University Hospital Giessen and Marburg, Philipps-University Marburg, Marburg, Germany.
Lancet Neurol. 2013 Mar;12(3):233-43. doi: 10.1016/S1474-4422(13)70014-0. Epub 2013 Jan 31.
Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients.
We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759).
89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group.
Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.
三项小型试验表明，静脉注射免疫球蛋白可影响轻度至中度阿尔茨海默病的生物标志物和症状。我们测试了此类患者使用静脉注射免疫球蛋白的安全性、有效剂量和输注间隔。
我们在美国的 7 个地点和德国的 5 个地点进行了一项多中心、安慰剂对照的 2 期试验。年龄在 50-85 岁之间、患有可能的阿尔茨海默病的患者被随机分配（通过计算机生成的随机序列，分组大小为 8），每隔 4 周输注一次（0·2、0·5 或 0·8 g/kg 体重的静脉注射免疫球蛋白或安慰剂）或每隔 2 周输注一次（0·1、0·25 或 0·4 g/kg，或安慰剂）。患者、护理人员、评估结果的研究人员、影像设施和临床研究组织的工作人员对治疗分配进行了盲法，但配药药剂师、统计师和负责最终 PET 分析的人员除外。治疗采用不透明的袋子和输液管进行盲法。主要终点是在意向治疗人群中，最后一次输注至最后一次就诊（取决于输注间隔，为 2 周或 4 周）之间的血浆淀粉样蛋白β（Aβ）（1-40）的中位数曲线下面积（AUC）。该试验在 ClinicalTrials.gov（NCT00812565）和 controlled-trials.com（ISRCTN64846759）上注册。
对 89 名患者进行了资格评估，其中 58 名符合条件，55 名纳入了主要分析。与安慰剂相比，六个干预组中的五个组的静脉免疫球蛋白组血浆 Aβ（1-40）的 AUC 中位数无显著差异（0·2 g/kg 组为-18·0 [范围-1347·0 至 1068·5]，0·5 g/kg 组为-364·3 [范围-5834·5 至 1953·5]，0·8 g/kg 组每 4 周一次，与安慰剂组的-116·3 [范围-1379·0 至 5266·0]相比；0·1 g/kg 组为-13·8 [范围-1729·0 至 307·0]，0·25 g/kg 组为-32·5 [范围-1102·5 至 451·5]，每 2 周一次，与安慰剂组的 159·5 [范围 51·5 至 303·0]相比；所有 p 值均>0·05）。0·4 g/kg 每 2 周组（47·0 [范围-341·0 至 72·5]）与安慰剂组的血浆 Aβ（1-40）中位数 AUC 差异具有统计学意义（p=0·0216）。干预组的 42 名患者中有 25 名（60%）与安慰剂组的 14 名患者中有 9 名（64%）发生不良事件。42 名患者中有 4 名（10%）接受静脉免疫球蛋白治疗，14 名患者中有 4 名（29%）接受安慰剂治疗，发生严重不良事件，包括干预组 1 例中风。
静脉免疫球蛋白可能具有可接受的安全性特征。我们的结果与之前的研究结果不一致。需要进行更大规模、更有力的试验，以评估静脉免疫球蛋白对阿尔茨海默病患者的认知和功能影响。
