Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study.

BACKGROUND: In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study. METHODS: Qualified patients were treated with 6 weeks of weekly conventional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high-albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and analyzed for all PE treatment groups and PE modalities. RESULTS: PE procedure-related AEs were more common in the active treatment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were associated with at least one AE, a similar rate than in other PE indications) than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared to peripheral venous access in all three active treatment groups (20.1% vs 13.1%, respectively). CONCLUSION: The TPE and LVPE procedures used in the AMBAR study on mild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.

Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study.

PURPOSE: This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. METHODS: Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) were performed. RESULTS: MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM 18FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. CONCLUSIONS: PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. TRIAL REGISTRATION: (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053).

Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer's disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study.

INTRODUCTION: We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). METHODS: Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. RESULTS: The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). DISCUSSION: PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.

A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study.

INTRODUCTION: This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS: PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. DISCUSSION: This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.

Impact of therapeutic and low volume plasma exchange on clinical laboratory parameters in patients treated for Alzheimer's disease from the AMBAR study.

INTRODUCTION: Little is known about the impact of plasma exchange (PE) on clinical laboratory parameters in Alzheimer's disease (AD) patients. METHODS: AD patients in the AMBAR trial (N = 322) received weekly therapeutic PE (TPE) for 6 weeks followed by monthly low-volume PE (LVPE) for12 months. Treatment were placebo (sham PE), low-albumin, low-albumin + IVIG (i.e., albumin alternated with intravenous immunoglobulin) and high-albumin + IVIG. RESULTS: Coagulation parameters transiently increased post-TPE. Blood calcium, platelets, and albumin levels decreased but remained within the reference range. Leukocyte counts increased. Fibrinogen, hemoglobin, total protein, gamma globulin, and IgG, transiently dipped below the reference range. Hypogammaglobulinemia (7.2 g/L) persisted in pre-TPE measurements. No changes were observed during the LVPE period. Cerebrospinal fluid parameters and vital signs were unchanged throughout. CONCLUSION: Laboratory parameters of AD patients were affected by TPE similarly to effects of PE-treatment for other pathologies. These effects were less pronounced or non-existent for LVPE.

Plasma exchange for Alzheimer's disease Management by Albumin Replacement (AMBAR) trial: Study design and progress.

INTRODUCTION: Preliminary studies have shown that treatment with plasma exchange (PE) plus therapeutic albumin replacement in patients with Alzheimer's disease (AD) induced mobilization of plasma and cerebrospinal fluid amyloid ß protein, associated with an improvement in memory and language functions, as well as the stabilization of brain perfusion, which persisted after treatment discontinuation. METHODS: Alzheimer's Management By Albumin Replacement (AMBAR) is a multicenter, randomized, blinded and placebo-controlled, parallel-group, phase IIb/III trial enrolling patients with mild to moderate AD. The study evaluates PE with different replacement volumes of therapeutic albumin (5% and 20% Albutein®, Grifols), with or without intravenous immunoglobulin (Flebogamma® 5% DIF, Grifols). Patients are randomized to one of three active treatment groups or one control (sham PE) group (1:1:1:1). The intervention regime includes a first 6-week stage of intensive treatment, followed by a second 12-month stage of maintenance treatment. The change from the baseline to the end of treatment periods in the ADAS-Cog and ADCS-ADL scores are the coprimary efficacy variables. Secondary efficacy variables include change from the baseline in scores on cognitive, functional, behavioral, and overall progression tests; changes in plasma and cerebrospinal fluid levels of amyloid ß and tau protein; and assessment of structural and functional changes in brain areas of interest. Safety and tolerability are assessed. RESULTS: The study has enrolled 496 patients from 41 centers (19 in Spain and 22 in the USA); 347 of these patients were randomized and underwent close to 5000 PEs, of which approximately 25% were sham PEs. DISCUSSION: We present an innovative approach for treating AD. The study has been designed to demonstrate clinical efficacy, defined as slow decline of the patient's cognition and brain function. The sample size has adequate power to detect differences between any of the active treatment groups and the control group, as well as between the three active treatment groups combined and the control group.