A phase 3 trial of IV immunoglobulin for Alzheimer disease

Abstract

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 Aβ42 (but not Aβ40) levels were observed in IVIg-treated 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.

Clinicaltrialsgov identifier: NCT00818662.

Classification of evidence: This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Figure 1. Participant flow

IVIg = IV immunoglobulin; mITT = modified intent to treat; MMSE = Mini-Mental State Examination.

Figure 2. Primary outcomes

(A) Estimated mean change from baseline to 18 months on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS) (scores ranging from 0 to 70 and higher scores indicating impairment) for the modified intent-to-treat population based on analysis of covariance analysis. No significant differences were observed. (B) Estimated mean change from baseline on the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (scores ranging from 0 to 78 and higher scores indicate less functional impairment). Error bars indicate estimated standard errors. No significant differences were observed. Numbers indicate participants contributing to the analysis at each timepoint. CI = confidence interval.