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

目的：这是一项随机双盲研究，比较两种药物的安全性， RPR 109413对特许静脉丙种球蛋白的患者可接受性和有效性 产品：Gamimune-N。 背景：静脉注射丙种球蛋白(IVIG)制剂已被 自1975年以来在美国进行测试；自1981年以来已有10个获得许可，其中7个 它们目前都是可用的。静脉注射丙种球蛋白预防糖尿病的效果 原发体液免疫紊乱患者感染情况 很好地接受了，尽管它从未受到控制 双盲研究。一项比较静脉注射免疫球蛋白和安慰剂的研究将是 被认为是不道德的，尽管有可能将新产品与 那些已经获得使用许可的。在过去几年里 努力的重点是开发安全性更高的产品， 尤其是关于传播病毒感染的风险，如 作为丙型肝炎，这项研究建议比较安全性、有效性和 一种新的巴氏杀菌IVIG制剂(RPR)的患者可接受性 109413)获得许可的制剂，Gamimune-N.RPR 109413是无菌的， 无防腐剂的未改性人多价液体制剂 Rhtne-Poulenc公司装甲部门生产的免疫球蛋白 制药业。它是由ISG制成的，由至少 1000名捐赠者。献血者接受艾滋病毒、乙肝表面抗原、丙型肝炎抗体检测， 在进入泳池之前，丙氨酸氨基转移酶水平升高。这个 ISG是通过相同的科恩分级工艺制备的，用于所有 当前许可的产品。Cohn组分III上清液为 经历由60℃处理组成的病毒灭活步骤 这种治疗方法被证明可以灭活几种代理病毒。它是 直接测试丙型肝炎的灭活是不现实的，因为 唯一的检测系统是非人类的灵长类动物，但这些其他病毒 已被证明对已知的人类病毒具有类似的敏感性 病原体。对免疫球蛋白进行吸附，以降低血清中 将异凝集素、聚乙二醇加入到沉淀物中， 对溶液进行透析，去除聚乙二醇钠，降低钠 集中精神。添加5%的甘露醇以增强稳定性。 最终制备的免疫球蛋白至少为98%，并含有微量的免疫球蛋白A和 免疫球蛋白。IgA的含量估计为55克/毫升，这是 与另一种低IgA制剂Gammagard相当。 方法：这是一项随机、双盲研究，比较两种药物的安全性， RPR 109413对特许静脉丙种球蛋白的患者可接受性和有效性 产品：Gamimune-N。这是一项多中心的II期研究，旨在 招募大约80名患者。每个中心最多可招收10名学生 病人。所有患者都有明显的体液障碍特征。 免疫和需要丙种球蛋白输注预防感染。 所有患者都接受了至少六次静脉注射免疫球蛋白，并已知 以耐受目前可用的制剂。免疫球蛋白缺乏 有产生抗IgA抗体风险的患者将是 不包括在内。患者将来到研究病房进行筛查访问 在进入研究的一个月内。如果他们符合入门条件 要求他们将进入接受六次输液的剂量 以及研究前三个月内给出的频率。他们 将收到RPR 109413或Gamimune-N，将被放入IV 药房的袋子，这样病人和调查人员都不会 就会知道使用的是哪种制剂。静脉注射丙种球蛋白将在 初始速率为0.01cc/kg/min，然后速率增加到0.02然后0.04 最后，每隔15分钟最大0.06毫升/公斤/分钟，除非 不良反应就会发生。这些费率是输液的标准费率 静脉注射丙种球蛋白及以下常用的非研究性输液 静脉注射丙种球蛋白。

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.