| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Type 2 diabetes |
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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 |
The 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 renal events.
Occurrence is defined as the first event of the following composite primary end points
Cardiovascular death
Resuscitated sudden death
Non-fatal myocardial infarction
Non-fatal stroke
Unplanned hospitalisation for heart failure
Onset of end-stage renal disease or renal death.
Doubling of baseline serum creatinine concentration sustained for at least 1 month
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to:
Determine whether aliskiren, compared to placebo, when added to conventional treatment, delays the occurrence of cardiovascular complications, defined as the first event of the following composite endpoint:
Cardiovascular death
Resuscitated sudden death
Non-fatal myocardial infarction
Non-fatal stroke
Unplanned hospitalisation for heart failure
To determine whether aliskiren, compared to placebo, when added to conventional treatment delays the occurrence of renal complications, defined as the first event of the following composite endpoint:
Doubling of baseline serum creatinine concentration (must be above the upper limit of normal according to the central laboratory) for at least one month
Onset of end-stage renal disease (defined as intiation of dialysis, renal transplant or serum creatinine above 6.0mg/dL)
Renal death |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory pharmacogenetic and mRNA expression profiling sub-study for CSPP100E2337.
Title: A randomised, double-blind, placebo-controlled, parallel group study to determine whether, in patients with type 2 diabetes at high risk for cardiovascular and renal events, aliskiren, on top of conventional treatment , reduces cardiovascular and renal morbidity and mortality.
Objectives:
a) Examining whether individual genetic variation in genes relating to drug metabolism, type 2 diabetes with renal and cardiovascular risk, and the drug target pathway confer differential response to aliskiren and b) examining the effect of aliskiren on gene expression in peripheral blood cells in type 2 diabetic patients at risk for renal and cardiovascular disease.
date 26-Mar-2007
Version of substudy 1st version |
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| E.3 | Principal inclusion criteria |
Inclusion criteria applicable at Visit 1
• Patients with type 2 diabetes. Patients have to be either currently treated with oral antidiabetics and /or insulin, or to have a documented fasting plasma glucose > or equal to 7.0 mmol/L (126mg/dL) or 2-h plasma glucose > or equal to 11.1 mmol/L (200mg/dL)
• Male or female patients > or equal to 35 years of age
• 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
Patient with at least one of the following
• Persistent macroalbuminuria (UACR > or equal to 200mg/g {or 22.6mg/mmol} in at least two out of three first morning void urine samples) and an eGFR > or equal to 30mL/min/1.73msquared as calculated by the abbreviated MDRD study equation (means of two consecutive measurements)
• Persistent microalbuminuria (UACR > or equal to 20mg/g and < 200mg/g
[or UACR > or equal to 2.26mg/mmol and < 22.6mg/mmol] in at least two of three morning void urines} and an mean eGFR > or equal to 30 and <60mL/min/1.73msquared calculated by the abbreviated MDRD study equation.
• A history of cardiovascular disease and a mean eGFR > or equal to 30 and <60mL/min/1.73msquared.
History of cardiovascular disease is defined as at least one of the following:
Previous MI( previous hospitalization with a discharge diagnosis of MI)
Previous stroke ( previous hospitalization with a discharge diagnosis of stroke)
A previous transient ischemic attack (TIA) is not sufficient to fufill this criterion
Previous hospitalisation for heart failure (HF) with discharge diagnosisof HF, with or without a preserved ejection fraction.
•Coronary artery disease (CAD) defined as follows
cornary artery bypass graft (CABG), angiographically proven stenosis > or equal to 50% in at least one major epicardial coronary artery or history of percutaneous coronary intervention (PCI)
•Patient's concomitant treatment must include an ACEI or an ARB. Patients should be on conventional treatment according to national guidelines for at least 4 weeks proir to randomisation (visit 3)
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| E.4 | Principal exclusion criteria |
For full list, please refer to the protocol
• Serum potassium > 5.0mmol/L (at the visit directly preceeding Visit 3)
• History of any cardiovascular event(stroke, transient ischemic cerebral attack, MI, unstable angina, CABG, PCI, hospitalisation due to HF) duirng the 3 months prior to Visit 1.
If a patient experiences such an event between Visit 1 and randomisation at Visit 3, he/she should be withdrawn from the screening phase. If suitable the patient can be re-screened at a later stage (see section 5.2)
• Hyperternsion (at Visit 3); any patient with a mean sitting systolic blood pressure (msSBP) > or equal to 135 and < 170 mmHg or msDBP > or equal to 85 and < 110mmHg unless treated with at least 3 anti-hypertensive medications.
• Hyperternsion (at Visit 3); any patient with msSBP) > or equal to 170mmHg or msDBP > or equal to 110mmHg.
• Congestive heart failure (NYHA Class III or IV).
• Concomitant treatment with two or more renin-angiotensin-aldosterone system blocking agents apart from the study drug e.g ACEI, ARB or aldosterone-antagonist or any renin inhibitor.
• Unstable serum creatinine: defined as > or equal to 20% difference between two consecutive serum creatinine measurements before visit 3.
A maximum of 4 measurements will be allowed. If the difference between the first two measurements is > or equal to 20% of the higher value, a third meaurement should be performed at the next visit. If the difference between the last two measurements is > or equal to 20% of the higher value, a fourth meaurement should be performed at the next visit. If the difference between the last two measurements performed is > or equal to 20% the patient is excluded.
• Second or third degree heart block without a pacemaker
• Concurrent potentially life threating arrhytmia or other uncontrolled arrhythmia.
• Clinically significant valvular heart disease.
• Known renal artery stenosis
• Type 1 diabetes mellitus (defined as onset of disease beofre the age of 35 and need of permanent insulin treatment within one year of diagnosis.
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs including, but not limited to, any of the following:
• History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection.
• 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 values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of cirrhosis, esophageal varices, or a history of portocaval shunt.
• History of malignancy of any organ treated or untreated, within the past five years whether or not there is evidence of local recurrence or metastases, with the exception of localised basal cell carcinoma of the skin.
•Any concurrent life threatening condition with a life expectancy less than 2 years.
• History or evidence of drug or alcohol abuse within the last 12 months.
• Pregnant or nursing (lactating) women.
• 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.
• History of non compliance to medical regimes or unwillingness to comply with the study protocol.
• Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment , whichever is longer.
• Persons directly involved in the execution of the protocol.
• Patients who have previously qualified to be randomised or enrolled into the active drug treatment period in a previous aliskiren study in this development programme (SPP100E development programme) or in the CSPP100C2201 ("AVOID" trial)
•Women of child-bearing potential
•Specific to the safety follow-up period: Aliskiren or aliskiren-containing fixed combination products must not be used in combination with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) in patients with diabetes.
•Specific to the safety follow-up period: Participating in another clinical trial, whether or not on investigational drug
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is the time to the first event of the primary composite endpoint consisting of CV death, resuscitated sudden death, non-fatal MI, non-fatal stroke, unplanned hospitalisation for HF, onset of ESRD, renal death, and doubling of
serum creatinine concentration from baseline, sustained for at least one month and above the upper limit of normal. It will be calculated in days for each patient as the difference between the date of the first event or censoring date if no event occurs and the date of randomisation visit (day1 ) plus one. The primary composite endpoint will be derived based on the adjudicated events. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| 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) | 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 | 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 | Yes |
| 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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| Study duration is between 2.5 years and 5.5 years. This includes a safety long-term follow-up phase. Following the recommendation of the DMC overseeing the trial all patients were required to discontinue study drug by 6 Jan 2012. A 12 month safety follow-up period post study drug discontination is implemented upon request of CHMP. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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