| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 diabetes mellitus patients on metformin treatment |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
|
| 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 |
The primary objective is to compare the effect on glucose control of 4 different AZD1656 dosing regimens with placebo in type 2 diabetes mellitus patients on metformin treatment, as evaluated by the difference in HbA1c between baseline and final visit at 4 months.
Extension Objectives:
- To investigate the safety and tolerability of AZD1656 compared to placebo and glipizide after 6 months by assessments of adverse events occurring during the study (including hypoglycaemic events), blood pressure, pulse, physical examination, body weight, safety laboratory variables and electrocardiogram.
- To evaluate other cardiovascular risk factors, such as total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and creactive protein, after 6 months in patients receiving AZD1656 as add-on treatment to metformin compared to placebo as add-on treatment to metformin.
|
|
| E.2.2 | Secondary objectives of the trial |
•To characterise the population pharmacokinetic and pharmacodynamic properties of AZD1656 in T2DM patients treated with metformin by utilisation of non-linear mixed effects modelling methodology.
•To evaluate other variables of glucose control after 4 months in patients receiving AZD1656 as add-on treatment to metformin compared to placebo as add-on treatment to metformin.
•To evaluate other cardiovascular risk factors after 4 months in patients receiving AZD1656 as add-on treatment to metformin compared to placebo as add-on treatment to metformin.
•To investigate the safety and tolerability of AZD1656 compared to placebo and glipizide by assessments of adverse events occurring during the study (including hypoglycaemic events), blood pressure, pulse, physical examination, body weight, safety laboratory variables and electrocardiogram.
•To explore the safety and tolerability of AZD1656 in patients with severely impaired glucose control during a 4 months treatment period. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures.
2. Male or female of non-childbearing potential (postmenopausal, and/or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy/tubal ligation) aged ≥ 18. Women will be defined as postmenopausal if last menstruation period was >1 year ago and serum FSH and LH are within the postmenopausal range, or if age >50 years and with last menstruation period >2 years ago.
3. Body mass index between ≥ 19 and ≤ 42 kg/m2.
4. Clinical diagnosis of T2DM.
5. Treated with maximally tolerated dose of metformin (≥ 1500mg/day) for at least 10 weeks prior to enrolment.
6. Patients with HbA1c ≥ 7.5 but ≤ 10% at enrolment visit (Visit 1) (HbA1c value according to international DCCT standard and obtained from the central laboratory used in the study) can enter cohort 1. Patients with HbA1c between >10 % and <12 % can enter the open-label arm with AZD1656 (cohort 2)
7. Patients must have taken at least 75% of their metformin tablets during the run-in period (ie, from Visit 2 to Visit 3).
For inclusion in the optional genetic research, patients must fulfil all of the inclusion criteria described above and:
• Provide informed consent for the genetic sampling and analyses.
|
|
| E.4 | Principal exclusion criteria |
Patients should not enter the study if any of the following exclusion criteria are fulfilled
1. Clinical diagnosis of Type 1 diabetes.
2. Positive test for Hepatitis B surface antigen or antibodies to HIV virus or antibodies to Hepatitis C virus. Results obtained from the central laboratory will be utilised.
3. Participation in weight loss programme (other than the lifestyle advice normally given to T2DM patients) or use of weight loss drugs (OTC or prescriptions) in the last 3 months
4. Participation in another clinical trial within 30 days prior to enrolment.
5. Unwilling or unable to perform self-monitoring of plasma glucose at home according to protocol.
6. Significant cardiovascular event within the last 6 months prior to enrolment (eg, myocardial infarction/acute coronary syndrome, revascularisation procedure, stroke or transient ischaemic attack) or heart failure New York Heart Association (NYHA) class III-IV.
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory results >3xULN at enrolment, obtained from the central laboratory used in the study.
8. Haemoglobin laboratory results <115 g/L at enrolment, obtained from the central laboratory used in the study.
9. History of psychiatric or somatic disease/condition (eg, gastrointestinal disease) that may interfere with the objectives of the study, as judged by the investigator.
10. History or ongoing symptoms/signs of severe allergy/hypersensitivity as judged by the investigator.
11. Known allergy to glipizide.
12. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma or in-situ carcinoma of the cervix.
13. Impaired renal function in terms of GFR<60 ml/min, based on Modification of Diet in Renal Disease Study Group (MDRD) calculationa.
14. Past or present alcohol or drug abuse within the last 5 years or positive test in drugs of abuse screens.
15. SBP >160 mmHg or DBP >95 mmHg at enrolment/screening.
16. Treatment with any other anti-diabetic agent than metformin during the last 10 weeks prior to enrolment/screening.
17. Proliferative retinopathy or other significant diabetes complications as judged by the investigator.
18. Use of warfarin or amiodarone within 3 months prior to enrolment (screening) and use of potent CYP450 inhibitors, eg, ketoconazole and/or macrolide antibiotics within 14 days before randomisation.
19. Use of anabolic steroids and systemic treatment with glucosteroids within 3 months before enrolment. Inhalation steroid treatment allowed.
20. Blood loss in excess of 450 mL 3 months prior to enrolment.
21. Intake of another investigational drug within 30 days (or at least 5 t1/2 of the drug, if longer than 30 days) before enrolment.
22. Prior exposure to GKAs.
23. Involvement in the planning and conduct of the study or staff at the investigational site.
24. Any other condition prohibiting the patient from participating in the study according to the protocol as judged by the investigator.
25. Previous bone marrow transplant (applicable only for genetic sampling).
26. Whole blood transfusion within 120 days of the date of genetic sample collection (applicable only for genetic sampling).
27. Unable or unwilling to use basal night-time insulin as rescue treatment during the study period in case of hyperglycaemia.
28. (Germany only!) QTc >/=450 ms on ECG at enrolment visit (visit 1) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in HbA1c from baseline to the final visit at 4 months, with treatment as a fixed factor and the corresponding baseline HbA1c as a covariate. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
|
| 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
|
| last patient's last visit |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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