Interleukin-1 Receptor Antagonist for the Treatment of Heart Failure in Patients With Left Ventricular Assist Devices

Phase 1

Completed

Conditions: Heart Failure

Interventions: Drug: Anakinra

Registration Number: NCT02547766

Lead Sponsor: University of Utah

Brief Summary: Heart failure remains a major cause of morbidity and mortality. Many patients with heart failure receive support from a left ventricular assist device (LVAD) at some point in the course of their disease. Some of these LVAD patients experience a durable recovery after ventricular unloading with an LVAD, which may be associated with inhibition of inflammatory cytokines. This small pilot study aims to determine the biologic and clinical efficacy of an interleukin-1 receptor antagonist (Anakinra) at inducing myocardial recovery in patients supported with left ventricular assist devices.

Detailed Description: More than 5 million Americans have heart failure, a number that is expected to increase 25% by the year 2030. Fifty percent of individuals diagnosed with heart failure die within 5 years of diagnosis. Of those patients who currently have heart failure, 5-10% have Stage D disease, requiring specialized interventions such as chronic inotropic support, mechanical circulatory support, or transplantation. Transplantation is considered curative for heart failure, but only about 2,200 heart transplants take place each year. Due to the imbalance between donors and possible recipients, a large number of patients remain who could benefit from transplantation that will never receive a heart. Many patients receive left ventricular assist devices (LVADs) to support their failing hearts, increasing their chances of survival while they wait to undergo transplantation.

It has been shown that up to 19% of patients show durable echocardiographic recovery (as measured by left ventricular ejection fraction \>40%) after ventricular unloading with an LVAD. Recovery mediated by unloading with the LVAD causes several changes at the molecular level. However, the mechanisms underlying recovery at the cellular level, also known as reverse remodeling, are only recently being studied. Thus, the window of opportunity to develop adjuvant treatments to enhance recovery is just now opening.

Interestingly, patients that experience durable echocardiographic recovery have higher circulating levels of anti-inflammatory cytokines. Inhibition of inflammatory cytokines, such as with the use of receptor antagonists for inflammation-associated cytokines like Anakinra, has also been shown to reduce adverse myocardial remodeling after ischemic events and to increase exercise activity in patients with systolic heart failure. This study proposes the exogenous administration of Anakinra to end-stage heart failure patients supported with LVADs in an effort to increase both the number of patients who experience recovery and the magnitude of recovery.

While this is a small trial aimed primarily at demonstrating biologic efficacy of Anakinra, clinical efficacy in this study is also investigated. Encouraging results in this pilot study may prompt the creation of a randomized, controlled trial designed to demonstrate efficacy from a functional clinical standpoint.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

To qualify for inclusion, patients must meet the following criteria: age >18 years at date of LVAD implantation who require circulatory support with an LVAD for either a bridge-to-transplant or destination therapy indication.
They must also be judged by the implanting surgeon to have an expected survival to trial completion (approximately 6 months after implantation), without regard to the likelihood of cardiac transplantation.

Exclusion Criteria

Exclusion criteria include the presence of a Right Ventricular Assist Device, as biventricular support is associated with decreased survival outcomes that could negatively impact the attrition rate over the course of the study.
Additional exclusion criteria include the inability of the patient or a trained caregiver to administer the study drug, and inability of the patient to complete the study questionnaire. - Patients with a creatinine clearance < 30 mL/min, evidence of an active infection, immunosuppression, or with an allergy to E. Coli derived products will also be excluded. -
Last, any patient with dependence on inflammatory modulating drugs will be excluded.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Anakinra Arm	Anakinra	All patients in this arm receive Anakinra in a pre-post design. That is, outcome markers are measured, the intervention (Anakinra) is applied, and the outcome markers are measured again at various intervals to determine effect.

Primary Outcome Measures

Name	Time	Method
Biologic Efficacy: Inflammation Marker - C-Reactive Protein	6 months post treatment	The primary endpoint was a reduction in inflammatory markers, specifically C-reactive protein (CRP).

Secondary Outcome Measures

Name	Time	Method
Clinical Efficacy: Ejection Fraction	6 months post treatment	Clinical efficacy was a secondary endpoint that was measured using ejection fraction (EF)
Biologic Efficacy: Inflammation Marker - Neutrophil Count	6 months post treatment	Secondary endpoints included the measure of additional inflammatory markers, including neutrophil count.
Biologic Efficacy: Inflammation Marker - TNFalpha	6 months post treatment	Secondary endpoints included the measure of additional inflammatory markers, including TNFalpha.