title: Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: University Hospital Giessen and Marburg, Philipps-University Marburg, Marburg, Germany. dodel@med.uni-marburg.de
authors: Richard
authors: R
authors: Dodel
authors: Axel
authors: A
authors: Rominger
authors: Peter
authors: P
authors: Bartenstein
authors: Frederik
authors: F
authors: Barkhof
authors: Kaj
authors: K
authors: Blennow
authors: Stefan
authors: S
authors: Förster
authors: Yaroslav
authors: Y
authors: Winter
authors: Jan-Philipp
authors: JP
authors: Bach
authors: Julius
authors: J
authors: Popp
authors: Judith
authors: J
authors: Alferink
authors: Jens
authors: J
authors: Wiltfang
authors: Katharina
authors: K
authors: Buerger
authors: Markus
authors: M
authors: Otto
authors: Piero
authors: P
authors: Antuono
authors: Michael
authors: M
authors: Jacoby
authors: Ralph
authors: R
authors: Richter
authors: James
authors: J
authors: Stevens
authors: Isaac
authors: I
authors: Melamed
authors: Jerome
authors: J
authors: Goldstein
authors: Stefan
authors: S
authors: Haag
authors: Stefan
authors: S
authors: Wietek
authors: Martin
authors: M
authors: Farlow
authors: Frank
authors: F
authors: Jessen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000097:blood; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012720:Severity of Illness Index
chemical_list: D016229:Amyloid beta-Peptides; D016756:Immunoglobulins, Intravenous; D010919:Placebos
references: Lancet Neurol. 2012 Mar;11(3):241-9
references: 22305802
references: Alzheimers Dement. 2011 Mar;7(2):151-60
references: 20810324
references: Nat Clin Pract Neurol. 2007 Jan;3(1):36-44
references: 17205073
references: Science. 2002 Mar 22;295(5563):2264-7
references: 11910111
references: Am J Geriatr Psychiatry. 2011 Jun;19(6):532-42
references: 21606896
references: Neurology. 1984 Jul;34(7):939-44
references: 6610841
references: Int Psychogeriatr. 2000 Jun;12(2):231-47
references: 10937543
references: Clin Chem Lab Med. 2010 May;48(5):603-7
references: 20201744
references: Exp Gerontol. 2002 Jul;37(7):943-8
references: 12086704
references: Neurology. 2012 Aug 21;79(8):763-9
references: 22875093
references: J Psychiatr Res. 1975 Nov;12(3):189-98
references: 1202204
references: Lancet Neurol. 2010 Jul;9(7):702-16
references: 20610346
references: CNS Spectr. 2008 Oct;13(10 Suppl 16):39-41
references: 18955962
references: Neuroimage. 2010 Jun;51(2):654-64
references: 20202480
references: Alzheimers Dement. 2013 Feb;9(1 Suppl):S39-44
references: 22858530
references: J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4
references: 15377700
references: Neurobiol Aging. 2009 Nov;30(11):1728-36
references: 18294736
references: Alzheimers Dement. 2011 Jul;7(4):367-85
references: 21784348
references: Neurology. 2001 Sep 11;57(5):801-5
references: 11552007