Intravenous immunoglobulin for treatment of mild-to- moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-fi nding trial

Methods We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and fi ve 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 fi nal 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 fi nal 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). Findings 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ1–40 was not signifi cantly diff erent for intravenous immunoglobulin compared with placebo for fi ve 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 diff erence in median AUC of plasma Aβ1–40 between the 0·4 g/kg every 2 weeks group (47·0 [range –341·0 to 72·5]) and the placebo group was signifi cant (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.