Study to Investigate the Effects of Vitamin D Administration on Plasma Renin Activity in Patients With Stable Chronic Heart Failure

An Open-label, Blinded-endpoint, Randomized, Prospective Trial Investigating the Effects of Vitamin D Administration on Plasma Renin Activity in Patients With Stable Chronic Heart Failure

The renin-angiotensin system (RAS) is a regulatory system that plays an essential role in patients with chronic heart failure (CHF). Plasma renin activity (PRA) is a strong and independent predictor of outcome, also in the presence of ACE inhibitors (ACE-i) and/or angiotensin receptor blockers (ARBs). Recently, it has been shown that vitamin D regulates renin transcription by activating the vitamin D receptor (VDR). Thus, specific activation of the VDR represents a novel target for therapeutic intervention in CHF. Currently, clinical data are lacking. The investigators aim to investigate the effect of the administration of vitamin D in patients with CHF.

Inclusion Criteria:

• Out clinical patients ≥ 18 years of age, male or female.
• Patients with a diagnosis of chronic heart failure (NYHA Class II, III or IV).
• Patients must at least be treated with an ACE-i at a stable dose (at least enalapril 10 mg daily or any other ACE-i, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; on equivalent doses, or maximum tolerated dose) or if intolerant to ACE-i with ARB therapy (Candesartan 8 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).
• Concomitant use of ACE-i and/or ARB and/or aldosterone antagonist is permitted.

Exclusion Criteria:

• LVEF >45% at visit 1 (local measurement, measured within the past 12 months assessed by echocardiogram, MUGA or ventricular angiography).
• History of hypersensitivity to the study drugs.
• Patients with phenylketonuria.
• Patients with fructose intolerance.
• Current acute decompensated heart failure.
• Hypercalcemia (>2.65 mmol/l, corrected for albumin).
• Hypercalciuria.
• Estimated glomerular filtration fraction (eGFR) between 30 and 60 ml/min/1.73m2 as measured by the modified of diet in renal disease (MDRD) formula.
• Nephrolithiasis.
• Sarcoidosis.
• Use of the following medication: corticosteroids, thyroxin, anti epileptic drugs, tetracyclines, quinolones
• Intake of supplements containing vitamin D and/or calcium.
• 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 (internal cardiac defibrillator).
• 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.
• 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.
• History or presence of any other diseases (i.e. including malignancies) with a life expectancy of < 5 years.
• Current double-blind treatment in heart failure (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 lactating women.
• Treatment with any of the following drugs within the past 4 weeks prior to Visit 1 (T0):
• Direct renin inhibition including Aliskiren
• Intravenous vasodilator and/or inotropic drugs