A Study of Donanemab (LY3002813) Compared With Aducanumab in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ 4)

Study Overview
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Brief Summary
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The main purpose of this study is to compare donanemab to aducanumab on brain amyloid plaque clearance in participants with early symptomatic Alzheimer's Disease (AD).

Official Title
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A Phase 3, Open-Label, Parallel-Group, 2-Arm Study to Investigate Amyloid Plaque Clearance With Donanemab Compared With Aducanumab-avwa in Participants With Early Symptomatic Alzheimer's Disease

Conditions
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Mild Cognitive Impairment (MCI), Alzheimer Disease

Intervention / Treatment
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* Drug: Donanemab
* Drug: Aducanumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gradual and progressive change in memory function reported by the participant or informant for ≥6 months. Meet florbetapir F18 PET scan criteria. A Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1. Must consent to apolipoprotein E (ApoE) genotyping Must have a mini mental state examination (MMSE) score between 20 and 30 Have a study partner who will provide written informed consent to participate, is in frequent contact with the participant (defined as at least 10 hours per week), and will accompany the participant to study visits or be available by telephone at designated times. Have adequate literacy, vision, and hearing for neuropsychological testing in the opinion of the investigator at the time of screening. Women not of childbearing potential may participate Exclusion Criteria: Significant neurological disease affecting the central nervous system (other than AD), that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson's disease, multiple concussions, history of transient ischemic attack or stroke, or epilepsy or recurrent seizures (except febrile childhood seizures). Current serious or unstable medical illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, psychiatric (including actively suicidal or deemed at risk of suicide, or current alcohol or substance abuse), immunologic, infectious, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses in this study; or has a life expectancy of approximately ≤24 months. History of clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions (including but not limited to erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis). History of bleeding disorder or use of medications with platelet anti-aggregant or anti-coagulant properties (unless aspirin at ≤325 milligram (mg). Have had prior or current treatment with donanemab or aducanumab Have known allergies to donanemab or aducanumab, related compounds, or any components of the formulation Prior or current participation in any immunotherapy study targeting Amyloid beta

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donanemab<br>Donanemab is administered intravenously (IV) every 4 weeks (Q4W). | Drug: Donanemab<br>* Participants received 700 milligram (mg) donanemab administered by intravenous (IV) infusion every 4 weeks (Q4W) for first three doses and then 1400 mg IV Q4W.<br>* Other names: LY3002813;|
| Active Comparator: Aducanumab<br>Aducanumab administered IV per US label. | Drug: Aducanumab<br>* Participants received aducanumab administered by IV infusion per US label (prescribing information/routine clinical practice).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Reach Complete Amyloid Plaque Clearance on Florbetapir F18 Positron Emission Tomography (PET) Scan (Superiority) on Donanemab Versus Aducanumab | Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease (AD). Amyloid PET scan assesses cerebral amyloid load using florbetapir tracer which is standardized into centiloids for evaluation of AD. Florbetapir exhibits high affinity specific binding to amyloid plaques. Centiloid values on centiloid scale is based on mean composite Standardized Uptake Value Ratio (SUVR) in cingulate, frontal, parietal and temporal cortexes using whole cerebellum as reference region. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. Complete brain amyloid plaque clearance is a binary outcome and is defined as a centiloid value <24.1 from the florbetapir F18 PET scan. | 6 Months | 
| Percentage of Participants Who Reach Complete Amyloid Plaque Clearance on Florbetapir F18 PET Scan in the Low/Medium (Intermediate) Subpopulation (Superiority) on Donanemab Versus Aducanumab | Complete brain amyloid plaque clearance is a binary outcome and is defined as a centiloid value <24.1 from the florbetapir F18 PET scan. | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Absolute Change From Baseline in Brain Amyloid Plaque on Florbetapir F18 PET Scan (Superiority) on Donanemab Versus Aducanumab | Florbetapir PET imaging was used as a quantitative amyloid biomarker. Quantitative amyloid burden was first formalized as the average Standardized Uptake Value Ratio (SUVR) in six predetermined cortical areas of the brain relative to the cerebellum as a reference region. Larger SUVR reflects the larger cortical amyloid burden relative to cerebellum. SUVR values were further calibrated to a centiloid (CL) scale. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan. A negative change indicates an improvement from baseline. | Baseline, 6 Months | 
| Mean Percent Change From Baseline in Brain Amyloid Plaque on Florbetapir F18 PET Scan (Superiority) Donanemab Versus Aducanumab | Florbetapir PET imaging was used as a quantitative amyloid biomarker. Quantitative amyloid burden was first formalized as the average Standardized Uptake Value Ratio (SUVR) in six predetermined cortical areas of the brain relative to the cerebellum as a reference region. Larger SUVR reflects the larger cortical amyloid burden relative to cerebellum. SUVR values were further calibrated to a centiloid (CL) scale. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan. A negative change indicates an improvement from baseline. | Baseline, 6 Months | 
| Change From Baseline in Brain Amyloid Plaque on Florbetapir F18 PET Scan in the Low/Medium (Intermediate) Tau Subpopulation (Superiority) on Donanemab Versus Aducanumab | Florbetapir PET imaging was used as a quantitative amyloid biomarker. Quantitative amyloid burden was first formalized as the average Standardized Uptake Value Ratio (SUVR) in six predetermined cortical areas of the brain relative to the cerebellum as a reference region. Larger SUVR reflects the larger cortical amyloid burden relative to cerebellum. SUVR values were further calibrated to a centiloid (CL) scale. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan. A negative change indicates an improvement from baseline. | Baseline, 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease with MCI or Mild Dementia