Evidence Matters

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

Background and Purpose:

There are limited efficacious treatments available for Alzheimer disease.
Sims et al (JAMA 2023) assessed the efficacy of the monoclonal antibody donanemab, which is designed to clear brain amyloid plague, at providing clinical benefit to early symptomatic Alzheimer disease.

Design, Setting, and Participants
- The study was a multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial from Jun 2020 to Nov 2021 (last patient visit for primary outcome in Apr 2023).
- 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 were enrolled.
  - Mean age of 73.0 years; 57.4% women [996]; 68.1% with low/medium tau pathology [1182] and 31.8% with high tau pathology [552].
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 blind manner if dose completion criteria were met.
Main Outcomes and Measures
- The primary outcome was the 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 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).

76% of participants (1320/1736) completed the trial.
23 of the 24 gated outcomes were statistically significant.
The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% confidence interval [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.
The LSM change in the combined population at 76 weeks was −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).
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.
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.

Donanemab treatment significantly slowed clinical progression at 76 weeks in participants with early symptomatic Alzheimer disease and amyloid and tau pathology.