TRAILBLAZER-ALZ 2
(2023)Objective
Donanemab - To assess the efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque, in early symptomatic Alzheimer disease.
Study Summary
Intervention
This was a multicenter, randomized, double-blind, placebo-controlled, 18-month (76-week) phase 3 trial. Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses, then 1400 mg) or placebo intravenously every 4 weeks for up to 72 weeks. Donanemab participants who met amyloid plaque clearance criteria were switched to placebo in a blinded manner.
Inclusion Criteria
Participants aged 60 to 85 years with early symptomatic Alzheimer disease (mild cognitive impairment or mild dementia) and evidence of amyloid pathology (≥37 Centiloids on PET) and tau pathology (low/medium or high based on PET imaging). Screening MMSE scores were 20-28.
Study Design
Arms: Donanemab vs. Placebo
Patients per Arm: Donanemab: 860 randomized, Placebo: 876 randomized
Outcome
- Low/medium tau population: Donanemab -6.02 (95% CI, -7.01 to -5.03) vs. Placebo -9.27 (95% CI, -10.23 to -8.31); difference, 3.25 (95% CI, 1.88 to 4.62); P<.001 (35.1% slowing of progression).
- Combined (low/medium + high tau) population: Donanemab -10.19 (95% CI, -11.22 to -9.16) vs. Placebo -13.11 (95% CI, -14.10 to -12.13); difference, 2.92 (95% CI, 1.51 to 4.33); P<.001 (22.3% slowing of progression).
• Secondary Outcome (CDR-SB score change at 76 weeks, higher scores indicate greater impairment):
- Low/medium tau population: Donanemab 1.20 (95% CI, 1.00 to 1.41) vs. Placebo 1.88 (95% CI, 1.68 to 2.08); difference, -0.67 (95% CI, -0.95 to -0.40); P<.001 (36.0% slowing of progression).
- Combined population: Donanemab 1.72 (95% CI, 1.53 to 1.91) vs. Placebo 2.42 (95% CI, 2.24 to 2.60); difference, -0.70 (95% CI, -0.95 to -0.45); P<.001 (28.9% slowing of progression).
• Amyloid Plaque Clearance (Combined population at 76 weeks): 76.4% of donanemab-treated participants achieved amyloid clearance (<24.1 Centiloids) vs. 0.3% of placebo-treated participants.
• Adverse Events: Amyloid-related imaging abnormalities of edema or effusion (ARIA-E) occurred in 24.0% of donanemab participants (52 symptomatic) vs. 2.1% in placebo (0 symptomatic). Infusion-related reactions occurred in 8.7% with donanemab vs. 0.5% with placebo. Three deaths in the donanemab group and one in the placebo group were considered treatment-related.
Bottom Line
Donanemab significantly slowed clinical progression at 76 weeks in participants with early symptomatic Alzheimer disease and amyloid and tau pathology, with 35% slowing in low/medium tau and 22% in combined population, though ARIA occurred in 24% of treated patients with 3 treatment-related deaths
Major Points
- Phase 3 trial enrolling 1736 participants with early symptomatic Alzheimer disease stratified by tau pathology (low/medium vs high)
- Primary outcome met: iADRS showed 35.1% slowing in low/medium tau population (difference 3.25 points, p<0.001)
- CDR-SB showed 36% slowing in low/medium tau population (difference -0.67, p<0.001)
- 80% of low/medium tau participants achieved amyloid clearance (<24.1 Centiloids) at 76 weeks
- Limited-duration dosing design: participants switched to placebo upon achieving amyloid clearance (52% completed by 1 year)
- High tau population showed smaller benefits (non-significant for iADRS, significant for CDR-SB)
- 38.6% lower risk of disease progression on CDR-G with donanemab treatment
- ARIA-E occurred in 24% of donanemab group (6.1% symptomatic); 3 treatment-related deaths after serious ARIA
- Plasma P-tau217 significantly reduced with donanemab treatment
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; participants and investigators blinded; CDR raters blinded to adverse event information
- Sample Size
- 1736
- Follow-up
- 76 weeks
- Centers
- 277
- Countries
- United States, Japan, Canada, United Kingdom, Spain, Netherlands, Australia, Puerto Rico
Primary Outcome
Definition: Change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range 0-144, lower scores indicate greater impairment)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (1.88 to 4.62) | <0.001 |
Limitations & Criticisms
- Limited racial/ethnic diversity (91.5% White participants)
- Variable donanemab dosing due to limited-duration design creates interpretation challenges
- High tau population showed attenuated benefits, limiting generalizability
- Three treatment-related deaths occurred after serious ARIA events
- Conducted during COVID-19 pandemic which was most common adverse event
- APOE ε4 carriers excluded from subset of analyses despite being majority of population
- Cannot directly compare to other amyloid-targeting trials due to design differences (tau stratification)
- Possible unblinding due to ARIA and infusion reactions
Citation
JAMA. 2023;330(6):512-527