Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH)

使用羟氯喹 (PATCH) 预防先天性心脏传导阻滞的方法

• 批准号: 8440727
• 负责人: Jill P Buyon
• 金额: $ 8.02万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440727
• 关键词: 10 year old; Address; Adult; Affect; Antibodies; Attention; Autoantibodies; Award; Basic Science; Biological Markers; Cardiac; Cardiomyopathies; Case-Control Studies; Child; Chloroquine; Clinical; Complex; Conceptions; Data; Data Collection; Databases; Defect; Development; Disease; Dose; Echocardiography; Enrollment; Europe; Evaluation; Face; Fetal Diseases; Fetus; Fibrosis; Funding; Health Status; Heart Block; Hydroxychloroquine; Immunoglobulin G; In Vitro; Injury; Institutional Review Boards; Interferon-alpha; Interferons; Intervention; Intravenous Immunoglobulins; Life; Ligation; Lupus; Mediating; Monitor; Morbidity - disease rate; Mothers; Multicenter Studies; Myocardial; Neonatal lupus erythematosus; Pathogenesis; Patient Recruitments; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Plasmapheresis; Pregnancy; Pregnant Women; Prevention; Preventive; Prophylactic treatment; Prospective Studies; Proteins; Protocols documentation; Randomized Controlled Trials; Rare Diseases; Receptor Signaling; Recruitment Activity; Recurrence; Registries; Research; Research Personnel; Resources; Rheumatism; Ribonucleoproteins; Risk; SS-A antibodies; Safety; Site; Staging; Steroids; Sympathomimetics; Systemic Lupus Erythematosus; Testing; Time; Tissues; Toll-like receptors; Translating; Translational Research; Translations; Treatment Efficacy; Umbilical Cord Blood; Woman; Work; base; bench to bedside; case control; design; experience; fetal; in utero; macrophage; mortality; neonatal morbidity; offspring; open label; prevent; prospective; screening; treatment strategy

DESCRIPTION (provided by applicant): One of the strongest clinical associations with autoantibodies directed to components of the Ro/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. Based on extensive data collection from the U.S. Research Registry for Neonatal Lupus, the risk of CHB is 10-fold higher in subsequent pregnancies of women who have had a previously affected child. Despite the attempt of large multicenter studies to forestall disease by serial in utero monitoring, irreversibe block and extensive myocardial injury have been documented within 7 days of a normal rhythm and PR interval. CHB is associated with a substantial mortality and morbidity. To date no preventative therapies have been successfully developed and complete block has never been reversed. Two recent prospective studies (20 mothers from U.S. and 15 from Europe) utilizing an identical protocol of IVIG at replacement doses demonstrated 1) this intervention does not prevent the recurrence of CHB 2) the recurrence rate of 17-18% is robust 3) recruitment of patients is feasible. During the time period of the IVIG trials, basic science exploring the pathogenesis of disease supported the notion that Toll Like Receptor (TLR) signaling following ligation of ssRNA (hY3) complexed to the Ro60 protein contributes to fibrosis. This observation led to in vitro studies addressing inhibition of endosomal acidification by chloroquine. Subsequent translation to patients was approached by evaluating hydroxychloroquine (HCQ) use in an extensive case control study restricted to lupus mothers and a separate retrospective evaluation of whether HCQ reduces the expected recurrence rate of CHB. The combined data suggest efficacy. Accordingly, the specific aim of this study is to determine whether HCQ prevents the recurrence of CHB. This will be approached in a Phase II trial of pregnant women with anti-Ro antibodies who have had a previous child with CHB. This is designed as an open-label trial employing Simon's 2-stage optimal design to allow for early stopping due to absence of efficacy. The first stage requires 19 subjects, which are expected to be enrolled with all pregnancies completed within two years. Serial echocardiograms (monitor PR interval) and evaluation of maternal and cord blood biomarkers (HCQ levels, IFNa signatures, and Ab titers) will be part of the protocol to address maternal compliance, pathobiology and efficacy. If 3 mothers have a child with 2nd or 3rd degree CHB, the study is terminated after the first stage. If < 3 recurrences are observed, the 2nd stage will be launched as part of a full scale RO1 application with an additional 35 subjects enrolled. The study governance will be at NYU and the IRB has approved the protocol at this site. An IND has been issued by the FDA. Ultimately, HCQ will be considered efficacious for CHB prevention if < 6 cases occur among 54 subjects. While it is acknowledged that a prospective randomized control study would be most robust, the rarity of disease may be limiting. However, data on women refusing drug will be equivalently maintained. A positive result will likely change the management of all anti-Ro positive women who have had a previous child with CHB. Furthermore, potential prevention would justify screening of all pregnant women for anti-Ro antibodies.

描述（由申请人提供）：与针对Ro/La核糖核蛋白复合物组分的自身抗体的最强临床关联之一是在后代中发展为先天性心脏传导阻滞（CHB），这是一个令人担忧的前景，面临2%具有这些反应性的原孕母亲。根据美国新生儿狼疮研究登记处收集的大量数据，先前有过感染儿童的妇女在随后的怀孕中患CHB的风险高出10倍。尽管有大型多中心研究试图通过连续的子宫内监测来预防疾病，但在正常心律和PR间期的7天内，已经记录了不可逆性传导阻滞和广泛的心肌损伤。慢性乙型肝炎与大量的死亡率和发病率有关。迄今为止，还没有成功开发出预防性治疗方法，完全阻滞也从未逆转过。最近的两项前瞻性研究（来自美国的20名母亲和来自欧洲的15名母亲）使用了相同的替代剂量的IVIG方案，结果表明：1)这种干预不能预防CHB的复发；2)17-18%的复发率是稳健的；3)招募患者是可行的。在IVIG试验期间，探索疾病发病机制的基础科学支持了这样一种观点，即ssRNA （hY3）与Ro60蛋白连接后Toll样受体（TLR）信号传导有助于纤维化。这一观察结果导致体外研究解决抑制内体酸化氯喹。在一项广泛的病例对照研究中，对羟氯喹（HCQ）的使用进行了评估，该研究仅限于狼疮母亲，并对HCQ是否降低慢性乙型肝炎的预期复发率进行了单独的回顾性评估。综合数据表明有效。因此，本研究的具体目的是确定HCQ是否可以预防慢性乙型肝炎的复发。这将在一项II期试验中进行，该试验的对象是先前有CHB儿童的抗ro抗体孕妇。这是一项开放标签试验，采用Simon的两阶段优化设计，允许由于缺乏疗效而早期停止。第一阶段需要19名受试者，预计将在两年内完成所有怀孕。连续超声心动图（监测PR间期）和母体和脐带血生物标志物（HCQ水平、IFNa特征和Ab滴度）的评估将成为方案的一部分，以解决母体依从性、病理生物学和疗效。如果三个母亲的孩子患有二度或三度慢性乙型肝炎，研究在第一阶段结束后终止。如果