Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.
Level 2 - randomized trial
Individual phase 3 randomized, double-blind, placebo-controlled clinical trial
PubMed 37459141 · doi:10.1001/jama.2023.13239
What was done
A multicenter (277 sites in 8 countries), randomized, double-blind, placebo-controlled phase 3 trial evaluated intravenous donanemab versus placebo in 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment or mild dementia) confirmed to have amyloid and low/medium (n=1182) or high (n=552) tau pathology by PET imaging. Participants received donanemab (n=860) or placebo (n=876) every 4 weeks for 72 weeks, with blinded switching to placebo upon meeting amyloid clearance criteria. The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS, 0–144) at 76 weeks; secondary endpoints included Clinical Dementia Rating Scale Sum of Boxes (CDR-SB, 0–18).
What was found
Trial completion was 76% (1320/1736). In the low/medium tau group, 76-week least-squares mean iADRS change was -6.02 (95% CI, -7.01 to -5.03) with donanemab vs -9.27 (95% CI, -10.23 to -8.31) with placebo (difference: 3.25 [95% CI, 1.88–4.62]; P < .001). In the combined population, the difference was 2.92 (95% CI, 1.51–4.33; P < .001). CDR-SB worsening was lower with donanemab in the low/medium tau group (difference: -0.67 [95% CI, -0.95 to -0.40]; P < .001) and combined population (difference: -0.70 [95% CI, -0.95 to -0.45]; P < .001). Amyloid-related imaging abnormalities of edema/effusion (ARIA-E) occurred in 205 participants (24.0%; 52 symptomatic) on donanemab vs 18 participants (2.1%; 0 symptomatic) on placebo. Infusion reactions occurred in 8.7% vs 0.5%. Three deaths in the donanemab arm and one in the placebo arm were considered treatment-related.
Why it matters
This trial confirms that targeting brain amyloid plaque with donanemab moderately slows clinical progression over 18 months in early Alzheimer disease, supporting disease-modifying efficacy while highlighting substantial ARIA safety risks.
Limits
Follow-up was limited to 76 weeks, leaving long-term durability and post-cessation outcomes unassessed. Twenty-four percent of participants discontinued the study early. Adverse event rates were high, including 24.0% ARIA-E and 3 treatment-related deaths in the intervention arm. Enrollment was restricted to PET-verified amyloid and tau pathology, limiting direct applicability to broader populations without specialized biomarker imaging.
Cited by
- context In trial data from pharmaceutical anti-amyloid therapies, patients homozygous for APOE4 (APOE4/4) deteriorated more than the control group.