PHASE II RANDOMIZED TRIAL OF IVIG WITH OR WITHOUT CYCLOPHOSPHAMIDE IN PEMPHIGUS

描述(由申请人提供)： 静脉注射免疫球蛋白越来越多地用于治疗PV，这是一种罕见的、危及生命的自身抗体介导的皮肤起泡性疾病。研究人员的目标是评估IVIg能否通过与一种细胞毒性药物结合来提高其有效性，并检查这种组合的毒性。这项建议是基于初步数据，这些数据表明，IVIg通过快速和选择性地降低天疱疮抗体的血清水平来发挥作用，天疱疮抗体是介导疾病的，联合使用细胞毒性药物可以增强这种效果。为了证实这一发现并确定它是否与改善结果有关，研究人员计划在PV患者中进行一项使用或不使用环磷酰胺的IVIg的随机试验，并检查其对血清天疱疮抗体水平、临床结果和毒性的影响。 其具体目的是：1)在随机的第二阶段试验中，评估静脉注射免疫球蛋白与环磷酰胺联合使用是否比单独使用免疫球蛋白更快地降低血清天疱疮抗体水平。在IVIg治疗开始后，这些抗体将在基线和规定的时间间隔在两组中使用间接免疫荧光和ELISA法进行检测。主要终点将是4个IVIg周期后一个月血清天疱疮抗体的下降；2)评估在4个IVIg周期后1个月联合应用IVIg和环磷酰胺是否能更快地控制疾病的临床活动；以及3)使用传统参数评估这两种方案的毒性。 这项工作的成功完成可能会提供一种更有效、更安全的方法来治疗对传统治疗无效的天疱疮。通过提高静脉注射免疫球蛋白的有效性，它还将降低这种非常昂贵的治疗的成本，并将其毒性降至最低。

DESCRIPTION (provided by applicant): Intravenous immunoglobin is increasingly used to treat PV, a rare, life-threatening, autoantibody-mediated blistering disease of the skin. The investigators' goal is to evaluate whether the effectiveness of IVIg can be improved by coupling it with a cytotoxic drug and examine the toxicity of this combination. The proposal is based on initial data that shows IVIg works by rapidly and selectively lowering serum level of the pemphigus antibodies that mediate the disease and that this effect is enhanced by the co-administration of a cytotoxic drug. To confirm this finding and determine whether it is associated with an improved outcome, the investigators plan to conduct a randomized trial of IVIg given with or without cyclophosphamide in patients with PV and examine the impact on serum pemphigus antibodies levels, clinical outcome and toxicity. The specific aims are to: 1) evaluate in a randomized Phase 2 trial whether the administration of IVIg together with cyclophosphamide lowers serum levels of pemphigus antibodies more rapidly than IVIg alone. These antibodies will be measured in the two groups at baseline and at defined intervals following initiation of IVIg therapy, using indirect immunofluorescence and ELISA assays. The primary endpoint will be a decrease in serum pemphigus antibodies one month after 4 IVIg cycles; 2) Evaluate whether the clinical activity of the disease is controlled more rapidly by the co-administration of IVIg and cyclophosphamide of the disease one month after four IVIg cycles, graded using a recently developed Disease Severity Index; and 3) Evaluate the toxicity of the two regimens, using conventional parameters. Successful completion of this work may provide a more effective and safer way to treat pemphigus unresponsive to conventional treatment. By improving the effectiveness of IVIg, it would also reduce the cost of this very expensive treatment and minimize its toxicity.