Intravenous immunoglobulins containing antibodies against  -amyloid for the treatment of Alzheimer's disease

Dodel, Richard; Du, Yansheng; Depboylu, Candan; Hampel, Harald; Frölich, Lutz; Haag, Anja; Hemmeter, Ulrich; Paulsen, Sönke; Teipel, Stefan J.; Brettschneider, S.; Spottke, Annika; Nölker, Carmen; Möller, Hans; Wei, Xing; Farlow, Martin R.; Sommer, Norbert; Oertel, Wolfgang H.

doi:10.1136/jnnp.2003.033399

Cited by 307 publications

(214 citation statements)

References 14 publications

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“…The lack of clinical efficacy of IVIg in the current study diverges from encouraging reports in some earlier phase investigations 9,10 ; the previous studies were too small to determine efficacy. The rationale for studying low doses of IVIg was partially pharmacoeconomic, since IVIg is in short supply and relatively expensive.…”

Section: Study Assessmentcontrasting

confidence: 54%

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A phase 3 trial of IV immunoglobulin for Alzheimer disease

et al. 2017

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Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. Results:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Ab42 (but not Ab40) levels were observed in IVIgtreated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrials.gov identifier: NCT00818662.

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Section: Study Assessmentcontrasting

confidence: 54%

“…8 Prior human studies involved small numbers of participants but showed good safety and tolerability, though were underpowered to detect efficacy. [9][10][11][12][13][14] We report the results of a phase 3 trial testing the safety and efficacy of 2 doses of IVIg in mild to moderate AD dementia.…”

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confidence: 99%

A phase 3 trial of IV immunoglobulin for Alzheimer disease

et al. 2017

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“…Naturally occuring antibodies against A are contained in IVIg and a first preliminary study giving 0.4 g/kg IVIg on three consecutive days led to a decrease of A in the cerebrospinal fluid [Dodel et al 2002]. The treatment of five patients with IVIg (0.4 g/kg on three consecutive days every month) over six months led to an improvement in a cognitive score [Dodel et al 2004]. In another uncontrolled trial in eight patients, IVIg was administered for six months, discontinued, and then resumed for another nine months [Relkin et al 2008b].…”

Section: New Indicationsmentioning

confidence: 99%

Review: New advances in the treatment of neurological diseases using high dose intravenous immunoglobulins

Stangel

2008

Ther Adv Neurol Disord

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Since the incidental discovery in 1981 that intravenous immunoglobulins (IVIg) are immunomodulatory, they have been investigated in a large number of putative autoimmune diseases. This has led to licensing for idiopathic thrombocytopenic purpura, Kawasaki disease, and in neurological disorders for Guillain-Barré syndrome (GBS). Although not licensed, randomized controlled trials have also shown IVIg efficacy in other neuroimmunological diseases such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating neuropathy (CIDP), myasthenia gravis, dermatomyositis, and stiff-person syndrome. However, other indications are currently being explored including Alzheimer's disease, postpolio syndrome, and narcolepsy. There are even reports from experimental studies in stroke. The results of recently published clinical trials in both the classical neuroimmunological disorders as well as for new indications are reported and their role in clinical practice is discussed.

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“…39 In addition, it has been observed that AD patients have considerably fewer antibodies to Ab in their blood than non-AD controls. 40,41 A pilot study conducted by Dodel et al 42 reported that cognitive functioning was stabilized in five patients with AD who were treated with IVIg for 6 months. Relkin et al 43 infused anti-Ab antibodies into AD patients at various frequencies (from once per week, to once per month).…”

Section: Passive Immunizationmentioning

confidence: 99%

Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

et al. 2008

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There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic b-amyloid (Ab) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Ab antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.

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Intravenous immunoglobulins containing antibodies against -amyloid for the treatment of Alzheimer's disease

Cited by 307 publications

References 14 publications

A phase 3 trial of IV immunoglobulin for Alzheimer disease

A phase 3 trial of IV immunoglobulin for Alzheimer disease

Review: New advances in the treatment of neurological diseases using high dose intravenous immunoglobulins

Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

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