndrome and acromegaly.
• Acute metabolic diabetic complications such as ketoacidosis or hyperosmolar state (coma).
3. Evidence of significant diabetic complications, e.g., symptomatic autonomic neuropathy or gastroparesis.
4. Acute infections which may affect blood glucose control within 4 weeks prior to visit 1 and other concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
5. A history of:
• Torsades de Pointes, sustained and clinically relevant ventricular tachycardia or ventricular fibrillation.
• percutaneous coronary intervention within the past 3 months.
• any of the following within the past 6 months: myocardial infarction (MI) (If the visit 1 ECG reveals patterns consistent with a MI and the date of the event cannot be determined, then the patient can enter the study at the discretion of the investigator and the sponsor); coronary artery bypass surgery; unstable angina; or stroke.
6. Congestive heart failure requiring pharmacologic treatment.
7. Any of the following ECG abnormalities:
• second degree AV block (Mobitz 1 and 2)
• third degree AV block
• prolonged QTc (> 500 msec)
8. Malignancy including leukemia and lymphoma (not including basal cell skin cancer) within the last 5 years.
9. Liver disease such as cirrhosis or chronic active hepatitis.
10. Significant renal dysfunction (see also exclusion criteria 21 laboratory abnormalities).
11. Donation of one unit (500 ml) or more of blood, significant blood loss equaling to at least one unit of blood within the past 2 weeks or a blood transfusion within the past 8 weeks. In addition, patients with anemia, as defined by hemoglobin < 12.0 mg/dL at visit 1, will be excluded.
12. Contraindications and warnings according to the country specific label for metformin not listed in the other exclusion criteria.
13. Treatment with any oral anti-diabetic other than metformin within 3 months prior to visit 1
14. Insulin treatment for longer than 10 days within the past 6 months.
15. Treatment with growth hormone or similar drugs.
16. Chronic oral or parenteral corticosteroid treatment (> 7 consecutive days of treatment) within 8 weeks prior to visit 1.
17. Treatment with class Ia, Ib and Ic or III anti-arrhythmics.
18. Use of other investigational drugs at visit 1, or within 30 days or 5 half-lives of visit 1, whichever is longer, unless local health authority guidelines mandate a longer period.
19. Treatment with any drug with a known and frequent toxicity to a major organ system within the past 3 months (i.e., cytostatic drugs).
20. Any of the following significant laboratory abnormalities:
• ALT, AST greater than 2 times the upper limit of the normal range (ULN) at visit 1, confirmed by a repeat measure within 3 working days.
• Total bilirubin greater than 2 times ULN and direct bilirubin greater than the upper limit of the normal range at visit 1, confirmed by a repeat measure within 3 working days.
• A positive Hepatitis B test (surface antigen -HBsAg).
• A positive Hepatitis C test (HCV antibodies).
• Serum creatinine levels ≥ 1.5 mg/dL (132 µmol/L) males, ≥ 1.4 mg/dL (123µmol/L) females, or a history of abnormal creatinine clearance.
• Clinically significant TSH outside of normal range at visit 1; thyroid hormone replacement is allowed if the dosage has been stable for at least 3 months.
• Clinically significant laboratory abnormalities, confirmed by repeat measurement, other than hyperglycemia, hyperinsulinemia, and glucosuria at visit 1.
• Fasting triglycerides > 700 mg/dL (> 7.9 mmol/l) at visit 1.
21. History of active substance abuse (including alcohol) within the past 2 years, potentially unreliable patients, and those judged by the investigator to be unsuitable for the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessment of the effect of vildagliptin on the incretin mediated enhancement of insulin secretion in patients with T2DM .
The primary efficacy variable is incretin effect assessed as
[C-peptide IAUC(0-4hr) (oral) – C-peptide IAUC(0-4hr) (i.v.)] / [C-peptide IAUC(0-4hr) (oral)] x 100%.
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| 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.8.3 |
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.8.6 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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