Interleukin-1 Blockade in HF With Preserved EF

NCT ID: NCT02173548

Last Updated: 2018-06-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2017-06-01

Brief Summary

• Heart Failure with Preserved Ejection Fraction (HFpEF) is a common form of heart failure
• Standard treatment for heart failure, show less than ideal results in HFpEF
• Evidence of systemic inflammation is common in all forms of heart failure, including HFpEF
• The main hypothesis of this study is that systemic inflammation contributes to heart failure symptoms and exercise limitations in patients with HFpEF
• The main objective is to treat patients with HFpEF and evidence of systemic inflammation with an anti-inflammatory drug targeting Interleukin-1 (or placebo) to determine effects on cardiovascular function

Detailed Description

Heart Failure with Preserved Ejection Fraction (HFpEF) is a common form of heart failure, characterized by symptoms of congestion and impaired exercise tolerance, secondary to impaired left ventricular filling (diastole) in absence of a significant impairment in contractility (LVEF>50%) or significant valvular abnormalities, shunts or intra- or extra-cavitary obstruction.

The standard treatment for patient with heart failure is very effective in Heart Failure with Reduced Ejection Fraction (HFrEF), but it not very effective in HFpEF.

Evidence of systemic inflammation is common in all forms of heart failure, including HFpEF, and predicts worse outcomes. C reactive protein (CRP) is the preferred inflammatory biomarker used as risk predictor for cardiovascular disease. Patients with heart failure (HFpEF or HFrEF) with elevated CRP levels are more likely to be severely limited by heart failure symptoms, are more likely to be admitted to the hospital for heart failure, and are more likely to die of cardiac causes.

Preclinical studies show that a key mediator of systemic inflammation, Interleukin-1 (IL-1), impairs cardiac and vascular function, and may contribute to the pathogenesis of heart failure.

The main hypothesis of this study is that systemic inflammation, and IL-1 in particular, contributes to heart failure symptoms and exercise limitations in patients with HFpEF.

The main objective is to treat patients with HFpEF and evidence of systemic inflammation with an IL-1 blocker, anakinra (recombinant human IL-1 receptor antagonist)(or placebo) to determine effects on exercise capacity measured as peak oxygen consumption at maximal cardiopulmonary exercise testing.

Conditions

Heart Failure With Normal Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Anakinra

Anakinra 100 mg given subcutaneously once daily for 12 weeks

Group Type: ACTIVE_COMPARATOR

Anakinra

Intervention Type: DRUG

Placebo

Matching Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Anakinra

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Kineret

Eligibility Criteria

Inclusion Criteria

1. Symptoms and signs of heart failure (NYHA II-III) and prior hospitalization for heart failure

2. Recent Imaging Study (<12 months) showing LVEF>50% and Left Ventricular End Diastolic Volume Index (LVEDVI) <97ml/m2

3. Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness as shown by one of the following

a. Invasive Hemodynamic measurements i. mean Pulmonary Capillary Wedge Pressure (mPCW) >12 ii. Left Ventricular End Diastolic Pressure (LVEDP) >16 mmHg b. Tissue Doppler Echocardiogram i. E/E' >15 ii. E/E' 8-15 and one of the following: Left Ventricular Hypertrophy (LVH), Atrial fibrillation, Left Atrial Enlargement (LAE), E/A <0.5 + DT (Deceleration Time) >280, c. Biomarkers i. Brain Natriuretic Peptide (BNP) >200pg/ml (not due to a concomitant disease such as pulmonary arterial hypertension, pulmonary embolism, acute renal failure, or other)

4. CRP > 2.0 mg/L

Exclusion Criteria

• Age <21
• Concomitant conditions or treatments which would affect completion of the study or interpretation of the study tests including but not limited to the following conditions:

• physical inability to walk or run on a treadmill
• angina or evidence of spontaneous or inducible ischemia
• uncontrolled arterial hypertension
• atrial fibrillation (or other arrhythmias)
• moderate to severe valvular heart disease
• chronic pulmonary disease
• anemia (Hgb<10 g/dl)
• Angina, uncontrolled hypertension or electrocardiograph (ECG) changes (i.e. ischemia, arrhythmias) that limit maximum exertion during cardiopulmonary exercise testing
• Anticipated need for cardiac resynchronization therapy (CRT) or automated-implantable cardioverter defibrillator (AICD) or coronary revascularization or cardiac surgery
• Active infection including chronic infection
• Active cancer (or prior diagnosis of cancer within the past 10 years)
• Recent (<14 days) or active use of immunosuppressive drugs (including but not limited to high-dose corticosteroids [>1_mg/kg of prednisone equivalent], Tumor Necrosis Factor (TNF)-α blockers, cyclosporine) not including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or corticosteroids used for IV dye allergy only)
• Chronic auto-immune or auto-inflammatory disease (including but not limited to rheumatoid arthritis, systemic lupus erythematosus)
• Neutropenia (absolute neutrophil count<1,800/mm3 [or <1,000/mm3 in African-American patients])
• Severe impairment in renal function (estimated glomerular filtration rate <30 ml/kg*min)
• Recent or planned use of vaccination with live attenuated viruses
• Allergy to rubber or latex
• Allergy to products derived from Escherichia coli
• Pregnancy or breastfeeding
• Inability to give informed consent

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Virginia Commonwealth University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio Abbate, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Virginia Commonwealth University

Benjamin Van Tassell, PharmD

Role: PRINCIPAL_INVESTIGATOR

Virginia Commonwealth University

Locations

Virginia Commonwealth University

Richmond, Virginia, United States

Countries

United States

References

Van Tassell BW, Trankle CR, Canada JM, Carbone S, Buckley L, Kadariya D, Del Buono MG, Billingsley H, Wohlford G, Viscusi M, Oddi-Erdle C, Abouzaki NA, Dixon D, Biondi-Zoccai G, Arena R, Abbate A. IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2018 Aug;11(8):e005036. doi: 10.1161/CIRCHEARTFAILURE.118.005036.

Reference Type: DERIVED

PMID: 30354558 (View on PubMed)

Van Tassell BW, Buckley LF, Carbone S, Trankle CR, Canada JM, Dixon DL, Abouzaki N, Oddi-Erdle C, Biondi-Zoccai G, Arena R, Abbate A. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin Cardiol. 2017 Sep;40(9):626-632. doi: 10.1002/clc.22719. Epub 2017 May 5.

Reference Type: DERIVED

PMID: 28475816 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R34HL118348-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HM20000118

Identifier Type: -

Identifier Source: org_study_id