Interleukin-1 Blockade In Recently Decompensated Heart Failure - 2

The REDHART2 (REcently Decompensated Heart failure Anakinra Response 2 Trial) study is a
phase II clinical trial of anakinra or placebo to determine improvement in aerobic exercise
capacity (by measuring maximal oxygen uptake (VO2)) in patients with recently decompensated
systolic heart failure (HF). The recently completed pilot REDHART study showed anakinra
treatment for 12 weeks led to a significant improvement in peak aerobic exercise capacity,
whereas anakinra treatment for 2 weeks did not, and no significant changes were seen in
placebo. The REDHART2 study is designed to expand and confirm the beneficial effect of
sustained anakinra treatment (24 weeks) on peak VO2, and to explore the potential effect size
on hospital readmissions for HF. The rationale of Interleukin-1 (IL-1) blockade with anakinra
in heart failure stems from the evidence of a) reduced adverse cardiac remodeling and heart
failure in animal models of acute myocardial infarction (AMI); b) reduced incidence of heart
failure in patients with ST-segment elevation AMI; c) enhanced IL-1 activity in patients with
heart failure, d) quenching of the acute inflammatory response in patients with acute
decompensated heart failure, e) direct cardiodepressant effects of IL-1 in animal models, f)
improved exercise capacity in pilot studies including patients with stable systolic heart
failure, stable diastolic heart failure, and, recently decompensated systolic heart failure
in the pilot REDHART study. Patients will be randomized 2:1 to active treatment, such that
patients will be twice as likely to receive anakinra versus placebo.

Inclusion Criteria:

All 6 criteria need to be met for enrollment of the patient in the study

1. Primary diagnosis for hospitalization is decompensated heart failure established as
the finding at admission of both conditions listed below:

- dyspnea or respiratory distress or tachypnea at rest or with minimal exertion;

- evidence of elevated cardiac filling pressure or pulmonary congestion (at least
one of the conditions must be met):

- pulmonary congestion/edema at physical exam OR chest XRay;

- plasma BNP levels ≥200 pg/mL;

- invasive measurement of left ventricular end-diastolic pressure >18 mmHg or of
pulmonary artery occluding pressure (wedge) >16 mmHg.

2. The patient has a prior documentation of impaired left ventricular systolic function
(ejection fraction ≤40%) at most recent assessment by any imaging modality (within 12
months).

3. The patient is now clinically stable, euvolemic, and meets standard criteria for
hospital discharge as documented by all the 3 conditions listed below:

- absence of dyspnea or pulmonary congestion/distress at rest;

- absence of pitting edema in the lower extremities, or in any other region;

- stable hemodynamic parameters (blood pressure, heart rate).

4. The patient is of age ≥21 years old, and is willing and able to provide written
informed consent.

5. The patient is willing and able to comply with the protocol (i.e.,
self-administration, or exercise test).

6. The patient has screening high sensitivity plasma C-reactive protein levels (hsCRP) >2
mg/L.

Exclusion Criteria:

Subjects will not be eligible if they meet any of the following 15 exclusion criteria.

1. The primary diagnosis for admission is NOT decompensated heart failure, including
diagnosis of acute coronary syndromes, hypertensive urgency/emergency, tachy- or
brady-arrhythmias.

2. Concomitant clinically significant comorbidities that would interfere with the
execution or interpretation of the study including but not limited to acute coronary
syndromes, uncontrolled hypertension or orthostatic hypotension, tachy- or
brady-arrhythmias, acute or chronic pulmonary disease or neuromuscular disorders
affecting respiration.

3. Recent (previous 3 months) or planned resynchronization therapy (CRT), or valve
surgeries.

4. Previous or planned implantation of left ventricular assist devices or heart
transplant.

5. Chronic use of intravenous inotropes.

6. Recent (<14 days) use of immunosuppressive or anti-inflammatory drugs (including oral
corticosteroids at a dose of prednisone equivalent of 0.5 mg/kg/day but not including
inhaled or low dose oral corticosteroids or non-steroidal anti-inflammatory drugs).

7. Chronic inflammatory disorder (including but not limited to rheumatoid arthritis,
systemic lupus erythematosus).

8. Active infection (of any type), including chronic/recurrent infectious disease (i.e.
HBV, HCV, and HIV/AIDS) - but excluding HCV+ with undetectable plasma RNA.

9. Active malignancy - excluding carcinoma in situ [any location] or localized
non-melanoma skin cancer.

10. Any comorbidity limiting survival or ability to complete the study.

11. Stage V kidney disease or on renal-replacement therapy.

12. Neutropenia (<1,500/mm3 or <1,000/mm3 in African-American patients).

13. Pregnancy.

14. Angina, hypertension, arrhythmias, electrocardiograph (ECG) changes, or other
non-cardiac limitations (i.e., peak respiratory exchange ratio VCO2/VO2 [RER]<1.0,
reflecting sub-maximal test) that limit maximum exertion during CPX obtained during
the baseline testing.

15. Hypersensitivity to Kineret or to E. coli derived products.