| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Diabetes Mellitus |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
|
| 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 |
| To compare the effect of 1 mg tesaglitazar once daily versus placebo once daily given as add?on therapy to metformin on the steady state exposure (AUCss) of metformin in patients with type 2 diabetes with a serum creatinine within normal range and having CrCL>70 mL/min or CrCL≤70 to ≥50mL/min, by assessment after a 12-week randomized treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
1.Compare effect of 1 mg tesaglitazar once daily versus placebo once daily given as addon therapy to metformin on the pharmacokinetics of metformin in patients with type 2 diabetes with a serum creatinine within normal range and having CrCL>70 mL/min or CrCL≤70 to ≥50mL/min, by assessment of Css,max, tss,max, Css,min and CLR of metfomin, after a 12-week randomized treatment period.
2.Compare the effects of 1 mg tesaglitazar once daily versus placebo once daily given as add-on therapy to metformin on GFR, in patients with type 2 diabetes with a serum creatinine within normal range and having CrCL>70 mL/min or CrCL≤70 to ≥50mL/min, by assessment of plasma clearance of 51Cr-EDTA, and endogenous CrCL after a 12-week randomized treatment period.
3.Evaluate the safety and tolerability of 1 mg tesaglitazar once daily given as add-on therapy to metformin, by assessment of AEs, laboratory values, ECG, pulse, blood pressure, hypoglycaemic events, body weight and physical examination. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1.Provision of a written informed consent at Visit 1
2.Men or women who are ≥18 years of age at time of consenting upon Visit 1
3.Female patients who are post menopausal, have undergone a hysterectomy, or if of childbearing potential, are using an effective 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
A highly effective method of birth control is defined as combination oral contraceptive, implant, long term injectable contraceptive, intrauterine device or tubal ligation. However, female patients using oestrogen containing hormonal anti conception methods (oral, transdermal, vaginal ring or combination injectables) must agree to use an additional anti conception method.
4.Diagnosed with type 2 diabetes. For patients <30 years the C-peptide level in conjunction with the onset of diabetes should be >0.8 ng/mL, 0.27 nmol/L.
5.FPG ≤13.3 mmol/L, 240 mg/dL
6.Treated with metformin alone for the last three months or more, or treated with metformin for the last three months plus one additional oral anti-diabetic agent in low dose (maximal daily dose of metformin 2.7 g/day). The additional anti-diabetic medication is required to be discontinued at the enrolment visit. The low doses of additional anti-diabetic medication are defined as a maximal daily dose of sulphonylurea comparable to glibenclamide/glyburide 5 mg (corresponding to 3.5 mg of Swedish microcristal form of glibenclamide), meglitinide comparable to repaglinide 1.5 mg or alpha-glucosidase inhibitors comparable to acarbose 150 mg.
Inclusion criteria at randomisation (Visit 2):
7.HbA1c ≤8.5 %
8.Mean FPG of two measurements (values from Visit 1 and 2, measured capillary) ≤11.7 mmol/L, 210 mg/dL |
|
| 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 ischemic attack, cerebrovascular accident, myocardial or peripheral vascular disease revascularization or angioplasty within 24 weeks prior to Visit 1
3.Pre-existing chronic heart failure (NYHA class I-IV)
4.High blood pressure (mean systolic blood pressure ≥160 mm Hg, mean diastolic blood pressure ≥90 mm Hg after 3 repeated measurements) with or without anti-hypertensive treatment.
5.History of thyroid ophthalmopathy
6.History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma
7.History of blood lipid induced eruptive xanthomas, or hypertriglyceridaemia induced pancreatitis
8.Suspected untreated proliferative diabetic retinopathy, as judged by the investigator
9.Other conditions predisposing for development of lactatic acidosis, eg, chronic obstructive pulmonary disease (COPD)
10.Pregnant or breastfeeding patients
11.Suspicion that the patient is infected according to World Health Organisation (WHO) risk categories 2 to 4 (See Appendix C)
12.Treatment of type 2 diabetes with combination therapy (ie, additional antidiabetic agents, except low dose of 1 oral antidiabetic agent, see Section 3.4.5)
13.Treatment with chronic insulin, within 24 weeks prior to Visit 1 (however, 1 temporary period of daily insulin injections no longer than 7 days is allowed)
14.Treatment with a thiazolidinedione (eg, pioglitazone, rosiglitazone) within 4 weeks prior to Visit 1
15.Treatment with fibrates, within 4 weeks prior to Visit 1
16.Treatment with glucocorticoids (equivalent to oral prednisolone >10 mg per day), within 4 weeks prior to Visit 1
17.Treatment with probenecid that can not be stopped at Visit 1
18.History of hypersensitivity or intolerance to any PPAR agonist
19.History of drug-induced myopathy or drug-induced CK elevation
20.History of drug-induced liver enzyme elevations
21.History of drug-induced neutropenia
22.History of alcohol or drug abuse within the last 5 years
23.Other serious or unstable medical or psychological condition identified in the patients’ medical history that, in the judgement of the investigator, would compromise the patients’ safety or successful participation in the Clinical Study
24.Receiving any investigational product during the last 12 weeks prior to Visit 1
25.Previous enrolment in this study
26.Any clinically significant abnormality identified on physical examinations, laboratory tests or ECG, which in the judgement of the investigator would compromise the patients’ safety or successful participation in the Clinical Study
27.Other serious or unstable medical or psychological condition identified in the patients’ medical history that, in the judgement of the investigator, would compromise the patients’ safety or successful participation in the Clinical Study
28.Fasting TG >7.0 mmol/L, 620 mg/dL
29.Hb <90 g/L, 9 g/dL
30.ANC <1.0x 109/L
31.Any of ALT, AST or ALP >2.5 times the upper limit of normal
32.Total bilirubin above the upper limit of normal unless exclusively caused by Gilbert’s syndrome
33.Creatinine > 135 μmol/L for men or > 110 μmol/L for women
34.Calculated creatinine clearance <50 mL/min (estimated by the Cockcroft-Gault equation)
35.CK >3 times the upper limit of normal
36.Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
This study has no end points, however the primary variable is:
AUCss of metformin during the last day-time 12-h dosing interval after 12-week treatment with metformin and tesaglitazar as compared to treatment with metformin and placebo in patients with type 2 diabetes with CrCL>70 mL/min or CrCL≤70 to ≥50mL/min. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| 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 | 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
|
| End of study is defined as date of database lock, which is the time point after which no patient will be exposed to study related activities. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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