Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial

Abstract

Importance: There are limited efficacious treatments for Alzheimer disease.

Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.

Design, setting, and participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).

Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.

Main outcomes and measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.

Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.

Conclusions and relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.

Trial registration: ClinicalTrials.gov Identifier: NCT04437511.

Figure 1.. Participant Flow in a Trial of Donanemab for Early Symptomatic Alzheimer Disease

^aInclusion criteria for tau pathology: low/medium or high tau indicated by standardized uptake value ratio >1.10 or positive visual read assessed by ¹⁸F-flortaucipir positron emission tomography (PET) imaging. ^bInclusion criteria for amyloid pathology (≥37 Centiloids) assessed with ¹⁸F-florbetapir or ¹⁸F-florbetaben PET. ^cInclusion criteria for Mini-Mental State Examination: score of 20 to 28. ^dPhosphorylated tau 181 (P-tau181) screening criterion was not implemented for the entire trial duration (eMethods in Supplement 3). ^eExclusion criteria for MRI include presence of amyloid-related imaging abnormalities of edema/effusion, >4 cerebral microhemorrhages, >1 area of superficial siderosis, and any intracerebral hemorrhage >1 cm or severe white matter disease. ^fSummary of other screen failure can be found in eTable 3 in Supplement 3 (lists reason if ≥20 participants). ^gStratified by baseline tau categorization and enrolling sites. ^hOne additional death occurred after treatment completion and in the follow-up period. ⁱAlzheimer disease progression to a degree prompting study discontinuation, per investigator judgment. ^jTreatment completion criteria: amyloid plaque level of 11 Centiloids on any single scan or 11 to <25 Centiloids on 2 consecutive scans. ^kParticipants who met treatment completion criteria are included in discontinuation and completion numbers. ^lPercentage calculated as No./total No. of participants with a PET scan at visit: n = 761 at 24 wk, n = 672 at 52 wk, and n = 620 at 76 wk. Corresponding number of participants and percentages for the low/medium tau population were 20.3% (n = 106) at 24 wk, 51.9% (n = 241) at 52 wk, and 73.5% (n = 321) at 76 wk.

Figure 2.. Integrated Alzheimer Disease Rating Scale (iADRS) and Sum of Boxes of the Clinical Dementia Rating Scale (CDR-SB) From Baseline to 76 Weeks

A, 35.1% slowing (95% CI, 19.90%-50.23%) of clinical progression. B, 22.3% slowing (95% CI, 11.38%-33.15%) of clinical progression. C, 36.0% slowing (95% CI, 20.76%-51.15%) of clinical progression. D, 28.9% slowing (95% CI, 18.41%-39.44%) of clinical progression. iADRS data were analyzed using the natural cubic spline model with 2 degrees of freedom (NCS2) and CDR-SB data were analyzed with mixed models for repeated measures (MMRM). For MMRM analyses, 95% CIs for least-squares mean changes were calculated with the normal approximation method. For the Alzheimer Disease Cooperative Study—Instrumental Activities of Daily Living, 13-item cognitive subscale of the Alzheimer Disease Assessment Scale, and CDR-SB clinical assessments analyzed with NCS2, see eFigure 1 (low/medium tau population) and eFigure 2 (combined population) in Supplement 3 and Table 2. For all clinical assessments analyzed with MMRM, see eFigure 3 (low/medium tau population) and 4 (combined population) in Supplement 3 and Table 2. P < .001 for all 76 week time points.

Figure 3.. Brain Amyloid, Plasma Phosphorylated Tau 217 (P-tau217), and Hazard Ratios for Risk of Disease Progression

Biomarker data shown were analyzed using mixed models for repeated measures (MMRM). For MMRM analyses, 95% CIs for the least-squares mean changes were calculated with the normal approximation method. P < .001 for all time points in panels A-D. B, P value is from Fisher exact test comparing the percent amyloid negative by treatment groups at each visit. E and F, The analysis was conducted using a Cox proportional hazards model. There were 163 events among 573 participants in the placebo group and 100 events among 555 participants in the donanemab group in the low/medium tau population and 288 events among 844 participants in the placebo group and 186 events among 805 participants in the donanemab group in the combined population. CDR-G indicates Clinical Dementia Rating Global Score.