USING ECULIZUMAB IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。阵发性睡眠性血红蛋白尿症（PNH）是一种血液疾病，其特征是严重贫血、慢性疲劳和间歇性黑色尿发作，称为血红蛋白尿症。PNH患者形成危及生命的血凝块或血栓的风险也增加，这是这种疾病的主要死亡原因（约50%）。患有PNH的人有一种获得性蛋白质缺乏症，这种蛋白质通常保护红细胞免受身体自然防御系统的一种成分的伤害，称为补体级联反应。缺乏这些补体抑制蛋白使PNH红细胞易于破坏（溶血），这可能导致患者贫血，在某些情况下，依赖输血。目前，医生处方类固醇或其他免疫抑制药物治疗，以帮助患者科普贫血症状，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，发病率为每百万人2至6人，在美国的患病率为10，000至30，000人。这种疾病可以发生在任何年龄，性别分布大致相等。PNH患者诊断后的估计生存率为50%，10年和28%，25年，大多数死亡原因是血栓形成或骨髓发育不良。 研究表明，缺乏补体末端抑制剂CD 59是PNH红细胞和血小板对自体补体作用敏感的原因。依库珠单抗是一种人源化单克隆抗体，与CD 59一样，抑制末端补体。 考虑到末端补体抑制剂CD 59的缺乏可能是PNH红细胞补体敏感性的原因，因此给予末端补体抑制剂依库珠单抗可以替代CD 59功能是合理的。此外，由于PNH的发病机制是由于PNH红细胞和血小板不能抑制终末补体的活化，因此可以合理地假设终末补体抑制剂应该有效地阻止血管内溶血，减少或减少输血的需要，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，在约75例PNH患者中静脉（IV）给予依库珠单抗或安慰剂。随机分配至安慰剂组的患者将接受安慰剂IV给药，每周一次，共5剂，然后每2周一次，共21周。随机分配至依库珠单抗组的患者将接受600 mg依库珠单抗IV，每周一次，持续4个剂量，然后在1周后接受900 mg依库珠单抗IV，持续1个剂量，然后每2周一次接受900 mg依库珠单抗IV，持续21周。 完成研究的每例患者可接受约16次输注。要求所有患者（包括提前终止研究的患者）完成所有评估。考虑到12周入组期、13周观察期（访视1和2）、26周治疗期和8周治疗后期，研究的估计持续时间约为59周。患者参与研究的估计最长持续时间（不包括入组期）为47周。患者在随机化完成研究评价后，将有资格入组开放标签扩展研究，直至第26周。提前停用试验用药物且未进入扩展研究的患者仍需要随访联系，直至末次给药后12周。

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.