Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) - A phase II clinical trial

Abstract

Background: Kawasaki disease (KD) is the most common acquired heart disease in children of the developed world, and triggers progressive coronary artery lesions (CAL) in 30% of cases if left untreated. Despite standard anti-inflammatory treatment for KD, CAL (dilation or aneurysm) still occurs in 5-10% of children, increasing their risk for fatal coronary artery complications. CAL is mediated by enhanced matrix metalloproteinase activity and elastin breakdown induced by the inflammatory process in the coronary artery wall. Doxycycline is an effective inhibitor of matrix metalloproteinases, and has been shown to reduce elastin breakdown and CAL in a mouse model of KD, but has not been evaluated in patients.

Objective: We aim to evaluate the efficacy of doxycycline in the prevention of CAL in children during the acute phase of KD.

Design: This is a phase II prospective, randomized, double-blinded, clinical trial in two steps. In Step 1, any child older than 1month with the diagnosis of KD will be included. Children with KD will be included in Step 2 if they develop coronary artery dilation (z-score≥2.5) within 20days from the onset of fever. Study subjects in Step 2 will be randomized to receive a 3-week course of doxycycline or placebo.

Evaluation: The efficacy of a 3-week doxycycline course during the acute phase of KD will be evaluated by measuring the decline in coronary artery z-scores from baseline with doxycycline treatment compared to placebo.

Clinical trial registration: This study was registered on clinicaltrials.gov (NCT01917721).

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1

Treatment protocol for the DEAL trial.

Figure 2

Coronary artery changes after doxycycline treatment compared to placebo Absolute and relative changes in coronary artery diameter z-score after doxycycline treatment compared to placebo during the acute phase of Kawasaki disease (KD). Ten patients were enrolled in a preliminary study and randomized to doxycycline (n=5) or placebo (n=5) treatment arms. From the acute phase of KD (T1) to the convalescent phase (T4), coronary artery diameter z-scores decreased more dramatically in the doxycycline arm compared to the placebo arm (with a relative change of z-score −2.55 vs. −1.57). This study served for our power calculation and sample size prediction.

Figure 3

Echocardiograms of the left anterior descending coronary artery (LAD) during the acute and convalescent phases of Kawasaki disease (KD). A: Diffuse dilation of the LAD (arrow) up to 34 mm in diameter during the acute phase of KD. B: Resolution of the diffuse dilation (diameter 17 mm) during the convalescent phase after a 3-week treatment course of doxycycline, Ao: aorta, LMCA: left main coronary artery.