Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings

Abstract

Purpose of review: To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study.

Recent findings: The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months.

Summary: The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

Figure 1. The iADRS Conceptual Framework

^aMeasured using ADAS-Cog₁₃ (hybrid of performance-based (standardized task) and clinician-reported outcome measure). ^bMeasured using ADCS-iADL (observer-reported outcome measure). AD = Alzheimer disease; ADAS-Cog₁₃ = Alzheimer Disease Assessment Scale–13-item Cognitive subscale; ADCS iADL = Alzheimer Disease Cooperative Study–Instrumental Activities of Daily Living subscale.

Figure 2. Expected iADRS Baseline Scores and Rate of Change by Clinical Presentation of AD

*Due to Alzheimer disease. Figure created using placebo data EXPEDITION-1, -2, and -3; AMARANTH; and DAYBREAK-ALZ; for details see Gueorguieva et al., Alz & Dem 2022; doi:10.1002/alz.12876. iADRS = Integrated Alzheimer's Disease Rating Scale.

Figure 3. Change in iADRS Score at 18 Months With Placebo vs a Hypothetical DMT With a 25% Treatment Effect

*Due to Alzheimer disease. Assumptions: (1) Change over 18 months with placebo is- 7 for MCI, -13 for mild dementia, and -20 for moderate dementia (calculated using placebo data EXPEDITION-1, -2 and -3; AMARANTH; and DAYBREAK-ALZ; for details see Gueorguieva et al., Alz & Dem 2022; doi:10.1002/alz.12876. (2) Disease progression portrayed as linear for simplicity of presentation. (3) DMT effect maintained over 18 months. iADRS = Integrated Alzheimer's Disease Rating Scale; DMT = disease-modifying therapy; MCI = mild cognitive impairment; pts = points.

Figure 4. Change in iADRS Score Over 36 Months With Placebo vs a Hypothetical DMT With a 25% Treatment Effect in Mild Dementia Due to AD

Assumptions: (1) Change over 18 months with placebo is −7 for MCI, −13 for mild dementia, and −20 for moderate dementia (calculated using placebo data EXPEDITION-1, -2, and -3; AMARANTH; and DAYBREAK-ALZ; for details see Gueorguieva et al., Alz & Dem 2022; doi:10.1002/alz.12876. (2) Disease progression portrayed as linear for simplicity of presentation. (3) DMT effect maintained over 36 months. AD = Alzheimer disease; DMT = disease-modifying therapy; iADRS = Integrated Alzheimer's Disease Rating Scale; MCI = mild cognitive impairment; pts = points.

Figure 5. Schematic of Primary Efficacy Findings in the TRAILBLAZER-ALZ Trial

*p < 0.05; **p < 0.005. At 18 months, p = 0.04. Placebo (gray line), N = 126; Donanemab (green line), N = 131. iADRS = Integrated Alzheimer's Disease Rating Scale; LS = least sum of squares; SE = standard error.

Figure 6. Potential DMT Effect on Disease Progression in an Individual Patient, Using iADRS Findings From the TRAILBLAZER-ALZ Trial (32% Slowing of Disease Progression)

*Not advocating for using in clinical practice. Assumptions: (1) Change over 18 months with placebo is - 7 for MCI, -13 for mild dementia, and -20 for moderate dementia (calculated using placebo data EXPEDITION-1, -2, and -3; AMARANTH; and DAYBREAK-ALZ; for details see Gueorguieva et al, Alz & Dem 2022; DOI:10.1002/alz.12876. (2) Disease progression portrayed as linear for simplicity of presentation. (3) DMT effect is that seen in TRAILBLAZER-ALZ and is maintained over 36 months. DMT = disease-modifying therapy; iADRS = Integrated Alzheimer's Disease Rating Scale; MCI = mild cognitive impairment.