Phase III infliximab for primary treatment of Kawasaki disease IND 11046 6/27/200

描述（由申请人提供）： 川崎病（KD，OMIM 300530）是一种自限性血管炎，是美国和日本儿童获得性心脏病的主要原因（Taubert et al. 1991）。美国约有126，000名受影响的儿童（4，200名儿童/年x 30岁），因此符合FDA关于孤儿疾病的标准（Holman et al. 2003）。 虽然大多数儿童对静脉注射免疫球蛋白（IVIG）有反应（Newburger et al. 1991），但约10-20%的儿童将出现持续性或复发性发热，需要额外治疗，并且发生冠状动脉异常的风险增加（Burns et al. 1998; Tremoulet et al. 2008）。 免疫系统的过度激活，靶向冠状动脉以及其他肌肉动脉，是KD的中心特征。促炎细胞因子肿瘤坏死因子a（TNF α）的水平在急性KD期间升高，并且在随后发生冠状动脉瘤的儿童中水平最高（Furukawa等人，1994）。 申请方假设英夫利西单抗（一种与TNF α高亲和力结合的合成单克隆抗体）可能使急性KD患者获益。因此，在24名IVIG初始治疗后持续发热的急性KD儿童中进行了一项由制药商发起、公司申办（Centocor）、多中心、随机、前瞻性试验，对比第二次IVIG输注与英夫利西单抗（Burns et al.，提交）。主要结果指标为英夫利西单抗的安全性、耐受性和药代动力学。英夫利西单抗耐受性良好，没有与输注相关的不良事件。然而，研究两组中的几名受试者发生了冠状动脉异常。因此，他们假设在标准的基础治疗中加入英夫利西单抗，早期阻断TNF α，将改善这些儿童的冠状动脉结局。 申请方拟在一项随机、双盲、安慰剂对照、多中心III期试验中检验该假设，该试验比较英夫利西单抗加标准治疗与安慰剂加标准治疗对急性KD的主要治疗。 研究的主要结局指标是随机化后第2周时右冠状动脉和左冠状动脉前降支的z评分中较大者。次要结局指标将是炎症标志物的变化、发热持续时间、住院时间和费用。影响T细胞活化的肌醇1，4，5-三磷酸3-激酶C（ITPKC）功能多态性和影响TNF α水平的TNF α-308 A等位基因的患者基因型将与治疗应答相关（Quasney et al. 2001; Onouchi et al. 2008）。如果将英夫利西单抗添加到KD的主要治疗中显示出获益，则申请人将寻求在KD患者中使用英夫利西单抗的许可。FDA的资助对于开展这项研究至关重要，因为在美国，很少有患者会从这种疗法中受益，因此这种新的适应症对制造商（Centocor）具有经济吸引力。

DESCRIPTION (provided by applicant): Kawasaki disease (KD, OMIM 300530) is a self-limited vasculitis that is the leading cause of acquired heart disease in children in the U.S. and Japan (Taubert et al. 1991). There are approximately 126,000 affected children in the U.S. (4,200 children/year x 30 years), thus meeting the FDA criterion for an orphan disease (Holman et al. 2003). While most children will respond to intravenous immunoglobulin (IVIG) (Newburger et al. 1991), approximately 10-20% will have persistent or recrudescent fever, will require additional therapy, and will be at increased risk of developing coronary artery abnormalities (Burns et al. 1998; Tremoulet et al. 2008). Hyper-activation of the immune system, which targets coronary as well as other muscular arteries, is a central feature of KD. Levels of the pro-inflammatory cytokine tumor necrosis factor a (TNFa) are elevated during acute KD and levels are highest in children in whom coronary artery aneurysms subsequently develop (Furukawa et al. 1994). The applicant postulates that infliximab, a synthetic monoclonal antibody that binds with high affinity to TNFa, might benefit patients with acute KD. Therefore, an investigator-initiated, company-sponsored (Centocor), multicenter, randomized, prospective trial was performed of second IVIG infusion versus infliximab in 24 children with acute KD who had persistent fever following initial treatment with IVIG (Burns et al., submitted). Primary outcome measures were infliximab safety, tolerability, and pharmacokinetics. Infliximab was well-tolerated with no adverse events related to infusions. However, several subjects in both arms of the study developed coronary artery abnormalities. Therefore, they postulate that earlier blockade of TNFa by the addition of infliximab to standard primary therapy will improve coronary artery outcome for these children. The applicant propose to test this hypothesis in a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial of infliximab plus standard therapy vs. placebo plus standard therapy for the primary treatment of acute KD. The primary outcome measure of the study will be the larger of the z scores for the right and the left anterior descending coronary arteries at week 2 after randomization. The secondary outcome measures will be change in markers of inflammation, duration of fever, duration of hospitalization, and cost. Patient genotype for the functional polymorphism in inositol 1,4,5-triphosphate 3-kinase C (ITPKC) that affects T-cell activation and for the TNFa -308A allele that affects TNFa levels will be correlated with response to therapy (Quasney et al. 2001; Onouchi et al. 2008). If the addition of infliximab to primary therapy of KD shows benefit, the applicant will seek licensing for the use of infliximab in KD patients. FDA funding is essential to carry out this study as too few patients in the U.S. would benefit from this therapy to make this new indication economically attractive to the manufacturer (Centocor).