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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Chronic Heart Failure

Intervention / Treatment
-----------------
* Drug: Vitamin D


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D<br>Patients were randomized by an automated computer system to 2000 IU oral cholecalciferol once daily or control (i.e. no extra medication), in a 1:1 ratio for a period of six weeks. Blood was collected in a sitting position on visits 2-4 and patients were asked to collect 24h urine samples prior to visits 2 and 4. Heart failure medication was maintained unchanged throughout the trial. Changes in diuretic dose were permitted if necessary to treat decompensation or renal dysfunction. | Drug: Vitamin D<br>* 2000 IU vitamin D daily, for 6 weeks<br>* Other names: Colecalciferol;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Renin Activity | The primary endpoint of this study is the PRA after 6 weeks of treatment with vitamin D compared to the PRA after 6 weeks without treatment. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoints are biochemical indices of kidney function and bone homeostasis |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on plasma values of additional markers of renin-angiotensin system activity, including angiotensin II, angiotensin converting enzyme activity and chymase activity |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on different markers of the vitamin D cascade, such as vitamin D, calcium, phosphate and PTH (parathyroid hormone) |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on plasma levels of NT-proBNP |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on urinary levels of markers of glomerular and tubular damage |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on extracellular matrix markers (PIIINP, PICP, PINP) and degradation markers (MMP1, MMP9, TIMP1, MMP1/TIMP1-complex) |  | 6 weeks | 
| To evaluate the effect of vitamin D administration on NYHA-class |  | 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart failure, Vitamin D, Plasma renin activity, Renin angiotensin system