Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial)

Abstract

Background Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target. Objectives The goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram. Design This is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ≥8 months old with a coronary artery Z score ≥3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection). Conclusion The safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.

Kawasaki disease: etiopathogenesis and novel treatment strategies

“…This then led to clinical trials for the use of IL-1R (Anakinra) in children with KD and is currently in phase IIa of clinical trials [52]. …”

“…Therefore, use of TNF-α blockers could be one of the therapeutic strategies in KD patients to prevent aneurysms formation and is undergoing clinical trials [17]. It has also been shown that nitric oxide (NO) production is increased in KD patients and goes down rapidly with IVIG treatment [52]. NO is known to maintain normal vascular tension.…”

“…High NO concentrations could therefore lead to vessel wall dilatation and lesions [53]. This is mediated by the inducible nitric oxide synthase enzyme (iNOS) present in myocardial cells, vascular smooth muscle cells, leukocytes and inflammatory cells which is upregulated during inflammatory response and in turn, promotes elevation of NO [52,54]. IVIG treatment has been shown to decrease the levels of NO in KD [52,53,55].…”

Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

“…A Phase IIa multicenter trial is aimed at assessing the efficacy and safety of anakinra in patients with KD who failed to respond to standard treatment (i.e., one infusion of 2 g/kg of IVIG) (clinicaltrials.gov NCT02390596). Another Phase II trial is intended to assess the safety and activity of anakinra in infants and children <2 years old with coronary artery abnormalities (clinicaltrials.gov NCT02179853) [95].…”

QUESTION 1: What is the best therapy for children with Kawasaki disease who fail to respond to initial intravenous immunoglobulin?

“…Eleven articles were not in English and were excluded. Restricting to meta-analysis or randomised controlled trials (RCTs), there were five published RCTs, two prospective RCTs with results awaited1 2 and two relevant meta-analyses (table 1). …”