IC14 for Treatment of Acute Decompensated Heart Failure

The proposed investigation is a pilot study to evaluate the safety and exploratory efficacy of IC14 administered via IV infusion in patients with ADHF.

The primary objective of this study is to determine safety of intravenous IC14 in patients acute decompensated heart failure. Exploratory biomarkers, clinical outcomes, and pharmacokinetic/pharmacodynamic measurements will be used to design further study of clinical efficacy of IC14 in the treatment of ADHF.

To characterize safety of IC14 administered via IV infusion, the following assessments are to be performed: treatment-emergent adverse events (AEs), safety laboratory studies, serious adverse events (SAEs), and presence of anti-drug antibodies.

To evaluate the effect of IC14, biomarkers including high-sensitivity C-reactive protein (hsCRP), B-type natriuretic peptide (BNP), urine sodium, and estimated glomerular filtration rate (eGFR) are measured at baseline and repeatedly after IC14 treatment. CRP is an established prognostic marker in heart failure that reflects systemic interleukin-6 as well as interleukin-1 activities. Measuring CRP area-under-the-curve allows for integrating measurements across multiple time points to quantify the acute inflammatory response more accurately.

Preliminary clinical efficacy will be measured by evaluating heart failure and cardiac performance outcomes at Day 10, including Dyspnea Visual Analogue Scale, Congestion Score, Doppler echocardiogram, non-invasive hemodynamics, bioimpedance analysis, cardiopulmonary exercise test and Kansas City Cardiomyopathy Questionnaire.

Pharmacokinetics will determine the serum concentration of IC14 over time. Pharmacokinetic measurements will be correlated with pharmacodynamic markers of IC14 biologic effect, including monocyte CD14 receptor occupancy.

Inclusion criteria

Patients may be included in the study only if they meet all of the following criteria:

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

• Pulmonary congestion/edema a physical exam OR chest x-ray;
• plasma BNP levels ≥200 pg/ml or N-terminal-proBNP ≥600 pg/ml; or
• invasive measurement of left ventricular end-diastolic pressure (LVEDP) >18 mmHg or of pulmonary artery occluding pressure (wedge pressure) >16 mmHg.
• The patient has a prior documentation of impaired left ventricular systolic function (left ventricular ejection fraction <40%) at most recent assessment by any imaging modality (within 12 months).
• The patient is symptomatic for moderate to severe dyspnea at time of enrollment as indicated by a score on the visual analog scale for dyspnea of 40 or more (in a scale of 1 to 100, where 0 is no shortness of breath and 100 is extremely short of breath) in the prior 12 hours.
• The patient has recently received (past 24 hours) or is scheduled to received intravenous loop diuretics.
• The patient is of age ≥21 years old, willing and able to provide written informed consent and to comply with the protocol (i.e., reporting of symptoms).
• The patient has screening plasma C-reactive protein levels >3 mg/L (0.3 mg/dL).
• Males and females of childbearing potential must use effective contraception.

Exclusion criteria

• The primary diagnosis for admission is NOT decompensated heart failure, including diagnosis of acute coronary syndromes, hypertensive urgency/emergency, tachy- or brady-arrhythmias.
• 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.
• Recent (previous 3 months) or planned cardiac resynchronization therapy (CRT) or valve surgeries.
• Previous or planned implantation of left ventricular assist devices or heart transplant.
• Current or planned use of intravenous inotropes.
• Recent (<14 days) use of immunosuppressive or anti-inflammatory drugs (including oral corticosteroids at a prednisone equivalent dose of ≥0.5 mg/kg/day but not including inhaled or low-dose oral corticosteroids, non-steroidal anti-inflammatory drugs or colchicine).
• Chronic inflammatory disorder (i.e., rheumatoid arthritis, systemic lupus erythematosus).
• Active infection (of any type), including chronic/recurrent infectious disease (including hepatitis B virus, hepatitis C virus, and HIV/AIDS) - but excluding HCV+ with undetectable plasma RNA.
• Active malignancy - excluding carcinoma in situ [any location] or localized non-melanoma skin cancer.
• Any comorbidity limiting survival or ability to complete the study, including end-stage heart failure.
• Stage V kidney disease or on renal-replacement therapy or renal transplant recipient.
• Neutropenia (<1,500/mm3 or <1,000/mm3 in Black/African-American patients).
• Pregnancy.
• Hypersensitivity to IC14 or previous adverse reaction to antibody-based treatments.