E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with chronic heart failure and reduced glomerular filtration rate. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10038443 |
E.1.2 | Term | Renal failure and impairment |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
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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 |
The primary objective of this study is to test if add-on therapy with aliskiren improves RBF in patients with CHF (NYHA Class II - IV) and RD treated with renin-angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor blockers (ARB). |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to examine the effect of addition of aliskiren on RD expressed as glomerular filtration rate(GFR) as measured by clearance of 125I-Iothalamate, filtration fraction(FF) as measured by GFR/Effective Renal Plasma Flow, circulating plasma values of markers of renin-angiotensin (RAS) system activity, including plasma renin activity, angiotensin II, angiotensin converting enzyme activity and chymase activity, levels of N Terminal-proBrain Natriuretic Peptides, left ventricular ejection fraction as measured by radionucleotide ventriculography, urinary levels of markers of glomerular and tubular damage, including urinary albumin ecretion (UAE), N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1), NYHA Association class, Patient’s and Physician’s global assessment score’s and on heart rate, systolic and diastolic blood pressure. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Out patients ≥ 18 years of age, male or female. • Patients with a diagnosis of chronic heart failure (NYHA Class II – IV) • LVEF ≤ 45% at visit 1 (local measurement, measured within the past 6 months assessed by echocardiogram, MUGA or ventricular angiography) • Estimated GFR between 30 and 60 ml/min/1.73m2 as measured by the MDRD formula • Patients must be treated with an ACE inhibitor at a stable dose (enalapril 10 mg daily at least or any other ACE inhibitor, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; on equivalent doses, or maximum tolerated dose) or if intolerant to ACE inhibitors with ARB therapy (Candesartan 32 mg daily or any other ARB in equivalent dose, or maximum tolerated dose) for at least 4 weeks prior to visit 1. • Patients must be treated with a beta blocker unless contraindicated or not tolerated at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose or in absence of that medication, the reason should be documented).
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E.4 | Principal exclusion criteria |
• History of hypersensitivity to any of the study drugs including history or allergy to ACEi’s as well as known or suspected contraindications to the study drugs or previous history of intolerance to high doses of ACEi’s during up titration process. • Patients treated concomitantly with both ARB and aldosterone antagonist. • Current acute decompensated heart failure (HF). • Symptomatic hypotension and/ or less than 90 mmHg SBP at randomisation • Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months. • Coronary or carotid artery disease likely to require surgical or PCI. • Right heart failure due to severe pulmonary disease. • Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the last year. • Patients with a history of heart transplant or who are on a transplant list or with LVAD device (left ventricular assistance device). • Documented ventricular arrhythmia with syncopal episodes within past 3 months that is untreated. • Documented history of ventricular tachycardia or ventricular fibrillation without ICD. • Symptomatic bradycardia, or second or third degree heart block without a pacemaker. • Implantation of a CRT (cardiac resynchronization therapy) device within prior 3 months. • Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation. • Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis. • 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: • Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase. • Primary liver disease considered to be life threatening. • Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to Visit 1. • Serum potassium ≥ 5.2 mEq/L at randomisation visit. • History or presence of any other diseases (i.e. including malignancies) with a life expectancy of < 5 years. • Current double-blind treatment in HF trials. • Participation in an investigational drug study at the time of enrollment or within the past 30 days or 5 half lives of enrollment whichever is longer. • Any surgical or medical condition that in the opinion of the investigator or medical monitor would jeopardize the evaluation of efficacy or safety. • History of noncompliance to medical regimens and patients who are considered potentially unreliable. • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test (> 5 mIU/ml). • Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels > 40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, and oral), and double-barrier methods (if accepted by local regulatory authority and ethics committee). Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. • Long-term requirement for NSAIDs or COX2 inhibitors, with the exception of aspirin at doses used for CV prophylaxis. • Treatment with any of the following drugs within the past 4 weeks prior to Visit 1: o Direct renin inhibitor including aliskiren Intravenous o vasodilators and/or inotropic drugs
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in Renal Blood Flow from baseline to 26 weeks with additive renin-inhibition with aliskiren |
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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 | Yes |
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 | No |
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) | 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) | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |