INTRAVENOUS IMMUNOGLOBULIN (IVIg) FOR TREATMENT OF AD (IVIg)

项目4：静脉注射免疫球蛋白治疗阿尔茨海默病 针对淀粉样β蛋白(Ap)的抗体已经显示出显著的阻止甚至 逆转阿尔茨海默病(AD)神经病理学的关键要素。不幸的是，试图治疗 通过主动接种的AD未能在大多数患者中产生抗A(3)抗体，并引起严重的 其他人的脑部发炎。被动免疫(注射外源抗体) 可以更稳定地传递治疗性抗体，同时避免许多安全和耐受性问题 与主动接种疫苗有关。静脉注射免疫球蛋白(IVIg)是一种非常有前途的药物 目的。IVIG是一种具有独特免疫调节特性的纯化人免疫球蛋白制剂 最近发现含有高滴度的多克隆抗AP抗体。IVIG已确立的安全性 作为FDA批准的免疫缺陷和自身免疫治疗药物临床使用超过25年的记录 障碍将减少与AD测试相关的时间和风险。在三项试验性研究中， 到目前为止，中度AD，IVIg治疗6至12个月显著改善痴呆症 症状，一般耐受性良好。此外，IVIg还可提高血浆抗AP抗体效价和 促进AP从脑脊液中的清除。正在进行的第二阶段研究将提供进一步的 有关静脉注射免疫球蛋白的药代动力学和作用机制的信息。大规模的，可控的， 需要进行前瞻性临床试验，以确定静脉注射免疫球蛋白是否对治疗AD有效。为了满足这一需求，我们 将进行为期30周的安慰剂对照、双盲、随机、多中心III期临床试验 检查静脉注射免疫球蛋白治疗轻中度AD是否有效和耐受性良好。总共有210个 可能的AD患者将被随机分配接受静脉滴注0.4g/kg或 生理盐水每两周一次，疗程6个月。结果将在12点之后在基线上进行评估 治疗24周和最后一次输液后6周。主要结果衡量标准将是 阿尔茨海默病认知分量表从基线到24周的平均变化 量表(ADAS-Cog)和ADCS-临床总体变化印象(ADCS-CGIC)。AP蛋白水平 将在四个时间点检测血浆中的抗AP抗体效价，以测试可能与 静脉注射免疫球蛋白治疗。其他次要结果指标包括神经精神病学清单，作为衡量 评定功能状态的行为改变、日常生活能力量表和ADCS 将药物经济学库存作为成本效果的指标。遵从性和不良事件将 在整个试验过程中都受到了仔细的监控。这项研究提供了80%-90%的可能性 检测双盲治疗6个月后主要结局指标的显著差异。

PROJECT 4: INTRAVENOUS IMMUNOGLOBULIN (IVIG) FOR TREATMENT OF ALZHEIMER'S DISEASE Antibodies against the amyloid beta (Ap) protein have demonstrated a remarkable ability to arrest and even reverse key elements of the neuropathology of Alzheimer's Disease (AD). Unfortunately, attempts to treat AD by active vaccination failed to generate anti-A(3 antibodies in a majority of patients and caused severe brain inflammation in others. Passive immunization (administration of antibodies from an exogenous source) can more consistently deliver therapeutic antibodies while avoiding many of the safety and tolerability issues associated with active vaccination. Intravenous Immunoglobulin (IVIg) is a very promising agent for this purpose. IVIg is a purified human immunoglobulin preparation with unique immune-modulating properties that was recently found to contain elevated titers of polyclonal anti-Ap antibodies. IVIg's established safety record from over 25 years of clinical use as an FDA-approved treatment for immune deficiency and autoimmune disorders will reduce the time and risks associated with testing in AD. In three pilot studies in mild to moderate stage AD to date, IVIg treatment for six to twelve months significantly improved dementia symptoms and was generally well-tolerated. In addition, IVIg increased plasma anti-Ap antibody titers and promoted clearance of Ap from the cerebrospinal fluid. An ongoing Phase II study will provide further information about IVIg's pharmacokinetic profile and mechanisms of action. A large scale, controlled, prospective clinical trial is needed to determine whether IVIg is useful for treating AD. To meet this need, we will carry out a 30-week placebo-controlled, double-blind, randomized, multi-center Phase III clinical trial examining whether IVIg is effective and well-tolerated for treating mild to moderate AD. A total of 210 probable AD patients will be randomly assigned to receive intravenous infusions of either IVIg 0.4g/kg or a physiologic saline solution every two weeks for six months. Outcome will be evaluated at baseline, after 12 and 24 weeks of treatment and six weeks after the final infusion. The primary outcome measures will be the mean change from baseline to 24 weeks on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and the ADCS-Clinical Global Impression of Change (ADCS-CGIC). Levels of Ap protein and anti-Ap antibody titers in plasma will be measured at four time points to test for possible correlation with IVIg treatment. Other secondary outcome measures include the Neuropsychiatric Inventory as a measure of behavioral change, the ADCS-Activities of Daily Living scale to assess functional status and the ADCS Pharmacoeconomic Inventory as an index of cost-effectiveness. Compliance and adverse events will be carefully monitored throughout the trial. This study has been powered to provide an 80-90% likelihood of detecting significant differences in the primary outcome measures after six months of double-blind treatment.