USING ECULIZUMAB IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。阵发性夜间血红蛋白尿（PNH）是一种以严重贫血、慢性疲劳和间歇性黑尿为特征的血液疾病，称为血红蛋白尿。PNH患者形成危及生命的血块或血栓的风险也增加，这是该疾病的主要死亡原因（约50%）。患有PNH的人获得性缺乏蛋白质，这种蛋白质通常会保护红细胞免受人体自然防御系统的一种成分的影响，这种成分被称为补体级联。这些补体抑制蛋白的缺乏使PNH红细胞容易被破坏（溶血），这可能导致患者贫血，在某些情况下，依赖输血。目前，医生开类固醇或其他免疫抑制药物治疗来帮助患者应对贫血症状，因为目前没有药物被批准专门治疗PNH。这是一种罕见的疾病，发病率为百万分之2至6，在美国的患病率为1万至3万。这种疾病可以发生在任何年龄，性别分布大致相同。确诊后PNH患者10年的估计生存率为50%，25年的估计生存率为28%，其中大多数死亡是由于血栓形成或骨髓发育不全。研究表明，缺乏终末补体抑制剂CD59是PNH红细胞和血小板对自体补体作用敏感的原因。Eculizumab是一种人源化单克隆抗体，与CD59一样，可抑制终末补体。考虑到缺乏终末补体抑制剂CD59可能是导致PNH红细胞补体敏感性的原因，因此给予终末补体抑制剂eculizumab可以替代CD59的功能是合理的。此外，由于PNH的发病机制是由于PNH红细胞和血小板无法抑制终末补体的激活，因此假设终末补体抑制剂应该有效地阻止血管内溶血，消除或减少输血的需要，并可能降低危及生命的血栓形成的倾向。这是一项随机、双盲、安慰剂对照、多中心研究，对大约75名PNH患者静脉注射Eculizumab或安慰剂。随机分配到安慰剂组的患者将每周接受一次安慰剂IV，共5次，然后每2周接受一次，共21周。随机分配到Eculizumab组的患者将每周接受600 mg Eculizumab IV一次，共4次剂量，1周后接受900 mg Eculizumab IV一次剂量，然后每2周接受900 mg Eculizumab IV，共21周。每个完成研究的患者可能会接受大约16次输液。所有患者，包括早期终止妊娠的患者，将被要求完成所有评估。该研究的估计持续时间约为59周，包括12周的入组期、13周的观察期（访问1和2）、26周的治疗期和8周的治疗后期。估计患者参与的最长时间（不包括入组期）为47周。患者将有资格参加一项开放标签扩展研究，随机化后完成研究评估至第26周。过早停止试验产品且未进入扩展研究的患者仍需要在最后一次给药后12周内进行随访接触。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Paroxysmal nocturnal hemoglobinuria (PNH) is a blood disorder characterized by the onset of severe anemia, chronic fatigue, and intermittent episodes of black-colored urine, known as hemoglobinuria. PNH patients are also at increased risk of forming life-threatening blood clots, or thromboses, which are a leading cause of death (approximately 50%) in this disease. People with PNH have an acquired deficiency of proteins that normally protect red blood cells from a component of the body's natural defense system, known as the complement cascade. The lack of these complement inhibitor proteins leaves the PNH red blood cells susceptible to destruction (hemolysis), which can cause patients to become anemic and, in some cases, dependent on blood transfusions. Currently, physicians prescribe either steroids or other immunosuppressive drug therapy to help patients cope with the symptoms of anemia, as no drugs are currently approved to specifically treat PNH. It is a rare condition with an incidence of 2 to 6 per million and a prevalence between 10,000 and 30,000 in the United States. The disease can occur at any age with a roughly equal sex distribution. The estimated survival of PNH patients after diagnosis is 50% at 10 yrs and 28% at 25 yrs, with a majority of the deaths resulting from thrombosis or bone marrow hypoplasia. Studies suggest that lack of the terminal complement inhibitor CD59 is responsible for the sensitivity of PNH erythrocytes and platelets to the effects of autologous complement. Eculizumab is a humanized monoclonal antibody that, like CD59, inhibits terminal complement. Considering that the lack of the terminal complement inhibitor CD59 is likely responsible for the complement sensitivity of PNH red cells, it is reasonable that administration of the terminal complement inhibitor eculizumab could provide a substitute for CD59 function. Further, since the pathogenesis of PNH is due to the inability of PNH red cells and platelets to inhibit the activation of terminal complement, it is logical to hypothesize that a terminal complement inhibitor should effectively stop the intravascular hemolysis, obviate or lessen the need for transfusion, and possibly decrease the propensity for life-threatening thrombosis. This is a randomized, double-blind, placebo-controlled, multicenter study of Eculizumab or placebo administered intravenously (IV) to approximately 75 patients with PNH. Patients randomized to the placebo group will receive placebo IV once a week for 5 doses, then once every 2 weeks for 21 weeks. Patients randomized to the Eculizumab group will receive 600 mg of Eculizumab IV once a week for 4 doses, followed by 900 mg Eculizumab IV 1 week later for 1 dose, then 900 mg Eculizumab IV every 2 weeks for 21 weeks. Each patient who completes the study may receive approximately 16 infusions. All patients, inclusive of early terminations, will be requested to complete all assessments. The estimated duration of the study, given a 12-week Enrollment Period, 13-week Observation Period (Visits 1 and 2), 26-week Treatment Phase, and 8-week Post-treatment Phase, is approximately 59 weeks. The estimated maximum duration of a patient's participation, excluding the Enrollment Period, is 47-weeks. Patients will be eligible to enroll in an open label extension study after randomization completing study evaluations to week 26. Patients who prematurely discontinue investigational product and do not enter the extension study will nevertheless require follow-up contacts through 12 weeks after their last dose.