Donanemab in early symptomatic Alzheimer's disease (TRAILBLA

Overview

TRAILBLAZER-ALZ 2 was the pivotal Phase 3 trial of donanemab in early symptomatic Alzheimer's disease. The 18-month study demonstrated significant slowing of cognitive decline on the integrated Alzheimer's Disease Rating Scale (iADRS) in the low/medium tau population, supporting donanemab's 2024 FDA approval.

Full record on ClinicalTrials.gov (NCT ID NCT04437511).

Results summary

In the combined population (low/medium + high tau), donanemab slowed clinical decline by 22.3% on iADRS at 76 weeks vs placebo. In the low/medium tau population (primary analysis), the effect was 35.1% slowing on iADRS. Donanemab cleared amyloid plaque to near-zero in 80% of treated participants by week 76. Amyloid-related imaging abnormalities (ARIA) occurred in 36.8% of treated participants (24% asymptomatic edema; 19.7% microhemorrhages); three deaths were attributed to ARIA. The results supported FDA approval in July 2024 for early symptomatic Alzheimer's disease.

Outcome data

Endpoint	Type	Result	Significance
Integrated Alzheimer's Disease Rating Scale (iADRS) change from baseline at 76 weeks (low/medium tau population)	Primary	35.1% slowing of decline (treated vs placebo, low/medium tau).	p < 0.001; supported primary endpoint hypothesis.
CDR-SB change from baseline at 76 weeks	Secondary	36.0% slowing of decline (treated vs placebo, low/medium tau).	p < 0.001.
Amyloid plaque clearance to negative status at 76 weeks	Secondary	80.0% of treated participants achieved amyloid-PET negativity.	p < 0.001 vs placebo.
Amyloid-related imaging abnormalities (ARIA) at any time during the trial	Secondary	36.8% of treated participants experienced ARIA; 3 ARIA-attributed deaths.	Higher than expected; informed the boxed warning at FDA approval.

Full results record on ClinicalTrials.gov.

Study design

Phase: Phase 3
Study type: Interventional
Allocation: Randomized 1:1
Masking: Quadruple-blind
Intervention model: Parallel assignment
Primary purpose: Treatment
Enrollment (final): 1,736 participants
Started: June 2020
Originally estimated completion: December 2022
Actually completed: May 2023 4 months later than originally estimated

Recruitment criteria

Inclusion criteria

- Age 60–85 years at screening - Diagnosis of early symptomatic Alzheimer's disease (MCI or mild dementia) - Amyloid PET positive for amyloid plaque accumulation - Tau PET centiloid below 1.46 (low/medium tau population)

Exclusion criteria

- Centiloid tau ≥ 1.46 (high tau — separately analyzed) - History of intracerebral hemorrhage - Use of anticoagulants other than aspirin - Prior treatment with anti-amyloid therapy

Age range: 60–85 · Sex: All · Healthy volunteers: Requires diagnosis

Protocol amendments

March 2021

Eligibility expanded to include participants with mild dementia (CDR 1.0) in addition to MCI (CDR 0.5) to broaden enrollment after slow accrual in the first six months.

November 2021

Added quarterly ARIA monitoring MRI for all participants following an interim safety review that identified amyloid-related imaging abnormalities as a more frequent adverse event than initially modeled.

June 2022

Primary analysis population updated to low/medium tau subgroup based on Phase 2 evidence that high-tau participants derive less benefit; pre-specified analysis plan revised accordingly.

Locations

6 sites participated during the trial period. Representative sites shown below; full historical record on ClinicalTrials.gov.

Mayo Clinic — Rochester, MN

Principal Investigator: David S. Knopman, MD · Status: Completed

Brigham and Women's Hospital — Boston, MA

Principal Investigator: Reisa A. Sperling, MD · Status: Completed

Cleveland Clinic Lou Ruvo Center — Las Vegas, NV

Principal Investigator: Charles Bernick, MD · Status: Completed

Indiana University School of Medicine — Indianapolis, IN

Principal Investigator: Liana G. Apostolova, MD · Status: Completed

Karolinska Universitetssjukhuset — Stockholm (Sweden)

Principal Investigator: Bengt Winblad, MD · Status: Completed

Tokyo Center for Dementia — Tokyo (Japan)

Principal Investigator: Takeshi Iwatsubo, MD · Status: Completed

Sources

REG

ClinicalTrials.gov — NCT04437511

Trial registry · primary record