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)

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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.

Trial registration: Clinical Trials.gov # NCT02179853, registered June 28, 2014

Section snippets

Introduction and rationale

Kawasaki disease (KD), the most common cause of acquired heart disease in children in Western developed countries and Asia, is a systemic vasculitis of unknown etiology. KD causes both a myocarditis and a vasculitis that damages the coronary arteries and other medium-sized muscular arteries leading to the formation of aneurysms [49], [53]. The major sequelae of aneurysms include thrombosis, late coronary artery stenosis, myocardial ischemia, myocardial infarction, and death [10], [15], [27].

Objectives

The goal of this study is to determine the safety, pharmacokinetics, and activity of anakinra in acute KD patients at least 8 months of age with a coronary artery Z score (internal dimension of the coronary artery normalized for body surface area and expressed as standard deviations from the mean)  3.0 in the right coronary artery (RCA) and/or left anterior descending (LAD) artery. This study is viewed as preparatory to a Phase III trial of anakinra to prevent or attenuate coronary artery damage

Study design

This two-center dose-escalation Phase I/IIa trial (See Dose Levels Table 2) will determine the safety, tolerability and immunomodulatory effects of anakinra in 30 acute KD patients at least 8 months old with CAA. The enrollment age limit is a condition of our IND and was imposed by the FDA until safety data for KD could be reviewed after completion of this trial. Enrollment will occur at two study sites: Rady Children's Hospital San Diego and Children's Hospital of Boston.

All subjects will be

Inclusion and exclusion criteria

Infants and children at least 8 months of age (age limited by Food and Drug Administration) within the first 20 days after fever onset who meet American Heart Association criteria for KD and have a Z score of ≥ 3.0 of the LAD and/or RCA or an aneurysm are study eligible (Table 4). Subjects with an active, culture-positive bacterial infection will be excluded.

Primary and secondary endpoints

The primary endpoint of the study is safety and tolerability of anakinra in the study population. The pre-specified secondary endpoints are the pharmacokinetics of anakinra, the changes in echocardiographic assessment of the internal diameters of the coronary arteries expressed as Z scores over the course of the study, and the change in biomarkers of inflammation including levels of hsCRP, α1-antitrypsin and fibrinogen, and the WBC and ESR. Innate immune cells and T cells will be studied prior

Ethics and informed consent

The study protocol was reviewed and approved by the Institutional Review Board at the University of California San Diego and Boston Children's Hospital. Written informed consent will be obtained from the parents or legal guardians and assent, when appropriate, will be obtained from the patient. This trial is registered with clinicaltrials.gov (NCT02179853).

Data analysis

All enrolled subjects at the maximum tolerated dose will be included in a case:control study and matched with historical controls from each center for age, sex, illness day, adjunctive therapies in addition to IVIG, and the worst coronary artery Z score for the RCA and LAD on the initial, pre-treatment echocardiogram. Measures of inflammation, including hsCRP, ESR and WBC, at two weeks will be compared to that of matched controls via paired statistical tests (e.g. McNemar's test for categorical

Discussion

Despite timely treatment with high dose IVIG and aspirin, some infants and children with KD develop CAA. However, there is no recommended therapy to halt the progression of arterial wall damage and prevent aneurysm formation. Thus, aneurysm prevention is a primary goal of treatment during the acute phase of the disease and is the focus of this trial. Data from both animal studies and evaluation of the IL-1 pathway in patients with acute KD support IL-1 blockade as a therapeutic option.

Studies

Conclusion

Thus, this dose-escalation Phase I/IIa trial will determine the safety, tolerability and immunomodulatory effects of anakinra in KD patients at least 8 months of age.

Acknowledgements

This work is supported by a University of California San Diego Department of Pediatrics Intramural Clinical Research grant (awarded to AHT), a Rady Children's Hospital San Diego Academic Enrichment grant (awarded to AHT), and a grant from the Gordon and Marilyn Macklin Foundation grant (awarded to JCB). Ancillary study support was provided by the Clinical and Translational Study Unit at Boston Children's Hospital. Anakinra was donated by the manufacturer, Sobi Pharmaceuticals.

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