Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH)

描述（由申请方提供）：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相关性之一是在后代中发生先天性心脏传导阻滞（CHB），这是2%具有这些反应性的孕中期母亲面临的令人担忧的前景。CHB的风险是10倍高，在随后怀孕的妇女谁以前有一个受影响的孩子。没有预防性治疗是成功的，完全阻滞从未被逆转。实验证据支持Toll样受体信号传导在CHB发病机制中的作用。由于羟氯喹（HCQ）抑制这一相关途径，因此启动了两项研究：1）一项病例对照研究，证明抗Ro抗体阳性SLE女性暴露于HCQ的胎儿的疾病风险降低，2）一项历史队列研究，CHB复发率降低70%。基于这些令人鼓舞的实验室到床边的结果，通过试点R 03启动了一项使用Simon 2阶段方法的开放标签前瞻性研究，假设HCQ显著降低了CHB的复发率。利用Simon的2阶段设计，目标是在第I阶段完成19名母亲的入组，这些母亲之前的妊娠并发CHB，如果发生少于3例复发病例，则打算应用R 01。截至2014年2月，32例妊娠入组，23例完成（19例无潜在混淆药物），2例超过26周（脆弱性罕见>26周），仅1例发生完全阻滞。这些数据支持第二阶段的开始。因此，具体目标1是完成开放标签II期试验的第II阶段，标题为羟基氯喹（PATCH）预防先天性心脏传导阻滞的方法，用于既往有CHB婴儿的孕妇。方案保持相同，HCQ在妊娠10周开始。系列超声心动图和评价母体和脐带血生物标志物（HCQ水平，IFN γ签名，自身抗体滴度）解决母体依从性，病理生物学和疗效。在5年内，最多将入组35例受试者（以确保无潜在混淆药物）。研究管理仍在纽约大学。已维持IND。最终，如果在总共54名受试者中发生<6例病例，则认为HCQ有效。一个积极的结果可能会改变所有抗Ro阳性的妇女谁有一个以前的孩子与CHB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，这一点特别重要，因为大多数受影响儿童的母亲本身完全没有症状。具体目标2阐述了妊娠期间HCQ暴露的眼科安全性。尽管在300多名儿童中报告了罕见的安全性问题，这些儿童的母亲在怀孕期间接受了不同剂量的HCQ治疗风湿性疾病，但由于HCQ干扰溶酶体代谢，因此可能会损害视网膜神经元，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（出生时种族和胎龄匹配）的视网膜发育数据有望进一步证实妊娠期间HCQ暴露的安全性。

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, IFN� 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.