Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease

A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial

Richard Dodel, Axel Rominger, Peter Bartenstein, Frederik Barkhof, Kaj Blennow, Stefan Förster, Yaroslav Winter, Jan Philipp Bach, Julius Popp, Judith Alferink, Jens Wiltfang, Katharina Buerger, Markus Otto, Piero Antuono, Michael Jacoby, Ralph Richter, James Stevens, Isaac Melamed, Jerome Goldstein, Stefan Haag & 3 others Stefan Wietek, Martin Farlow, Frank Jessen

Research output: Contribution to journalArticle

121 Citations (Scopus)

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). 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 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 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 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. Interpretation: 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. Funding: Octapharma AG.

Original languageEnglish
Pages (from-to)233-243
Number of pages11
JournalThe Lancet Neurology
Volume12
Issue number3
DOIs
StatePublished - Mar 2013

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Intravenous Immunoglobulins
Alzheimer Disease
Placebos
Area Under Curve
Therapeutics
Safety
Random Allocation
Pharmacists
Amyloid
Caregivers
Germany
Biomarkers
Stroke
Research Personnel

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

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Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease : A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. / Dodel, Richard; Rominger, Axel; Bartenstein, Peter; Barkhof, Frederik; Blennow, Kaj; Förster, Stefan; Winter, Yaroslav; Bach, Jan Philipp; Popp, Julius; Alferink, Judith; Wiltfang, Jens; Buerger, Katharina; Otto, Markus; Antuono, Piero; Jacoby, Michael; Richter, Ralph; Stevens, James; Melamed, Isaac; Goldstein, Jerome; Haag, Stefan; Wietek, Stefan; Farlow, Martin; Jessen, Frank.

In: The Lancet Neurology, Vol. 12, No. 3, 03.2013, p. 233-243.

Research output: Contribution to journalArticle

Dodel, R, Rominger, A, Bartenstein, P, Barkhof, F, Blennow, K, Förster, S, Winter, Y, Bach, JP, Popp, J, Alferink, J, Wiltfang, J, Buerger, K, Otto, M, Antuono, P, Jacoby, M, Richter, R, Stevens, J, Melamed, I, Goldstein, J, Haag, S, Wietek, S, Farlow, M & Jessen, F 2013, 'Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial', The Lancet Neurology, vol. 12, no. 3, pp. 233-243. https://doi.org/10.1016/S1474-4422(13)70014-0
Dodel, Richard ; Rominger, Axel ; Bartenstein, Peter ; Barkhof, Frederik ; Blennow, Kaj ; Förster, Stefan ; Winter, Yaroslav ; Bach, Jan Philipp ; Popp, Julius ; Alferink, Judith ; Wiltfang, Jens ; Buerger, Katharina ; Otto, Markus ; Antuono, Piero ; Jacoby, Michael ; Richter, Ralph ; Stevens, James ; Melamed, Isaac ; Goldstein, Jerome ; Haag, Stefan ; Wietek, Stefan ; Farlow, Martin ; Jessen, Frank. / Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease : A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. In: The Lancet Neurology. 2013 ; Vol. 12, No. 3. pp. 233-243.
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T1 - Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease

T2 - A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial

AU - Dodel, Richard

AU - Rominger, Axel

AU - Bartenstein, Peter

AU - Barkhof, Frederik

AU - Blennow, Kaj

AU - Förster, Stefan

AU - Winter, Yaroslav

AU - Bach, Jan Philipp

AU - Popp, Julius

AU - Alferink, Judith

AU - Wiltfang, Jens

AU - Buerger, Katharina

AU - Otto, Markus

AU - Antuono, Piero

AU - Jacoby, Michael

AU - Richter, Ralph

AU - Stevens, James

AU - Melamed, Isaac

AU - Goldstein, Jerome

AU - Haag, Stefan

AU - Wietek, Stefan

AU - Farlow, Martin

AU - Jessen, Frank

PY - 2013/3

Y1 - 2013/3

N2 - 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). 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 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 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 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. Interpretation: 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. Funding: Octapharma AG.

AB - 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). 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 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 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 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. Interpretation: 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. Funding: Octapharma AG.

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