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。根据从美国新生儿狼疮研究登记中心收集的大量数据，先前有过受影响孩子的妇女在随后怀孕时患慢性乙肝的风险高出10倍。尽管大型多中心研究试图通过宫内连续监测来预防疾病，但在正常节律和PR间期的7天内，已记录到不可逆转的传导阻滞和广泛的心肌损伤。CHB与相当大的死亡率和发病率有关。到目前为止，还没有成功的预防性治疗方法，完全阻断也从未逆转过。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)使用相同的IVIG替代剂量方案表明：1)这种干预不能防止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这样的观点，即与Ro60蛋白复合的单链RNA(HY3)连接后的Toll样受体(TLR)信号有助于纤维化。这一观察导致了体外研究，解决了氯喹抑制内体酸化的问题。随后的转化是通过评估羟氯喹(HCQ)的使用来进行的，该研究在一项仅限于狼疮母亲的广泛病例对照研究中进行，并对羟基氯喹是否降低CHB的预期复发率进行了单独的回顾性评估。综合起来的数据显示出了有效性。因此，这项研究的具体目的是确定HCQ是否可以预防CHB的复发。这将在一项针对患有Ro抗体的孕妇的第二阶段试验中进行，这些孕妇之前有过患有慢性乙肝的孩子。这是一项开放标签试验，采用西蒙的两阶段优化设计，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怀孕。系列超声心动图(监测PR间期)和评估孕妇和脐带血生物标记物(HCQ水平、IFNA签名和抗体滴度)将成为解决产妇依从性、病理生物学和疗效的方案的一部分。如果3位母亲的孩子患有二度或三度慢性乙肝，研究在第一阶段后终止。如果 &lt；3重复出现，第二阶段将作为全面RO1应用程序的一部分启动，另外还将招收35个科目。研究治理将在纽约大学进行，IRB已经在这个地点批准了该方案。FDA已经发布了IND。最终，如果54名受试者中发生6例，HCQ将被认为是预防CHB的有效方法。虽然人们承认，前瞻性随机对照研究将是最可靠的，但疾病的罕见可能是有限的。然而，有关女性拒绝吸毒的数据将得到同等程度的维护。一个积极的结果可能会改变所有抗Ro阳性妇女的管理，这些妇女之前曾生过患有慢性乙肝的孩子。此外，潜在的预防将证明对所有孕妇进行抗Ro抗体筛查是合理的。 与公共卫生相关：所有携带抗Ro抗体的妇女，无论她们自己的健康状况如何，都面临着生下威胁生命的先天性心脏病的前景。虽然风险只有2%，但复发率高出10倍。尽管能够确定处于危险中的母亲，但到目前为止还没有成功的预防性疗法。这项研究评估了一种廉价且相对安全的治疗方法--羟基氯喹作为预防方法的使用。这项工作的影响很大，因为阳性结果将改变所有已知具有抗Ro抗体的女性的管理，并证明对所有女性进行这些抗体检测是合理的，即使她们没有症状，作为早期怀孕筛查的一部分。

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. PUBLIC HEALTH RELEVANCE: All women with anti-Ro antibodies irrespective of their own health status face the prospect of having a child with life- threatening congenital heart block. Although the risk is only 2%, the recurrence rate is 10 times higher. Despite being able to identify the mother at risk, no preventive therapies have been successful to date. This study evaluates the use of an inexpensive and relatively safe therapy, hydroxychloroquine, as prevention. The impact of this work is high since a positive result will alter both the management of all women known to have anti-Ro antibodies as well as justify testing all women for these antibodies, even if they are asymptomatic, as part of an early pregnancy screen.