Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years

Abstract

Introduction: Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD.

Methods: A possible disease-modifying effect of solanezumab was assessed using a new statistical method including noninferiority testing. Performance differences were compared during the placebo-controlled period with performance differences after the placebo patients crossed over to solanezumab in the delayed-start period.

Results: Noninferiority of the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog₁₄) and Alzheimer's Disease Cooperative Study Activities of Daily Living inventory instrumental items (ADCS-iADL) differences was met through 132 weeks, indicating that treatment differences observed in the placebo-controlled period remained, within a predefined margin, after the placebo group initiated solanezumab. Solanezumab was well tolerated, and no new safety concerns were identified.

Discussion: The results of this secondary analysis show that the mild subgroup of solanezumab-treated patients who initiated treatment early, at the start of the placebo-controlled period, retained an advantage at most time points in the delayed-start period.

Keywords: Alzheimer's disease; Anti-amyloid-β antibody; Clinical trials; Delayed-start; Solanezumab.

Fig. 1

Model of delayed-start design and analysis in the solanezumab EXPEDITION program. T₀ = beginning time point in the placebo-controlled period; T₁ = end time point in the placebo-controlled period/beginning time point in the delayed-start period; T₂ = postbaseline time point in the delayed-start analysis (multiple time points are analyzed in the MMRM analysis; the primary time point for the delayed-start analysis in the EXPEDITION program was 108 weeks, that is, 28 weeks after the start of the delayed-start period); Δ₁ = the true treatment difference at T₁; Δ₂ = the true treatment difference at T₂. Abbreviation: MMRM, mixed-model repeated measure.

Fig. 2

Flow of study participants. Abbreviations: AD, Alzheimer's disease; lab, laboratory measure; ECG, electrocardiogram; MMSE, Mini-Mental Status Examination. ^aDisease severity was based on MMSE score at baseline (mild, MMSE 20–26; moderate, MMSE 16–19). Baseline MMSE was outside of the study eligibility range (>26) for some randomized subjects, and these individuals were not categorized based on disease severity or included in pooled mild AD data set.

Fig. 3

Delayed-start analysis of ADAS-Cog₁₄, ADCS-iADL, MMSE, and CDR-SB among patients with mild AD in the solanezumab EXPEDITION program through 3.5 years. P values for treatment difference shown at all time points at which P < .05. Abbreviations: ADAS-Cog₁₄, 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale; ADCS-iADL, Alzheimer's Disease Cooperative Study Activities of Daily Living inventory, instrumental items; MMSE, Mini-Mental Status Examination; CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes; AD, Alzheimer's disease; NI, noninferiority criterion met (90% one-sided confidence interval for Δ₂ – 0.5Δ₁ >0); LS, least squares.

Fig. 4

Differences in least squares means between delayed-start and early-start treatment groups and 95% confidence intervals for ADAS-Cog₁₄, ADCS-iADL, CDR-SB, and MMSE among patients with mild AD in the solanezumab EXPEDITION program through 3.5 years. Shading represents the placebo-controlled period. Abbreviations: ADAS-Cog₁₄, 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale; ADCS-iADL, Alzheimer's Disease Cooperative Study Activities of Daily Living inventory, instrumental items; CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes; MMSE, Mini-Mental Status Examination; AD, Alzheimer's disease.

Fig. S1

Noninferiority statistics for early-start compared with delayed-start treatment groups for ADAS-Cog14, ADCS-iADL, CDR-SB, and MMSE among patients with mild AD in the solanezumab Expedition program through 3.5 years. Point estimates represent Δ₂–0.5Δ₁, and error bars represent the lower 90% confidence limit. Abbreviations: ADAS-Cog₁₄, 14-item Alzheimer's disease assessment scale–cognitive subscale; ADCS-iADL, Alzheimer's Disease Cooperative Study activities of daily living inventory, instrumental items; CDR-SB, clinical dementia rating scale–sum of boxes; MMSE, mini-mental status examination; AD, Alzheimer's disease.

Fig. S2

Delayed-start analysis of ADAS-Cog₁₁ and ADCS-bADL among patients with mild AD in the solanezumab Expedition program through 3.5 years. Abbreviations: LS, least squares; ADAS-Cog₁₁, 11-item Alzheimer's disease assessment scale–cognitive subscale; ADCS-bADL, Alzheimer's disease cooperative study activities of daily living inventory, basic items; NI, noninferiority criterion met (90% one-sided confidence interval for Δ₂–0.5Δ₁ >0); DS, delayed-start.

Fig. S3

Delayed-start analysis of ADAS-Cog₁₄, ADCS-iADL, MMSE, and CDR-SB among patients with mild AD in the solanezumab Expedition program by placebo-controlled study (Expedition and Expedition 2) through 3.5 years. Abbreviations: ADAS-Cog₁₄, 14-item Alzheimer's disease assessment scale–cognitive subscale; ADCS-iADL, Alzheimer's disease cooperative study activities of daily living inventory, instrumental items; MMSE, mini-mental status examination; CDR-SB, clinical dementia rating scale–sum of boxes; AD, Alzheimer's disease; LS, least squares; DS, delayed-start; NI, noninferiority criterion met (90% one-sided confidence interval for Δ₂–0.5Δ₁ >0).

Fig. S4

Categorical changes in ARIA-H. Categories: 0, 1, 2–5, 6–10, >10, and >10 with additional increase. Abbreviation: ARIA-H, amyloid-related imaging abnormality-hemorrhage/hemosiderin deposition.