Clinical trial NCT02173548: Interleukin-1 Blockade in HF With Preserved EF
Official title: Interleukin-1 Blockade in Heart Failure With Preserved Ejection Fraction (HFpEF): a Randomized Placebo-controlled Double Blinded Study (D-HART2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure With Normal Ejection Fraction
Keywords: heart failure
HFpEF
diastole
diastolic heart failure
inflammation
interleukin-1
C-reactive protein
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-06-25
Enrollment: 31
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Aerobic Exercise Capacity
timeFrame: Baseline to 12 weeks
measure: Change in Ventilatory Eefficiency
timeFrame: Baseline to 12 weeks
Secondary outcomes:
measure: Echocardiographic Assessment of Diastolic and Systolic Function (Left Ventricular Ejection Fraction)
timeFrame: 12 weeks
measure: Change in Diastolic and Contractile Reserve (e' Velocity and E/e' Ratio)
timeFrame: Baseline to 12 weeks
measure: Change in Inflammation (C Reactive Protein Levels)
timeFrame: Baseline to 12 weeks
measure: Change in Quality of Life Questionnaire-Minnesota Living With Heart Failure Questionnaire (MLWHF)
timeFrame: Baseline to 24 weeks
measure: Change in Quality of Life Questionnaire-Duke Activity Status Index (DASI)
timeFrame: Baseline to 12 weeks
measure: Hospital Admission for Acute Decompensated Heart Failure
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Virginia Commonwealth University
name: Antonio Abbate, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Virginia Commonwealth University
name: Benjamin Van Tassell, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.