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

项目4：静脉注射免疫球蛋白（IVIG）治疗阿尔茨海默病 针对淀粉样蛋白β（Ap）蛋白的抗体已经证明了显著的阻止甚至 逆转阿尔茨海默病（AD）神经病理学的关键要素。不幸的是， 主动接种AD不能在大多数患者中产生抗A β抗体， 其他人的脑炎症。被动免疫（给予外源性抗体） 可以更一致地递送治疗性抗体，同时避免许多安全性和耐受性问题， 与积极接种疫苗有关。静脉注射免疫球蛋白（IVIg）是一种非常有前途的药物 目的. IVIg是一种纯化的人免疫球蛋白制剂，具有独特的免疫调节特性 其最近被发现含有升高滴度的多克隆抗Ap抗体。IVIg已确定的安全性 作为FDA批准的免疫缺陷和自身免疫性疾病治疗药物， 这些疾病将减少与AD测试相关的时间和风险。在三项轻度至中度的试点研究中， 迄今为止，中度AD，IVIg治疗6至12个月显著改善痴呆 症状，一般耐受良好。此外，IVIg增加血浆抗Ap抗体滴度， 促进Ap从脑脊液中的清除。正在进行的II期研究将提供进一步的 关于IVIg的药代动力学特征和作用机制的信息。一个大规模的，可控的， 需要进行前瞻性临床试验以确定IVIg是否对治疗AD有用。为了满足这一需求，我们 将开展为期30周的安慰剂对照、双盲、随机、多中心III期临床试验 检查IVIg对于治疗轻度至中度AD是否有效且耐受良好。共有210 可能的AD患者将被随机分配接受静脉输注IVIg 0.4g/kg或 每两周注射一次生理盐水，持续六个月。结果将在基线时评估，12 治疗24周和最后一次输注后6周。主要结局指标为 阿尔茨海默病评估的认知子量表自基线至24周的平均变化 量表（ADAS-Cog）和ADCS-临床总体印象变化量表（ADCS-CGIC）。Ap蛋白水平 在四个时间点测量血浆中的抗Ap抗体滴度，以测试与 IVIg治疗。其他次要结局指标包括神经精神量表， 行为变化、评估功能状态的ADCS-日常生活活动量表和ADCS 药物经济学库存作为成本效益的指标。依从性和不良事件将 在整个审判过程中受到严密监控。本研究有把握提供80-90%的可能性 双盲治疗6个月后，检测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.