| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Men or women who are >18 years of age or older at the enrolment visit (visit 1) diagnosed with type 2 diabetes and treated with diet alone or on treatment with a single oral anti diabetic agent or low doses of two agents. |
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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 |
Is to assess whether tesaglitazar given as monotherapy is non-inferior to glibenclamide given as monotherapy during 52 weeks in improving glycaemic control in patients with type 2 diabetes as determined by the absolute change in glycosylated haemoglobin A1c (HbA1c), from baseline to the end of the randomized treatment period.
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| E.2.2 | Secondary objectives of the trial |
To compare the effects of tesaglitazar monotherapy versus glibenclamide monotherapy by evaluation of:
-the change in lipid and lipoprotein variables
-responder rates as determined by the proportion of patients achieving a pre specified changed from baseline to the end of the randomized treatment period, TG, HDL-C, non-HDL-C and LDL-C
-proportion of patients reaching pre-specified target levels for TG, HDL C, non HDL-C and LDL-C
-the change in FPG, insulin, proinsulin and C peptide
-insulin sensitivity by assessment of change in the calculated variable HOMA
-the responder rates and proportion of patients achieving a pre-specified target levels for both HbA1c and FPG
To compare the effects on the levels of risk markers for cardiovascular disease, on the levels of inflammatory markers, on a marker of thrombosis/coagulation (fibrinogen), on urinary albumin excretion, on the waist-hip ratio.
To evaluate the pharmacokinetics, and safety and tolerability
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Inclusion criteria at enrolment (visit 1):
1. Provision of a written informed consent at visit 1
2. Men or women who are > or equal to 18 years of age at time of consenting upon visit 1
3. Female patients post menopausal, hysterectomized or if of childbearing potential using a reliable method of birth control
Post menopausal patients are defined as patients with:
- natural or induced menopause with last menstruation >1 year ago, or
- bilateral oophorectomy
Reliable birth control is defined as barrier method (condoms with spermicide, diaphragm with spermicide), oral contraceptive, implant, long term injectable contraceptive, intrauterine device, or tubal ligation.
4. Diagnosed with type 2 diabetes
5. Treated with diet alone or treatment with a single oral agent or low doses of two agents. All anti-diabetic medications are to be discontinued at visit 1
Inclusion criteria at placebo run-in (visit 2, lab values from visit 1):
6. For patients < 30 years old C-peptide concentrations has to be >0.8 ng/mL, 0.3 nmol/L
7. HbA1c > or equal to 7 % for patients not on any anti-diabetic drug for 12 weeks prior to visit 1
8. HbA1c < or equal to 10%
9. FPG < or equal to13.3 mmol/L, 240 mg/dL
Inclusion criteria at randomization (visit 5, lab values from visit 3 and 4):
10. HbA1c > or equal to 7 % for patients not on any anti-diabetic drug for 12 weeks prior to visit 1
11. HbA1c < or equal to 10%
12. Mean FPG from two measurements (lab values from visit 3 and 4) FPG < or equal to 13.3 mmol/L, 240 mg/dL.
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| E.4 | Principal exclusion criteria |
1. Type 1 diabetes, history of diabetic ketoacidosis, or corticosteroid-induced type 2 diabetes
2. Active arterial disease such as unstable angina, myocardial infarction, transient ischaemic attack (TIA), cerebrovascular accident (CVA), myocardial or peripheral vascular disease (PVD) revascularization or angioplasty within 24 weeks prior to visit 1
3. NYHA heart failure Class III or IV, or unstable Class I or II as judged by the investigator. For definitions see Appendix F.
4. History of thyroid ophthalmopathy
5. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma
6. History of blood lipid induced eruptive xanthomas or hypertriglyceridaemia induced pancreatitis
7. Pregnant or breastfeeding patients
8. Suspicion that the patient is infected according to world health organisation (WHO) risk categories 2 to 4
9. Treatment with chronic insulin, within 24 weeks prior to visit 1 (however, one temporary period of daily insulin injections no longer than 7 days is allowed)
10. Treatment with combination therapy (i.e. two anti diabetic agents, except low doses of two agents, see Section 3.4.4) within 12 weeks prior to visit 1
11. Treatment with a thiazolidinedione within 4 weeks prior to visit 1
12. Treatment with fibrates, within 4 weeks prior to visit 1
13. Treatment with glucocorticoids (equivalent to oral prednisolon >10 mg per day), within 4 weeks prior to visit 1
14. Treatment with probenecid that cannot be stopped at visit 1
15. History of hypersensitivity or intolerance to any PPAR agonist
16. Intolerance to glibenclamide at any time in the past, or preexisting medical conditions that is contraindicated for the use of glibenclamide
17. History of drug-induced myopathy or drug-induced CK elevation
18. History of drug-induced liver enzyme elevations
19. History of drug-induced neutropenia
20. History of alcohol or drug abuse within the last 5 years
21. Other serious or unstable medical or psychological condition identified in the patient’s medical history that, in the judgement of the investigator, would compromise the patients’ safety or successful participation in the Clinical Study
22. Receiving any investigational product within 12 weeks prior to visit 1
23. Previous enrolment in this study.
Exclusion criteria at placebo run-in (visit 2, lab values from visit 1)
24. Any clinically significant abnormality identified on physical examination, laboratory tests or ECG, which in the judgement of the investigator would compromise the patients´ safety or successful participation in the study.
25. NYHA heart failure Class III or IV, or unstable Class I or II as judged by the investigator. For definitions see Appendix F.
26. Fasting TG >7.0 mmol/L, 620 mg/dL
27. Hb < 90 g/L, 9 g/dL
28. ANC < 1.0 x 109/L
29. Any of alanine aminotransferase (ALT), aspartate transaminase (AST) or alkaline phosphatase (ALP) >2.5 times the upper limit of normal
30. Total bilirubin above the upper limit of normal unless exclusively caused by Gilbert’s syndrome
31. Creatinine >2 times the upper limit of normal
32. CK >3 times the upper limit of normal
Exclusion criteria at randomization (visit 5, lab values from visit 4)
33. Any clinically significant abnormality identified on physical examination, laboratory tests or ECG, which in the judgement of the investigator would compromise the patients´ safety or successful participation in the Clinical Study
34. NYHA heart failure Class III or IV, or unstable Class I or II as judged by the investigator. For definitions see Appendix F
35. Other serious or unstable medical or psychological condition identified on medical history that, in the judgement of the investigator, would compromise the patients’ safety or successful participation in the Clinical Study
36. High blood pressure (mean diastolic BP >120 mmHg) or malignant hypertension
37. Hb <90 g/L, 9 g/dL
38. ANC < 1.0 x 109/L
39. Any of ALT, AST or ALP >2.5 times the upper limit of normal
40. Total bilirubin above the upper limit of normal unless exclusively caused by Gilbert’s syndrome
41. Creatinine >2 times the upper limit of normal
42. CK >3 times the upper limit of normal
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change in glycosylated haemoglobin A1c (HbA1c), from baseline to the end of the randomized treatment period. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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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| End of study is defined as date of database lock. The study is expected to start in June 2004, and to be completed in July 2006 |
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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 | 25 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 25 |
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