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

Abstract

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.

Keywords: Alzheimer's disease; albumin; albutein; clinical trial; plasma exchange; plasmapheresis.

FIGURE 1

Flowchart of patients through the study. One patient randomized to placebo was implanted by error with a real central catheter and was then transferred and treated as a high‐albumin+intravenous immunoglobulin (IVIG) patient; four patients in the low‐albumin+IVIG arm and three patients in the high‐albumin+IVIG arm completed the study under a previous version of the protocol that was not blinded

FIGURE 2

Least square (LS) mean change from baseline scores (± standard error of the mean) in the Alzheimer's Disease Cooperative Study Group–Activities of Daily Living (ADCS‐ADL) and the Alzheimer's Disease Assessment Scale–Cognitive (ADAS‐Cog) scales (co‐primary efficacy variables; panels A–F and G–L, respectively) performed on mild to moderate Alzheimer's disease (AD) patients (all‐patient [panels A, D, G, J], moderate AD [panels B, E, H, K], and mild AD [panels C, F, I, L] populations) treated with plasma exchange (PE) with albumin replacement. TPE denotes the 2‐month period of conventional therapeutic PE; LVPE denotes the period up to month 14 of low‐volume PE. The difference between the treated patient groups (PE‐treated patients combined [n = 242; panels A–C and G–I], and three active groups: low/high‐albumin dose, with/without intravenous immunoglobulin [n = 78‐86; panels D–F and J–L]) and the placebo group (n = 80) at month 14 (primary endpoint) was evaluated using a mixed model for repeated measures (MMRM) approach, with adjustment for multiple dose groups according to the Hochberg procedure for α level of 0.05. Both statistical significance (P < .05) and borderline significance (P < .1) versus placebo are indicated

FIGURE 3

Least square (LS) mean change from baseline scores (± standard error of the mean) in the Clinical Dementia Rating Sum of Boxes (CDR‐sb), and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC) scales (global efficacy secondary variables; panels A–F and G–L, respectively) performed on mild to moderate Alzheimer's disease (AD) patients (all‐patient [panels A, D, G, J], moderate AD [panels B, E, H, K], and mild AD [panels C, F, I, L] populations) treated with plasma exchange (PE) with albumin replacement. TPE denotes the 2‐month period of conventional therapeutic PE; LVPE denotes the period up to month 14 of low‐volume PE. The difference between the treated patient groups (PE‐treated patients combined [n = 242; panels A–C and G–I], and three active groups: low/high‐albumin dose, with/without intravenous immunoglobulin [n = 78–86; panels D–F and J–L]) and the placebo group (n = 80) at months 2, 6, 9, 12, and 14 was evaluated using analysis of covariance with treatment group as a fixed effect, and the corresponding baseline value, age and AD severity, as a covariate. Both statistical significance (P < .05) and borderline significance (P < .1) versus placebo are indicated

FIGURE 4

Least square (LS) mean change from baseline in cerebrospinal fluid levels (± standard error of the mean) of Aβ₄₀ (panels A, B, C), Aβ₄₂ (panels D, E, F), T‐tau (panels G, H, I), and P‐tau (panels J, K, L) between the finalization and beginning of each of the two plasma exchange with albumin replacement (PE) periods (TPE: conventional therapeutic PE up to month 2; LVPE: low‐volume PE up to month 14) performed on mild to moderate Alzheimer's disease (AD) patients (all‐patient [panels A, D, G, J], moderate AD [panels B, E, H, K], and mild AD [panels C, F, I, L] populations). The difference between the group of PE‐treated patients combined (n = 226 at baseline; n = 205 at end of TPE; n = 159 at end of LVPE) and the placebo group (n = 71 at baseline; n = 72 at end of TPE; n = 63 at end of LVPE) was evaluated using analysis of covariance with treatment group as a fixed effect, and the corresponding baseline value, age and AD severity, as a covariate. Both statistical significance (P < .05) and borderline significance (P < .1) versus placebo are indicated