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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure
• Intervention / Treatment: Drug: Vitamin D

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vitamin D; 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; 2000 IU vitamin D daily, for 6 weeks; 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	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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Netherlands Foundation for Cardiovascular Excellence
• Investigators: Principal Investigator: W. T. Ruifrok, MD, University Medical Center Groningen; Study Director: R. A. de Boer, MD, PhD, University Medical Center Groningen; Study Chair: W. H. van Gilst, PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• Schroten NF, Ruifrok WP, Kleijn L, Dokter MM, Sillje HH, Lambers Heerspink HJ, Bakker SJ, Kema IP, van Gilst WH, van Veldhuisen DJ, Hillege HL, de Boer RA. Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial). Am Heart J. 2013 Aug;166(2):357-364.e2. doi: 10.1016/j.ahj.2013.05.009. Epub 2013 Jun 24.

Helpful Links

• Official website of the UMCG

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: March 12, 2010
• First Submitted That Met QC Criteria: March 23, 2010
• First Posted (Estimate): March 24, 2010

Study Record Updates

• Last Update Posted (Estimate): February 15, 2013
• Last Update Submitted That Met QC Criteria: February 13, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Vitamin D; Heart failure; Renin angiotensin system; Plasma renin activity
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Vitamin D
• Other Study ID Numbers: WTR-ECG-4