Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH)

描述(由申请人提供)：针对Ro/La核糖核蛋白复合体组件的自身抗体与临床上最强烈的关联之一是在后代中出现先天性心脏传导阻滞(CHB)，2%具有这些反应的初孕母亲面临着一个令人担忧的前景。先前有过受影响孩子的妇女在随后怀孕时罹患慢性乙肝的风险要高出10倍。没有一种预防性治疗是成功的，完全阻断也从未逆转。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。由于羟基氯喹(HCQ)抑制了这一途径，因此启动了两项研究：1)病例对照研究，证明了抗Ro抗体阳性的SLE妇女在接触HCQ的胎儿中疾病风险降低；2)历史队列研究，CHB复发率降低70%。基于这些令人鼓舞的床边试验结果，通过Pilot R03启动了一项使用Simon的两阶段方法的开放标签前瞻性研究，假设HCQ显著降低CHB的复发率。利用Simon的两阶段设计，目标是在I阶段完成19名母亲的登记，这些母亲以前的怀孕因CHB而复杂化，如果复发病例少于3例，则打算申请R01。截至2014年2月，共登记了32例妊娠，23例妊娠完成(19例未服用潜在的混杂药物)，2例超过第26周(脆弱性罕见&26周)，仅发生1例完全阻断。这些数据支持第二阶段的开始。因此，具体目标1是完成开放式标签第二阶段试验的第二阶段，名为使用羟氯喹预防先天性心脏传导阻滞(PATH)，用于先前有CHB儿童的孕妇。方案保持不变，HCQ在怀孕10周时启动。系列超声心动图和母血和脐带血生物标志物(HCQ水平、干扰素�签名、自身抗体效价)的评估涉及产妇依从性、病理生物学和疗效。在5年内，最多将有35名受试者入选(以确保不会出现潜在的混淆药物)。研究治理仍然留在纽约大学。一直在维护IND。最终，如果在总共54名受试者中出现6例，则HCQ将被认为有效。一个积极的结果可能会改变所有曾生过慢性乙肝孩子的抗Ro阳性女性的管理，并说明翻译科学的重要性。一种可能的预防措施将证明对所有具有抗Ro抗体的孕妇进行筛查是合理的，特别是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解决怀孕期间接触氢氯喹酮的眼科安全性问题。尽管超过300名母亲在怀孕期间接受不同剂量的氢氯喹酮治疗风湿病的儿童报告了罕见的安全问题，但人们仍然担心，因为氢氯喹酮干扰溶酶体新陈代谢，因此可能会损害视网膜神经元。通过光学相干断层扫描获得的5岁儿童和对照组(与出生时的种族和胎龄匹配)的视网膜发育数据有望为怀孕期间接触HCQ的安全性提供进一步的保证。

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.