Interleukin-1 Blockade in HF With Preserved EF

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.

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