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。根据美国新生儿狼疮研究登记处收集的大量数据，CHB的风险在以前受影响的孩子的妇女随后怀孕时高出10倍。 尽管大型多中心研究试图通过子宫内连续监测来预防疾病，但在正常心律和PR间期的7天内记录了不可逆性阻滞和广泛的心肌损伤。 CHB与相当大的死亡率和发病率相关。到目前为止，还没有成功开发出预防性治疗方法，完全阻滞从未被逆转。最近的两项前瞻性研究（20名来自美国的母亲和15名来自欧洲的母亲）采用相同的IVIG替代剂量方案，证明1）这种干预不能预防CHB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这样的观点，即与Ro 60蛋白复合的ssRNA（hY 3）连接后的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氯喹抑制内体酸化的问题。后续 通过在局限于狼疮母亲的广泛病例对照研究中评价羟氯喹（HCQ）的使用，以及单独回顾性评价HCQ是否降低CHB的预期复发率，来探讨对患者的转化。 综合数据表明疗效。 因此，本研究的具体目的是确定HCQ是否可以预防CHB的复发。这将在具有抗Ro抗体的孕妇的II期试验中进行，这些孕妇以前曾有过CHB儿童。 这是一项开放标签试验，采用Simon的2阶段最佳设计，允许因缺乏疗效而提前停药。 第一阶段需要19名受试者，预计将在两年内完成所有妊娠。 系列超声心动图（监测PR间期）和评价母体和脐带血生物标志物（HCQ水平、IFNa特征和Ab滴度）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3位母亲的孩子患有2度或3度CHB，则研究在第一阶段结束后终止。 如果 如果观察到< 3例复发，则第2阶段将作为全规模RO 1应用的一部分启动，另外招募35例受试者。 研究管理将在纽约大学进行，IRB已批准该研究中心的方案。 FDA已发布IND。最终，如果在54名受试者中发生< 6例病例，则HCQ将被认为对CHB预防有效。虽然人们承认前瞻性随机对照研究将是最可靠的，但疾病的罕见性可能是有限的。 然而，关于拒绝吸毒的妇女的数据将同样保留。 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。 此外，潜在的预防将证明筛查所有孕妇的抗Ro抗体是合理的。

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.