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TRAILBLAZER-ALZ 6

Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction

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Year of Publication: 2025

Authors: Wang H, Monkul Nery ES, Ardayfio P, ..., Sims JR

Journal: Alzheimer's & Dementia

Citation: Alzheimer's Dement. 2025;21:e70062

Link: https://doi.org/10.1002/alz.70062

Clinical Question

Can a modified donanemab titration schedule reduce ARIA-E risk without sacrificing amyloid clearance in early Alzheimer's disease?

Bottom Line

A gradual up-titration of donanemab (350→700→1050→1400 mg) significantly reduces ARIA-E frequency and severity compared with standard dosing while maintaining equivalent amyloid plaque reduction, pharmacokinetics, and p-tau217 lowering. This regimen should be considered as a safer alternative dosing approach in early symptomatic Alzheimer's disease.

Major Points

  • ARIA-E at 24 weeks: 23.7% (standard), 13.7% (modified titration), 18.6% (dose skipping), 18.3% (Cmax)
  • Modified titration met the primary endpoint with 94.1% posterior probability of ≥20% RRR; posterior RRR 0.405 (SD 0.123)
  • Modified titration had significantly lower radiographic ARIA-E severity (P=0.011) and 86.3% had no ARIA-E vs 76.3% in standard arm
  • Dose skipping and Cmax arms did not meet prespecified success criteria
  • Amyloid plaque reduction, p-tau217 reduction, cumulative exposure, and pharmacokinetics were comparable between modified titration and standard arms
  • 52-week data confirmed durability: 15.6% (modified titration) vs 24.2% (standard); 87% probability of ≥20% RRR

Design

Study Type: Multicenter, randomized, double-blind phase 3b study

Randomization: 1

Blinding: Double-blind (placebo infusions used to preserve blinding across different dosing schedules)

Allocation: 1:1:1:1

Enrollment Period: First patient visit February 2023; ongoing

Follow-up Duration: 76-week double-blind period; primary analysis at 24 weeks, supportive data at 52 weeks

Centers: 0

Countries: United States

Sample Size: 843

Analyzed: 843

Analysis: Bayesian logistic regression for primary endpoint with fixed effects for treatment regimen, APOE ε4 status, baseline microhemorrhage, baseline cortical superficial siderosis, and baseline amyloid level; ANCOVA for amyloid PET; MMRM for longitudinal analyses; Cox proportional hazards for time-to-first-ARIA

Power Calculation: Powered assuming 40% relative reduction in ARIA-E by week 24 vs standard arm (assumed standard ARIA-E rate 18.5% based on TRAILBLAZER-ALZ 2 open-label addendum); false positive rate controlled at one-sided 5%

Registration: NCT05738486

Inclusion Criteria

  • Age 60-85 years
  • Gradual and progressive change in memory function for ≥6 months
  • MMSE score 20-28 (inclusive) at visit 1
  • Amyloid PET scan from central read consistent with amyloid pathology

Exclusion Criteria

  • Significant neurological disease other than AD (other dementias, serious brain infection, Parkinson's disease, multiple concussions, epilepsy or recurrent seizures except febrile childhood seizures)
  • Contraindications for MRI or PET
  • Screening MRI demonstrating ARIA-E
  • >4 cerebral microhemorrhages
  • >1 area of cortical superficial siderosis
  • Any macrohemorrhage (cerebral hemorrhage >1 cm)
  • Severe white matter disease (Fazekas score 3)

Arms

FieldControlModified titrationDose skippingCmax
N208212210213
InterventionDonanemab 700 mg monthly × 3 doses, then 1400 mg monthlyDonanemab 350 mg → 700 mg → 1050 mg → 1400 mg monthly (gradual up-titration)Donanemab 700 mg, then placebo × 2, then 1400 mg monthly thereafterDonanemab 350 mg every 2 weeks × 6 doses, then 700 mg × 2 doses, then 1400 mg monthly
Duration76 weeks double-blind period76 weeks double-blind period76 weeks double-blind period76 weeks double-blind period

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Relative risk reduction (RRR) of ARIA-E frequency at 24 weeks for each alternative dosing arm vs standard arm (success if posterior probability of ≥20% RRR was >80%)PrimaryARIA-E 23.7% (standard arm)ARIA-E 13.7% (modified titration); 18.6% (dose skipping); 18.3% (Cmax)
Secondary
Secondary
Secondary
Secondary
Secondary
Secondary
Safety
Safety

Subgroup Analysis

Randomization stratified by baseline amyloid PET Centiloids (24.1-<54, 54-<79, 79-<107, ≥107) and APOE ε4 genotype (heterozygous, homozygous, non-carrier); Bayesian model adjusted for APOE ε4 status, baseline microhemorrhage, baseline cortical superficial siderosis, and baseline amyloid level

Criticisms

  • Predominantly White (>91%) US-based population limits generalizability
  • Tau pathology not required for enrollment (differs from TRAILBLAZER-ALZ 2 randomized population)
  • Ongoing study with primary analysis based on 24-week data; long-term clinical efficacy outcomes not yet reported
  • Dose skipping and Cmax arms did not show significant ARIA-E reduction, limiting clinical alternatives to modified titration
  • Cox proportional hazard model without adjustment for baseline ARIA risk factors beyond treatment groups

Funding

Eli Lilly and Company

Based on: TRAILBLAZER-ALZ 6 (Alzheimer's & Dementia, 2025)

Authors: Wang H, Monkul Nery ES, Ardayfio P, ..., Sims JR

Citation: Alzheimer's Dement. 2025;21:e70062

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