Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH)

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。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。没有任何预防治疗是成功的，完全阻滞从未逆转。实验证据支持toll样受体信号在慢性乙型肝炎发病机制中的作用。由于羟氯喹（HCQ）抑制了这一相关途径，因此开展了两项研究：1)一项病例对照研究表明，抗ro抗体阳性的SLE妇女暴露于羟氯喹的胎儿的疾病风险降低；2)一项历史队列研究表明，慢性乙型肝炎的复发率降低了70%。基于这些令人鼓舞的从实验室到床边的结果，一项使用Simon的2阶段方法的开放标签前瞻性研究通过试点R03启动，假设HCQ显着降低CHB的复发率。利用Simon的两阶段设计，目标是完成19位第一阶段的母亲的登记，这些母亲以前的妊娠合并CHB，如果复发病例少于3例，则R01应用。截至2014年2月，32例妊娠登记，23例完成妊娠（19例未使用潜在的混杂药物），2例超过26周（罕见的26周），只有一例发生完全阻滞。这些数据支持第二阶段的开始。因此，Specific Aim 1是完成开放标签II期试验的II期，该试验名为羟氯喹预防先天性心脏传导阻滞（PATCH），适用于既往有CHB儿童的孕妇。方案仍然相同，妊娠10周开始进行HCQ。连续超声心动图和评估产妇和脐带血生物标志物（HCQ水平，IFNα特征，自身抗体滴度）解决产妇依从性，病理生物学和疗效。在5年的时间里，将招募多达35名受试者（以确保没有潜在的混淆药物）。研究管理仍在纽约大学进行。已维护IND。最终，如果54名受试者中出现的HCQ少于6例，则认为HCQ有效。阳性结果可能会改变所有抗- ro阳性且先前有CHB孩子的妇女的管理，并说明转化科学的重要性。一种潜在的预防措施将证明对所有孕妇进行抗ro抗体筛查是合理的，这一点尤其重要，因为大多数受感染儿童的母亲本身完全没有症状。具体目标2解决妊娠期间接触HCQ的眼科安全性。尽管在300多名母亲在怀孕期间用不同剂量的HCQ治疗风湿病的儿童中报告了罕见的安全问题，但由于HCQ干扰溶酶体代谢，因此可能损害视网膜神经元，因此仍然存在担忧。通过光学相干断层扫描获得的5岁儿童和对照组（种族和出生时胎龄相匹配）视网膜发育数据有望进一步保证妊娠期间接触HCQ的安全性。

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. The risk of CHB is 10-fold higher in subsequent pregnancies of women who have previously had an affected child. No preventive therapies have been successful and complete block has never been reversed. Experimental evidence supports a role of Toll-like receptor signaling in the pathogenesis of CHB. Since hydroxychloroquine (HCQ) inhibits this implicated pathway, two studies were initiated: 1) a case control study that demonstrated a reduction in risk of disease in HCQ-exposed fetuses of anti-Ro antibody-positive women with SLE, and 2) a historical cohort study in which the recurrence rate of CHB was decreased by 70%. Based on these encouraging bench-to-bedside results, an open label prospective study using Simon's 2-Stage approach was initiated via a pilot R03 with the hypothesis that HCQ significantly reduces the recurrence rate of CHB. Exploiting Simon's 2-Stage design, the goal was to complete enrollment of 19 mothers in Stage I whose previous pregnancies were complicated by CHB with the intent of an R01 application should fewer than 3 recurrent cases occur. As of February 2014 with 32 pregnancies enrolled, 23 completed (19 on no potentially confounding medications) and 2 beyond the 26th week (vulnerability rare >26 weeks), only one case of complete block occurred. These data support commencement of Stage II. Accordingly, Specific Aim 1 is to complete Stage II of the open label Phase II trial, entitled Preventive Approach To Congenital Heart Block with Hydroxychloroquine (PATCH), in pregnant women who have had a previous CHB child. The protocol remains identical, with HCQ initiated by 10 weeks gestation. Serial echocardiograms and evaluation of maternal and cord blood biomarkers (HCQ levels, IFNα signatures, autoantibody titers) address maternal compliance, pathobiology and efficacy. Over 5 years, up to 35 subjects will be enrolled (to assure no potentially confounding medications). Study governance remains at NYU. An IND has been maintained. Ultimately, HCQ will be considered efficacious if <6 cases occur among a total of 54 subjects. A positive result will likely change the management of all anti-Ro positive women who have had a previous child with CHB and illustrate the importance of translational science. A potential prevention would justify screening all pregnant women with anti-Ro antibodies, particularly relevant since the majority of mothers of affected children are themselves totally asymptomatic. Specific Aim 2 addresses the ophthalmologic safety of HCQ exposure during pregnancy. Despite the rarity of safety issues reported in over 300 children whose mothers were treated with varied doses of HCQ for rheumatic disease during pregnancy, concerns remain since HCQ interferes with lysosomal metabolism and thus may be damaging to retinal neurons. Data on retinal development in children age 5 and controls (matched for race and gestational age at birth) obtained by optical coherence tomography are expected to provide further reassurances regarding the safety of HCQ exposure during pregnancy.