NCT05738486, known as TRAILBLAZER-ALZ 6, is a Phase 3, randomized, double-blind, placebo-controlled, multicenter trial evaluating different donanemab dosing regimens to optimize amyloid-related imaging abnormality (ARIA) management while maintaining efficacy. Sponsored by Eli Lilly and Company, this trial enrolled 1,175 participants.
Donanemab (marketed as Kisunla in the US) is a monoclonal antibody that targets pyroglutamate-amyloid-beta (AβpE3*), a highly aggregation-prone form of amyloid-beta found in plaques. The TRAILBLAZER-ALZ 6 study specifically investigates whether modified dosing can reduce the incidence of ARIA, particularly ARIA-E (amyloid-related imaging abnormality-edema), while preserving amyloid plaque removal and clinical benefit.
This trial addresses a significant limitation of anti-amyloid therapies: the trade-off between efficacy and ARIA risk. Understanding optimal dosing may enable broader patient access to this disease-modifying therapy.
| Parameter |
Value |
| NCT Number |
NCT05738486 |
| Phase |
PHASE3 |
| Status |
ACTIVE_NOT_RECRUITING |
| Sponsor |
Eli Lilly and Company |
| Enrollment |
1,175 participants |
| Enrollment Type |
ACTUAL |
| Study Type |
INTERVENTIONAL |
| Intervention |
Donanemab (LY3002813) |
| Treatment Duration |
Up to 18 months |
| Start Date |
2023-02-28 |
| Completion Date |
2027-05-01 |
| Last Updated |
2025-11-14 |
- Alzheimer's Disease
- Mild Cognitive Impairment due to AD
- Dementia
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neurodegenerative Diseases
- Neurocognitive Disorders
- Mental Disorders
Early Alzheimer's disease, encompassing mild cognitive impairment (MCI) due to AD and mild dementia due to AD, affects approximately 10-15% of the elderly population. These stages represent the optimal therapeutic window for disease-modifying interventions that can preserve neuronal function before extensive neurodegeneration occurs.
The approval of donanemab (TRAILBLAZER-ALZ 2) in 2024 demonstrated that amyloid-targeting can slow clinical decline in early AD. However, ARIA remains a significant safety concern that limits broader utilization.
Donanemab specifically targets pyroglutamate Aβ (AβpE3)*, a modified form of amyloid-beta with enhanced aggregation propensity:
- N-terminal truncation: AβpE3* is generated by truncation at residue 3 and enzymatic cyclization
- High aggregation: The pyroglutamate modification dramatically increases fibril formation rate
- Plaque deposition: AβpE3* is enriched in mature amyloid plaques
- Toxicity: Oligomers of AβpE3* are highly synaptotoxic
By targeting this particularly pathogenic form, donanemab achieves:
- Rapid amyloid plaque removal
- Reduced plaque burden below threshold
- Clinical benefit correlated with plaque clearance
Amyloid-Related Imaging Abnormalities (ARIA) represent the primary safety concern for all anti-amyloid antibodies:
- Pathophysiology: Antibody binding to vascular amyloid disrupts vessel integrity
- Location: Typically lobar (affecting cortical regions)
- Symptoms: Headache (most common), confusion, focal neurological deficits
- Imaging: Hyperintense signal on FLAIR MRI
- Incidence: 12-24% in Treatment Arms vs. ~2% Placebo
- Types: Cerebral microhemorrhages (CMBs), superficial siderosis
- Mechanism: Vessel wall degradation from cleared amyloid
- Incidence: Higher in participants with prior CMBs or ApoE4 carriers
- Risk factors: Anticoagulant use, hypertension
The original TRAILBLAZER-ALZ 2 employed a loading dose approach:
- Initial dose: 700 mg (based on weight)
- Subsequent doses: 1400 mg every 4 weeks
- This approach maximized plaque clearance but produced significant ARIA incidence
TRAILBLAZER-ALZ 6 investigates alternative dosing strategies:
- Lower initial dose: May reduce immune reaction and vascular disruption
- Slower titration: Gradual increase may allow vessel adaptation
- Modified schedule: Different intervals may optimize benefit/risk profile
This is a Phase 3, randomized, double-blind, placebo-controlled trial with multiple dose-finding arms. The adaptive design allows comparison of several dosing regimens.
- Randomization: Multiple arms comparing different dosing regimens
- Blinding: Double-blind with matching placebos for each regimen
- Treatment Period: Up to 72 weeks
- Primary Objective: Compare ARIA incidence across dosing approaches
- Secondary Objective: Assess amyloid removal and cognitive outcomes
Arm 1 (Control/Standard):
- Similar to TRAILBLAZER-ALZ 2 dosing
Arm 2 (Modified Loading):
- Lower initial dose with gradual escalation
Arm 3 (Low-Dose Continuous):
- Lower fixed dose throughout treatment
Arm 4 (Titration-Based):
- Dose adjusted based on tolerability
- Age 60-85 years
- Early AD (MCI due to AD or mild AD dementia)
- MMSE score 22-30
- Clinical Dementia Rating 0.5 or 1.0
- Amyloid positivity by PET or CSF
- Stable AD medications
- History of stroke within 24 months
- Active psychiatric condition
- Significant cardiovascular disease
- Evidence of cerebral amyloid angiopathy
- Prior anti-amyloid therapy within 5 years
- Incidence of ARIA-E: Percentage of participants experiencing any occurrence of ARIA-E (amyloid-related imaging abnormality-edema/effusion) during the treatment period.
Efficacy:
- Change from baseline in amyloid plaque burden (Centiloids)
- Change from baseline in ADAS-Cog14
- Change from baseline in CDR-SB
Safety:
- Incidence of ARIA-H (any and symptomatic)
- Treatment-emergent adverse events
- Severe ARIA requiring hospitalization
- Plasma p-tau217 (phosphorylated tau)
- CSF Alzheimer biomarkers
- Amyloid PET SUVR
- Tau PET (subset)
This trial has significant implications:
- Optimized Safety: Reduced ARIA may enable broader use
- Practical Benefits: Lower doses may reduce infusion frequency
- Population Access: May enable treatment of patients currently excluded (anticoagulated, cerebral amyloid angiopathy)
- Dose Selection: Results will inform optimal regimen for the Phase 4 program
The findings will help refine the risk-benefit profile of donanemab and inform shared decision-making between clinicians and patients.
¶ Safety Profile and Management
Known risk factors for ARIA include:
- ApoE4 carrier status: Higher ARIA risk (~2x)
- Baseline microhemorrhages: CMBs predict ARIA-H
- Higher dose: More intensive dosing increases risk
- Rapid plaque clearance: Speed of clearance correlates with ARIA
Pre-Treatment:
- Baseline MRI
- Genetic testing (ApoE optional)
During Treatment:
- MRI at Week 12, 24, 52
- Clinical monitoring at each infusion
- Patient/caregiver education
Management of ARIA:
- Temporary drug discontinuation
- Corticosteroid treatment for symptomatic ARIA-E
- Dose reduction upon re-initiation
| Trial |
Dose |
ARIA-E Rate |
ARIA-H Rate |
| TRAILBLAZER-ALZ 2 |
High loading |
24% |
18% |
| TRAILBLAZER-ALZ 3 |
Maintenance |
15% |
12% |
| TRAILBLAZER-ALZ 6 |
Various |
TBD |
TBD |
- Phase 1 (NCT01873061): First-in-human
- Phase 2 TRAILBLAZER-ALZ (NCT02624778): Dose-finding
- Phase 3 TRAILBLAZER-ALZ 2 (NCT03528590): Registration trial - Approved 2024
- Phase 3 TRAILBLAZER-ALZ 6 (NCT05738486): Dosing optimization
- Phase 3 TRAILBLAZER-ALZ 3 (NCT04640077): Prevention trial
Results from TRAILBLAZER-ALZ 6 may support:
- Label modification: Updated dosing recommendations
- Expanded indication: Access for higher-risk populations
- New contraindication language: If certain risks identified
The trial was conducted at multiple centers globally:
- Chandler, Arizona
- Irvine, California
- Long Beach, California
- Sherman Oaks, California
- Atlantis, Florida
- Canada
- United Kingdom
- Germany
- Japan
- Australia