Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH)

使用羟氯喹 (PATCH) 预防先天性心脏传导阻滞的方法

• 批准号: 8781413
• 负责人: Jill P Buyon
• 金额: $ 8.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781413
• 关键词: 10 year old; Address; Adult; Affect; Antibodies; Attention; Autoantibodies; Award; Basic Science; Biological Markers; Cardiac; Cardiomyopathies; Case-Control Studies; Child; Chloroquine; Clinical; Complex; Conceptions; Data; Data Collection; Databases; Defect; Development; Disease; Dose; Echocardiography; Enrollment; Europe; Evaluation; Face; Fetal Diseases; Fetus; Fibrosis; Funding; Health Status; Heart Block; Hydroxychloroquine; Immunoglobulin G; In Vitro; Injury; Institutional Review Boards; Interferon-alpha; Interferons; Intervention; Intravenous Immunoglobulins; Life; Ligation; Lupus; Mediating; Monitor; Morbidity - disease rate; Mothers; Multicenter Studies; Myocardial; Neonatal lupus erythematosus; Pathogenesis; Patient Recruitments; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Plasmapheresis; Pregnancy; Pregnant Women; Prevention; Preventive; Prophylactic treatment; Prospective Studies; Proteins; Protocols documentation; Randomized Controlled Trials; Rare Diseases; Receptor Signaling; Recruitment Activity; Recurrence; Registries; Research; Research Personnel; Resources; Rheumatism; Ribonucleoproteins; Risk; SS-A antibodies; Safety; Site; Staging; Steroids; Sympathomimetics; Systemic Lupus Erythematosus; Testing; Time; Tissues; Toll-like receptors; Translating; Translational Research; Translations; Treatment Efficacy; Umbilical Cord Blood; Woman; Work; base; bench to bedside; case control; design; experience; fetal; in utero; macrophage; mortality; neonatal morbidity; offspring; open label; prevent; prospective; screening; treatment strategy

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.

描述（由申请人提供）：与针对 Ro/La 核糖核蛋白复合物成分的自身抗体最强烈的临床关联之一是后代发生先天性心脏病 (CHB)，2% 的初孕母亲患有这些反应，这是一个令人担忧的前景。根据美国新生儿狼疮研究登记处收集的大量数据，曾生育过受影响孩子的女性在随后怀孕时患 CHB 的风险要高出 10 倍。 尽管大型多中心研究尝试通过连续子宫内监测来预防疾病，但在正常节律和 PR 间期 7 天内已记录到不可逆性传导阻滞和广泛的心肌损伤。 CHB 与较高的死亡率和发病率相关。迄今为止，还没有成功开发出预防性疗法，并且完全阻断也从未被逆转。最近的两项前瞻性研究（来自美国的 20 名母亲和来自欧洲的 15 名母亲）采用了相同的替代剂量 IVIG 方案，证明 1) 这种干预措施不能预防 CHB 复发 2) 17-18% 的复发率很稳健 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了这样的观点，即 ssRNA (hY3) 与 Ro60 蛋白复合后，Toll 样受体 (TLR) 信号传导会导致纤维化。 这一观察结果引发了针对氯喹抑制内体酸化的体外研究。通过在一项仅限于狼疮母亲的广泛病例对照研究中评估羟氯喹 (HCQ) 的使用，以及对 HCQ 是否降低 CHB 预期复发率进行单独的回顾性评估，随后将其转化为患者。 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 复发。这将在一项 II 期试验中针对曾生过患有 CHB 孩子的具有抗 Ro 抗体的孕妇进行。 这是一项开放标签试验，采用西蒙的两阶段优化设计，以便因缺乏疗效而提前停止。 第一阶段需要19名受试者，预计在两年内完成所有妊娠。 系列超声心动图（监测 PR 间期）以及母体和脐带血生物标志物（HCQ 水平、IFNa 特征和 Ab 滴度）的评估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 级或 3 级 CHB，则研究在第一阶段后终止。 如果 观察到复发次数< 3 次，第二阶段将作为全面 RO1 应用的一部分启动，并另外招募 35 名受试者。 该研究将在纽约大学进行管理，IRB 已在该网站批准了该方案。 FDA 已发布 IND。最终，如果 54 名受试者中发生的病例少于 6 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是最有力的，但疾病的罕见性可能会受到限制。 然而，有关女性拒绝吸毒的数据将同等保留。 阳性结果可能会改变所有曾生育过慢性乙型肝炎孩子的抗 Ro 阳性女性的治疗。 此外，潜在的预防措施证明对所有孕妇进行抗 Ro 抗体筛查是合理的。