Evaluation of cognitive, functional, and behavioral effects observed in EMERGE, a phase 3 trial of aducanumab in people with early Alzheimer's disease

Abstract

Introduction: In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment effects by analyzing item-level data and the persistence of treatment benefit.

Methods: Participants with early Alzheimer's disease (AD) were stratified by apolipoprotein E (APOE) ε4 status and randomized (1:1:1) to receive low- or high-dose aducanumab, or placebo. Prespecified principal component analyses (PCAs) per the Statistical Analysis Plan were followed by post hoc examination of individual domains/items across all five clinical endpoints. Progression analysis assessed reduction in clinical decline.

Results: High-dose aducanumab demonstrated clinically meaningful slowing of progression across clinical endpoints measuring cognition, daily function, and behavioral symptoms. Delay of progression over 18 months was consistent across measures; treatment effects increased over time.

Discussion: Across multiple analyses aducanumab slowed cognitive decline, prolonged functional independence, and attenuated behavioral symptoms in participants with early AD. These outcomes comprise the elements of a clinically meaningful response to treatment.

Highlights: Endpoints in EMERGE assessed different aspects of cognition, daily function, and behavioral symptoms. Treatment benefits were observed across subdomains on all five clinical endpoints. Aducanumab meaningfully slowed disease progression in participants with early AD.

Keywords: Alzheimer's disease; anti‐Aβ mAb; behavioral symptoms; clinical meaningfulness; cognitive decline; functional independence; treatment effect.

FIGURE 1

Trial profile. *Other reasons for not meeting inclusion/exclusion criteria include inability to comply with study requirements; presence of diabetes mellitus that, in the judgment of the investigator, cannot be controlled or adequately managed; inability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations; other unspecified reasons that, in the opinion of the investigator or sponsor, make the individual unsuitable for enrollment; history of or positive test result at screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for both hepatitis B surface antigen AND hepatitis B core antibody); use of allowed chronic medications at doses that have not been stable for at least 4 weeks prior to screening visit 1 and screening up to day 1, or use of Alzheimer's disease (AD) medications at doses that have not been stable for at least 8 weeks. ^†Some categories with < 1% patients are not displayed, including loss of capacity, pregnancy, and protocol amendment. ^‡Following the 78‐week placebo‐controlled study period, there was an optional dose‐blind long‐term extension (LTE) period up to week 134. MRI, magnetic resonance imaging; PET, positron emission tomography.

FIGURE 2

Longitudinal change in each Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) item in EMERGE: high‐dose aducanumab versus placebo. Adjusted mean change from baseline in each item on the CDR‐SB and at weeks 26, 50, and 78 are plotted with aducanumab high‐dose treatment (blue) and placebo (gray). Higher scores indicate greater impairment. Longitudinal change on (A) Memory (B) Orientation, (C) Judgment and Problem Solving, (D) Community Affairs, (E) Home and Hobbies, and (F) Personal Care are presented here. Percent of treatment differences between high‐dose aducanumab and placebo at week 78 are noted in each panel.

FIGURE 3

Alzheimer's Disease Assessment Scale–Cognitive Subscale (13‐item) (ADAS‐Cog13), Mini‐Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS‐ADL‐MCI) item changes at week 78. Adjusted mean item change from baseline to week 78 in the (A) ADAS‐Cog13 score, (B) MMSE score, and (C) ADCS‐ADL‐MCI score for high‐dose aducanumab (blue) and placebo (gray). On the ADAS‐Cog13, higher scores indicate greater impairment. Scoring range varies for each individual item: Word recognition (0–12), Orientation (0–8), Delayed word recall (0–10), Word recall (0–10), Number cancellation (0–5), Naming objects and fingers (0‐5), Ideation praxis (0–5), Word finding difficulty in spontaneous speech (0–5), Commands (0–5), Spoken language ability (0–5), Remembering test instructions (0–5), Comprehension (0–5), and Constructional praxis (0–5). On the MMSE, lower scores indicate greater impairment. Scoring range varies for each individual item: Orientation to time (0–5), Orientation to place (0–5), Attention and calculation (0–5), Recall (0–3), Comprehension (0–1), Registration (0–3), Write a sentence (0–1), Copy this design (0–1), Read this and do what it says (0–3), Naming (0–2), and Repeat what I say (0–1). On the ADCS‐ADL‐MCI score, lower scores indicate greater impairment. Scoring range varies for each individual item: Finding personal belongings (0–3), Select first clothes (0–3), Usual dressing (0–4), Clean room (0–2), Balance banking (0–2), Write things down (0–2), Clean laundry (0–2), Keep appointments (0–3), Use a telephone (0–4), Make a meal (0–3), Travel (0–3), Talk about current events (0–4), Read more than 5 min (0–3), Watch television (0–3), and Go shopping (0–2); Left on his/her own (0–3), Use household appliance (0–4), and Perform pastime (0–3). Higher scores indicate better ability to perform activities of daily living. ^*Percent treatment differences between high‐dose aducanumab and placebo are noted for each item.

FIGURE 4

Neuropsychiatric Inventory Questionnaire (NPI‐10) items and caregiver distress in EMERGE: high‐dose aducanumab versus placebo. Adjusted mean NPI‐10 item change from baseline at week 78 (A) and associated caregiver distress score (B). Each item on the NPI‐10 has a subscore between 0 and 12, with higher scores indicative of greater severity. Each corresponding caregiver distress score has a range between 0 and 5. This figure shows high‐dose aducanumab (blue) and placebo (gray) at week 78. *Percent treatment differences between high‐dose aducanumab and placebo are noted in each panel.

FIGURE 5

Odds ratio for progression in clinical endpoints at week 78: high‐dose versus placebo. The estimated percentage of progressors in the placebo group and high‐dose aducanumab group, as well as the odds ratio (95% confidence interval [CI]) of treatment with high‐dose compared with placebo in the opportunity to complete population for high‐dose aducanumab versus placebo are presented for Alzheimer's Disease Assessment Scale–Cognitive Subscale (13‐item) (ADAS‐Cog13); Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory (Mild Cognitive Impairment version) (ADCS‐ADL‐MCI); Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB); and Mini‐Mental State Examination (MMSE).