E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012601 |
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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 |
Primary objective of this study is to determine whether aliskiren, when added to conventional treatment, compared to placebo, delays the occurrence of cardiovascular and/or renal complications in patients with type 2 diabetes at high risk for cardiovascular and/or renal events. Occurrence is defined as the first event of the following composite primary endpoint: 1) Cardiovascular (CV) death, 2) Resuscitated sudden death, 3) Non-fatal myocardial infarction (MI), 4) Non-fatal stroke, 5) Unplanned hospitalization for heart failure (HF), 6) Onset of end- stage renal disease (ESRD) or renal death and 7) Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill this endpoint, the serum creatinine concentration must be above the upper limit of normal for men and women according to the central laboratory. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to determine whether aliskiren, when added to conventional treatment, compared to placebo, in patients with type 2 diabetes at high risk for cardiovascular and renal events delays the occurrence of cardiovascular complications, defined as the first event of the following composite endpoint: 1) CV death, 2) Resuscitated sudden death, 3) Non-fatal MI, 4) Non-fatal stroke and 5) Unplanned hospitalization for HF delays the occurrence of renal complications, defined as the first event of the following composite endpoint: 1) Doubling of baseline serum creatinine concentration sustained for at least one month. (To fulfill this criteria, serum creatinine concentration must be above the upper limit of normal for men and women according to the central laboratory, 2) Onset of ESRD or 3) renal death |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Inclusion criteria applicable at Visit 1: 1. Patients with type 2 diabetes. Patients have to be either currently treated with oral anti-diabetics and/or insulin, or have to have a documented fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL) or 2-h plasma glucose ≥ 11.1 mmol/L (200 mg/dL) (WHO 2006a) 2. Male or female patients ≥ 35 years of age. 3. Patients who provide written informed consent to participate in the study after the purpose and nature of the investigation have been clearly explained to them. Additional inclusion criteria applicable at Visit 3: 4. Patients with at least one of the following: Persistent macroalbuminuria (UACR ≥ 200 mg/g or 22.6 mg/mmol) in 2 out of three first morning void urine samples and an eGFR ≥ 30 mL/min/1.73m2 as calculated by the abbreviated MDRD study equation Persistent microalbuminuria (UACR ≥ 20 mg/g and < 200 mg/g or [UACR ≥ 2.26 mg/mmol and <22.6 mg/mmol]) in 2 out of three first morning void urine samples and an eGFR ≥ 30 and < 60 mL/min/1.73m2 calculated by the abbreviated MDRD study equation History of cardiovascular disease and an eGFR ≥ 30 and < 60 mL/min/1.73m2 History of cardiovascular disease is defined as at least one of the following: Previous hospitalization for MI Previous hospitalization for stroke (i.e. previous hospitalization with a discharge diagnosis of stroke; a previous transient ischemic attack (TIA) is not sufficient to fulfill this criterion) Previous hospitalization for heart failure (HF) with a discharge diagnosis of HF, with or without a preserved ejection fraction. Coronary artery disease (CAD) defined as coronary artery bypass graft (CABG)], angiographically proven stenosis ≥ 50% in at least one major epicardial coronary artery or history of percutaneous coronary intervention (PCI) 5. Patients must be treated with either an Angiotensin-converting-enzyme-inhibitor (ACEI) or an Angiotensin-II-receptor blocker (ARB). Patients should be on conventional treatment according to national guidelines. Patient must not have had any adjustments to their concomitant antihypertensive therapy for at least four (4) weeks prior to randomization (Visit 3). |
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E.4 | Principal exclusion criteria |
1. Serum potassium > 5.0 mmol/L (at the visit directly preceding Visit 3) 2. History of any cardiovascular event (stroke, TIA, MI, unstable angina, CABG, percutaneous coronary intervention, hospitalization due to HF) during the 3 months prior to Visit 1 If a patient experiences such an event between Visit 1 and randomization at Visit 3, he/she should be withdrawn from the screening phase. If suitable, the patient can be re-screened at a later stage. 3. Hypertension (at Visit 3): any patient with a mean sitting systolic blood pressure (msSBP) ≥ 135 and < 170 mmHg or mean sitting diastolic blood pressure (msDBP) ≥ 85 and <110 mmHg unless treated with at least 3 anti-hypertensive medications 4. Hypertension (at Visit 3): any patient with msSBP ≥ 170 mmHg or msDBP ≥ 110 mmHg 5. Congestive heart failure NYHA class III and IV 6. Concomitant treatment with two (2) or more renin-angiotensin-aldosterone system blocking agents, e.g. ACEI, ARB or aldosterone-antagonist. 7. Unstable serum creatinine 8. Second (II) or third (III) degree heart block without a pacemaker. 9. Concurrent potentially life threatening arrhythmia or other uncontrolled arrhythmia. 10. Clinically significant valvular heart disease. 11. Known renal artery stenosis. 12. Type 1 diabetes mellitus (defined as onset of disease before the age of 35 and need of permanent insulin treatment within one year of diagnosis) 13. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of the study drugs including, but not limited to, any of the following: History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection (patients with previous bariatric surgery > 6 months prior to Visit 1 are allowed to participate). Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase. Evidence of hepatic disease as determined by any one of the following: SGPT value exceeding 3 x Upper Limit of Normal (ULN) at Visit 1, a history of hepatic encephalopathy, a history of cirrhosis, esophageal varices, or a history of portocaval shunt. 14. History of malignancy other than basal cell skin cancer within the past two years. 15. Any concurrent life threatening condition with a life expectancy less than 2 years. 16. History or evidence of drug or alcohol abuse within the last 12 months. 17. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study. 18. History of hypersensitivity to any of the study drugs or to medications belonging to the same therapeutic class as the study drugs including history or allergy to ARBs or ACEIs as well as known or suspected contraindications to the study drugs. 19. History of noncompliance to medical regimens or unwillingness to comply with the study protocol. 20. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer 21. Any condition that in the opinion of the investigator or the Novartis medical monitor would jeopardize the evaluation of efficacy or safety. 22. Persons directly involved in the execution of this protocol. 23. Patients who have previously qualified to be randomized or enrolled into the active drug treatment period in a previous aliskiren study in this development program (SPP100E development program) or in the CSPP100C2201 (AVOID) trial. 24. Patients with previous renal transplant or under immunosuppressive therapy 25. Pregnant or nursing (lactating) women (pls see protocol) |
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E.5 End points |
E.5.1 | Primary end point(s) |
To determine whether aliskiren, compared to placebo, when added to conventional treatment, delays the occurrence of cardiovascular and/or renal complications in patients with type 2 diabetes at high risk for cardiovascular and renal events. Occurrence is defined as the first event of the following composite primary endpoint: Cardiovascular (CV) death Resuscitated sudden death Non-fatal myocardial infarction (MI) Non-fatal stroke Unplanned hospitalization for heart failure (HF) Onset of end-stage renal disease (ESRD) or renal death Onset of ESRD is defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 µmol per liter) Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration must be above the upper limit of normal for men and women according to the central laboratory. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Information not present in EudraCT |
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) | 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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |