SAFETY, TOLERANCE, AND CLINICAL EFFICACY OF RPR 109413 AND GAMIMUNE-N

目的：这是一项随机、双盲研究， RPR 109413对许可IVIG的患者可接受性和疗效 产品，Gamimune-N. 背景：静脉注射丙种球蛋白（IVIG）制剂已被 自1975年以来在美国进行了测试;自1981年以来已有10个获得许可，其中7个 这些是目前可用的。 IVIG在预防 原发性体液免疫紊乱患者的感染是 很好地接受，虽然它从来没有受到控制， 双盲研究。一项比较IVIG和安慰剂的研究将是 被认为是不道德的，尽管可以将新产品与 那些被许可使用的。 过去几年 努力集中在开发具有增加的安全性的产品， 特别是关于传播病毒感染的风险， 丙型肝炎本研究旨在比较安全性、有效性和 新的热巴氏灭菌IVIG制剂（RPR）的患者可接受性 109413）与许可制剂Gamimune-N. RPR 109413是一种无菌， 无防腐剂，液体 未修饰的人多价体的制备 免疫球蛋白，由Rhtne-Poulenc Rünner的Armour Division生产 药业 它是由ISG制备的，ISG由至少 1000个捐赠者。 对献血者进行艾滋病毒、HBsAg、丙型肝炎抗体检测， 和ALT水平的升高。 的 ISG通过用于所有实施方案的相同科恩分馏方法制备。 目前的许可产品。 科恩级分III上清液为 进行包括在60 ℃下处理的病毒灭活步骤。 这种处理显示出抑制了几种替代病毒。 是 直接检测丙型肝炎灭活是不切实际的，因为 唯一的测试系统是非人类灵长类动物，但这些其他病毒 对已知的人类病毒也有类似的敏感性 病原体 述IgG是 吸附，以降低浓度 异凝集素，加入聚乙二醇沉淀复合物， 并将溶液透析以除去PEG并降低钠 浓度. 添加5%甘露醇以增强稳定性。 最终制剂是至少98%的IgG和痕量的IgA， IgM抗体 伊加含量估计为<5.5g/ml， 与另一种低伊加制剂Gammagard相当。 方法：这是一项随机、双盲研究， RPR 109413对许可IVIG的患者可接受性和疗效 产品，Gamimune-N. 这是一项多中心II期研究，旨在 约80名患者。 每个中心最多招募10名 患者 所有患者均具有特征性的体液性疾病， 免疫和需要丙种球蛋白输注以预防感染。 所有患者均接受过至少6次IVIG输注， 以适应现有的制剂。 伊加缺乏 有产生抗IgA抗体风险的患者将被 排除 患者将来到研究病房进行筛选访视 在进入研究的一个月内。 如果他们遇到入口 要求他们将进入接受六次输注的剂量 在研究前三个月内给出的频率。 他们 将接受RPR 109413或Gamimune-N，将其置于IV中 在药房旁边的袋子里 这样病人和研究人员 他知道使用的是哪种制剂。IVIG将以 初始速率为0.01 cc/kg/min，速率增至0.02，然后增至0.04 最后以15分钟间隔最大为0.06 cc/kg/min，除非 发生不良反应。 这些速率是输注 IVIG及以下常用于非研究性输注的药物 IVIG

Purpose: This is a randomized, double-blind study comparing the safety, patient acceptability and efficacy of RPR 109413 to a licensed IVIG product, Gamimune-N. Background: Intravenous gammaglobulin (IVIG) preparations have been tested in the US since 1975; ten have been licensed since 1981, seven of which are currently available. The efficacy of IVIG in preventing infections in patients with primary disorders of humoral immunity is well accepted, though it has never been subjected to a controlled double-blind study. A study comparing IVIG to placebo would be considered unethical, though it is possible to compare new products to those that have been licensed for use. In the past several years efforts have focused on developing products with increased safety, especially with regard to the risk of transmitting viral infections such as Hepatitis C. This study proposes to compare the safety, efficacy, and patient acceptability of a new, heat-pasteurized IVIG preparation (RPR 109413) to a licensed preparation, Gamimune-N. RPR 109413 is a sterile, preservative-free, liquid preparation of unmodified human polyvalent immunoglobulins manufactured by Armour Division of Rhtne-Poulenc Rorer Pharmaceutical. It is prepared from ISG made from a pool of at least 1000 donors. Donors are tested for HIV, HBsAg, Hepatitis C antibody, and increased levels of ALT before being accepted into the pool. The ISG is prepared by the same Cohn fractionation process used for all of the currently licensed products. The Cohn fraction III supernatant is subjected to a viral inactivation step consisting of treatment at 60 C. This treatment was shown to inactivate several surrogate viruses. It is not practical to test inactivation of Hepatitis C directly since the only test system is non-human primates, but these other viruses have been shown to have similar sensitivity to viruses known to be human pathogens. The IgG is adsorbed to reduce the concentration of isoagglutinins, polyethylene glycol is added to precipitate complexes, and the solution is dialyzed to remove the PEG and reduce the sodium concentration. Five percent mannitol is added to enhance stability. The final preparation is at least 98% IgG with trace amounts of IgA and IgM. The amount of IgA is estimated to be < 5 5g/ml, which is comparable to the other low IgA preparation, Gammagard. Methods: This is a randomized, double-blind study comparing the safety, patient acceptability and efficacy of RPR 109413 to a licensed IVIG product, Gamimune-N. It is a multicenter phase II study intended to enroll approximately 80 patients. Each center will enroll up to 10 patients. All patients have well characterized disorders of humoral immunity and require gammaglobulin infusions for infection prophylaxis. All patients have received at least six infusions of IVIG and are known to tolerate the currently available preparations. IgA deficient patients who are at risk for making anti-IgA antibodies will be excluded. Patients will come to the research ward for a screening visit within one month of entering the study. If they meet the entry requirements they will be entered to receive six infusions at the dose and frequency given during the three months preceding the study. They will receive either RPR 109413 or Gamimune-N which will be put in IV bags by the pharmacy so that neither the patient nor the investigators will know which preparation is used. The IVIG will be infused at an initial rate of 0.01 cc/kg/min and the rate increased to 0.02 then 0.04 and finally a maximum of 0.06 cc/kg/min at 15 minute intervals unless adverse reactions occur. These rates are standard for the infusion of IVIG and below those commonly used for infusions of non-investigational IVIG.