A double-blind, placebo-controlled, randomized trial investigating the safety and efficacy of Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction

INTERVENTION: Trade Name: Rasilez Product Name: Aliskiren Product Code: SPP100 Pharmaceutical Form: Tablet CAS Number: 173334571 Other descriptive name: ALISKIREN Concentration unit: mg milligram(s) Concentration type: range Concentration number: 150‐300 Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Patients with chronic heart failure and reduced glomerular filtration rate. ; MedDRA version: 9.1 Level: HLT Classification code 10038443 Term: Renal failure and impairment ; MedDRA version: 9.1 Level: LLT Classification code 10008908 Term: Chronic heart failure PRIMARY OUTCOME: Main Objective: 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). Primary end point(s): Change in Renal Blood Flow from baseline to 26 weeks with additive renin‐inhibition with aliskiren Secondary Objective: 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. 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 abse