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)是一种自限性脉管炎，是美国和日本儿童获得性心脏病的主要原因(Taubert等人。1991年)。在美国大约有126,000名受影响的儿童(4,200名儿童/年×30岁)，因此符合FDA的孤儿疾病标准(Holman等人)。2003年)。而大多数儿童对静脉注射免疫球蛋白(IVIG)会有反应(Newburger等人)。(1991年)，大约10-20%的人将出现持续或复发的发热，需要额外的治疗，并将面临发展为冠状动脉异常的更高风险(Burns等人)。1998年；Treouse et al.2008年)。 以冠状动脉和其他肌肉动脉为靶点的免疫系统过度激活是KD的主要特征。促炎细胞因子肿瘤坏死因子a(TNFa)水平在急性KD期间升高，在随后发展为冠状动脉动脉瘤的儿童中水平最高(Furukawa等人)。(1994年)。申请人假设英夫利昔单抗，一种与TNFa高亲和力结合的合成单抗，可能对急性KD患者有益。因此，一项由研究人员发起、公司赞助(Centocor)的多中心随机前瞻性试验在24名急性KD儿童中进行了第二次IVIG输注与英夫利昔单抗的比较，这些儿童在首次IVIG治疗后持续发烧(Burns等人提交)。主要观察指标为英夫利昔单抗的安全性、耐受性和药代动力学。英夫利昔单抗耐受性良好，没有与输液有关的不良事件。然而，研究双方的几名受试者都出现了冠状动脉异常。因此，他们推测，在标准的初级治疗基础上加用英夫利昔单抗早期阻断TNFa将改善这些儿童的冠状动脉预后。申请人建议在一项随机、双盲、安慰剂对照的多中心3期临床试验中验证这一假设，该试验是英夫利昔单抗加标准疗法与安慰剂加标准疗法用于急性KD的主要治疗。 这项研究的主要结果衡量标准将是随机分组后第2周右冠状动脉和左冠状动脉前降支的z分数中较大的一个。次要结果指标将是炎症标志物、发烧持续时间、住院时间和费用的变化。影响T细胞激活的肌醇1，4，5-三磷酸3-激酶C(ITPKC)功能多态和影响TNFa水平的TNFa-308a等位基因的患者基因型将与治疗反应相关(Quasney等人)。2001年；Onouchi等人。2008年)。如果将英夫利昔单抗添加到KD的初步治疗中显示出益处，申请者将寻求在KD患者中使用英夫利昔单抗的许可。FDA的资金对开展这项研究至关重要，因为在美国，从这种疗法中受益的患者太少，无法使这一新适应症在经济上吸引制造商(Centocor)。

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).