The Effects of Active VItamin D on Left Atrial Volume Index (AVID-LAVI)

A Pilot Study of the Effects of Active VItamin D on Left Atrial Volume Index in Patients With Heart Failure and Preserved Ejection Fraction

This is a pilot feasibility study to determine the effects of an activated vitamin D compound (paricalcitol) on heart structure (size) and function (ability to relax) in patients with normal kidney function and a form of heart failure known as HFPEF (heart failure and preserved ejection fraction). This study will also examine heart failure-related hospitalizations and changes in cardiac-stretch and biological markers that are believed to change along with heart size. Patients in this pilot study will be treated for a period of 48 weeks with paricalcitol at a dose previously approved by FDA (1 mcg per day) and followed-up for 4 weeks after treatment is completed.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Paricalcitol

Detailed Description

Heart failure (HF) is among the top ten causes of hospitalizations in the US. It is estimated that ~40-50% of patients with HF have preserved ejection fraction (EF). Patients with heart failure and preserved ejection fraction (HFPEF) have normal systolic function, but impaired cardiac relaxation. The main causes of HFPEF include left-ventricular hypertrophy (LVH) and hypertension, hypertrophic cardiomyopathy, aortic stenosis with a normal EF, coronary artery disease and restrictive cardiomyopathies.

Only a few small clinical trials have tested therapeutic interventions in patients with HFPEF, producing either small or negative effects. Relatively few drugs have effects on cardiac relaxation and are not candidates for chronic use, as they may have significant side effect profiles and/or are inconvenient to administer. Paricalcitol, an FDA-approved activated form of vitamin D, has been shown to slow LVH progression and improve parameters associated with diastolic function in animal models (see refs). Treatment with paricalcitol has also been associated with decreased cardiovascular morbidity and mortality in a historical cohort study of patients with end-stage renal disease (see refs).

This is a single-center, single-arm, pilot study in 20 patients with HFPEF and normal renal function on stable medical therapy to evaluate the effects of paricalcitol on cardiac structure and function.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 01886
      • Massachusetts General Hospital

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:

• Sign informed consent.
• Willing and able to adhere to all study-related procedures, including study medication regimen.
• ≥ 18 years old.
• Previous clinical diagnosis of heart failure with preserved ejection fraction: NYHA Class II-IV.
• Satisfy these echocardiographic criteria within the last year: Left ventricular ejection fraction ≥ 50%, cardiac magnetic resonance or ventriculogram; Left atrial size ≥ 4 cm in long axis or > 5.2 cm in four chamber length; Septal wall thickness > 1.2 cm (females) or 1.3 cm (males); Doppler evidence of moderate or severe diastolic dysfunction (≥ Grade II) by transmitral inflow, pulmonary venous flow, color M-mode and/or tissue Doppler (per European Society of Cardiology guidelines).
• Experienced ≥ 1 of the following in last 12 months: Hospitalization for acute heart failure (primary diagnosis); Long term treatment with loop diuretic; Mean pulmonary capillary wedge pressure ≥ 16 mm Hg at catheterization for dyspnea; Left ventricular end diastolic pressure (LVEDP) ≥ 19 mm Hg at catheterization for dyspnea; Acute treatment with intravenous loop diuretic or hemofiltration.
• On stable medical therapy in last 30 days before study entry (defined as no change in angiotensin converting enzyme inhibitors [ACEI], angiotensin receptor blockers, aldosterone inhibitors, beta-blockers or calcium channel blockers.
• Satisfy these criteria at initial lab screening: Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min; Corrected serum Ca 8.0-10.0 mg/dL (2.0-2.5 mmol/L); Phos ≤ 5.2 mg/dL (1.68 mmol/L); Serum albumin ≥ 3.0 g/dL (30 g/L);
• Negative serum pregnancy test for females of childbearing potential (within 2 weeks of starting study treatment).
• Women of childbearing potential must be practicing barrier/oral contraception during study-related treatment, or be surgically sterile or one year post-menopausal, be non-nursing and non-pregnant.

Exclusion Criteria:

• Taking > 1,000 IU of vitamin D preparation daily within last 30 days.
• Received activated vitamin D preparation including paricalcitol (Zemplar®), doxercalciferol (Hectorol®) or calcitriol (Rocalctrol®, Calcijex®) within last 90 days prior to study entry.
• History of nephrolithiasis.
• Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg at Screening; confirmed by repeat).
• Secondary hypertension (i.e. renal artery stenosis, primary aldosteronism or pheochromocytoma).
• Severe hepatic impairment.
• Use of known inhibitors (ie, ketoconazole) or inducers (ie, carbamazepine) of cytochrome P450 3A (CYP3A) within 2 weeks prior to taking study drug.
• HIV positive.
• Condition with prognosis < 1 year at study entry other than heart failure.
• Significant valvular disease defined as moderate or severe aortic or mitral stenosis, mitral or aortic regurgitation.
• Infiltrative cardiac disease (sarcoid, amyloid, hemochromatosis, lymphoma, etc.).
• Arrhythmogenic right ventricular cardiomyopathy.
• Active myocarditis.
• Constrictive or restrictive pericarditis.
• Acute coronary artery disease symptoms defined as emergency department visit or hospital admission with unstable angina, ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) within 90 days before study entry.
• Poor echocardiographic windows.
• Current active treatment in another investigational study or participation in another investigational study within 1 month before screening.
• Active malignancies except in situ carcinoma of the cervix, localized squamous or basal cell carcinoma of skin.
• Other serious concurrent or recent medical or psychiatric condition which, in Investigator's opinion, makes the patient unsuitable for participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paricalcitol; Paricalcitol oral capsules (1 mcg per day for 48 weeks)	Drug: Paricalcitol; Paricalcitol oral capsules 1 mcg/day for 48 weeks; Other Names: Zemplar®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left atrial volume index (LAVI) by transthoracic echocardiography.	The analysis will include all patients with at least two echocardiographic studies (baseline and one follow up). The primary endpoint will be determined upon completion of the study (ie, when all enrolled patients have been treated for up to 48 weeks with study medication).	Baseline and Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of and time-to-first heart failure-related hospitalizations		52 weeks
Overall cardiac and non-cardiac mortality rates		52 weeks
Changes in biological, inflammatory, LVH and strain biomarkers that have been linked to cardiovascular disease.	High-sensitivity troponin-T, NT-proBNP, high-sensitivity C-reactive protein, propeptide procollagen type I, ST-2, Galectin-3, GDF-15 and osteoprotegerin	Baseline and 48 weeks
Changes in standard mineral metabolite parameters (calcium, phosphorus, calcium-phosphate-product and PTH)		Baseline and 48 weeks
Changes in self-reported Patient Global Assessment		Baseline and 48 weeks
Change in diastolic function parameters (including E, A, IVRT, DT)		Baseline and Week 48
Change in tissue doppler parameters (including Ea, Aa)		Baseline and Week 48
Change in pulmonary venous inflow (including S, D, a reversal)		Baseline to Week 48
Change in cardiac ejection fraction		Baseline and Week 48
Change in end-diastolic and end-systolic left ventricular internal dimension		Baseline and Week 48

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Hector Tamez, MD, MPH, Massachusetts General Hospital; Principal Investigator: Ravi Thadhani, MD, MPH, Massachusetts General Hospital

Publications and helpful links

General Publications

• Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, Rigor DL, Stillman I, Tamez H, Kroeger PE, Wu-Wong RR, Karumanchi SA, Thadhani R, Kang PM. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16810-5. doi: 10.1073/pnas.0611202104. Epub 2007 Oct 17.
• Wu J, Garami M, Cheng T, Gardner DG. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest. 1996 Apr 1;97(7):1577-88. doi: 10.1172/JCI118582.
• Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular function in rats. J Clin Invest. 1987 Jun;79(6):1706-12. doi: 10.1172/JCI113010.
• Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003 Jul 31;349(5):446-56. doi: 10.1056/NEJMoa022536.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Anticipated): May 1, 2014
• Study Completion (Anticipated): June 1, 2014

Study Registration Dates

• First Submitted: June 26, 2012
• First Submitted That Met QC Criteria: June 27, 2012
• First Posted (Estimate): June 28, 2012

Study Record Updates

• Last Update Posted (Estimate): August 16, 2013
• Last Update Submitted That Met QC Criteria: August 15, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Preserved ejection fraction; Left ventricular hypertrophy; Activated vitamin D; Cardiac lusitropic effect; Hospitalizations
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: AVID-LAVI