A Study to Verify the Clinical Benefit of Aducanumab in Participants With Early Alzheimer's Disease

Study Overview
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Brief Summary
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The primary objective of this study is to verify the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score as compared with placebo in participants with early Alzheimer's disease.

Official Title
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A Phase 3b/4 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Verify the Clinical Benefit of Aducanumab (BIIB037) in Participants With Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Aducanumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: The participant must have confirmed amyloid beta pathology by cerebrospinal fluid (CSF) or amyloid PET Must have a history of subjective memory decline with gradual onset and slow progression over the 6 months before Screening, confirmed by study partner The participant must have 1 informant/care partner who, in the Investigator's opinion, has frequent and sufficient contact with the participant (at least 10 hours/week in person or by phone) as to be able to provide accurate information about the participant's cognitive and functional abilities over time Must meet all of the following clinical criteria for MCI due to Alzheimer's disease or mild Alzheimer's disease according to National Institute on Aging and Alzheimer's Association (NIA-AA) criteria Have an MMSE score between 22 and 30 inclusive Have a CDR memory score >0.5 Have a Clinical Dementia Rating Scale Global Score (CDR-GS) of 0.5 or 1.0 Have a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score of 85 or lower indicative of objective cognitive impairment Apart from a clinical diagnosis of early Alzheimer's disease, the participant must be in good health as determined by the Investigator based on medical history and screening assessments Must consent to apolipoprotein E (ApoE) genotyping. (Note: Participants are not required to be ApoE ε4 carriers) Key Exclusion Criteria: Any uncontrolled medical or neurological/neurodegenerative condition (other than Alzheimer's disease) that, in the opinion of the Investigator, might be a contributing cause of the participant's cognitive impairment Clinically significant and/or unstable psychiatric illness within 6 months prior to Screening Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening History of severe allergic or anaphylactic reactions or of hypersensitivity to any of the inactive ingredients in the drug product Participation in any study with purported disease-modifying effect in Alzheimer's disease within 12 months prior to Screening unless documentation of receipt of placebo is available Current use or previous use of medications with a purported disease-modifying effect in Alzheimer's disease, outside of investigational studies Use of any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the participant at higher risk for AEs, or impair the participant's ability to perform cognitive testing or complete study procedures Use of any investigational drug Prior exposure to aducanumab either commercially or by participation in a previous study with aducanumab. (Participants are eligible if they did not receive active aducanumab.) A negative PET scan result with any amyloid-targeting ligand within 12 months prior to Screening NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 60 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aducanumab<br>Participants will receive aducanumab, up to 10 milligrams per kilograms (mg/kg), monthly (once every four weeks), administered as intravenous (IV) infusion. | Drug: Aducanumab<br>* Administered as specified in the treatment arm.<br>* Other names: Aduhelm;|
| Placebo Comparator: Placebo<br>Participants will receive placebo, monthly (once every four weeks), administered as IV infusion. | Drug: Placebo<br>* Administered as specified in the treatment arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in CDR-SB Score at Week 78 | The CDR integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic participant examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. The Sum of boxes scoring methodology (CDR-SB) sums the score for each of the 6 domains and provides a value ranging from 0 to 18 with higher scores indicating greater impairment. Positive change from baseline indicates greater impairment. | Baseline, Week 78 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) Score at Weeks 78 and 106 | The iADRS composite captures decline in both cognition and daily function. The iADRS is a simple linear combination of Alzheimer's disease assessment scale, cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study scale for activities of daily living in mild cognitive impairment (ADCS-ADL-MCI). The iADRS scale ranges from 0-138, higher scores indicating better performance. | Baseline, Weeks 78 and 106 | 
| Change From Baseline in ADCS-ADL-MCI Score at Weeks 78 and 106 | The ADCS-ADL-MCI is a functional evaluation scale for MCI participants, based on information provided by an informant who rates 18 areas of daily living, with total score ranging from 0-53. Higher scores indicate greater independent, healthy functioning. Positive change from baseline indicates healthy functioning. | Baseline, Weeks 78 and 106 | 
| Change From Baseline in ADAS-Cog13 Score at Weeks 78 and 106 | The ADCS-ADAS-Cog13 is a brief objective cognitive assessment of the severity of cognitive symptoms of Alzheimer's disease. The ADAS-Cog13 score ranges from 0 to 85, with higher scores indicating worse performance. | Baseline, Weeks 78 and 106 | 
| Change From Baseline in Mini-Mental State Examination (MMSE) Score at Weeks 78 and 106 | The MMSE is a brief cognitive screening tool that provides clinicians the ability to rapidly assess cognitive ability in less than 10 minutes. The MMSE score ranges from 0-30, with higher scores indicating better performance. | Baseline, Weeks 78 and 106 | 
| Change From Baseline in Neuropsychiatric Inventory-10 (NPI-10) Score at Weeks 78 and 106 | The NPI-10 is a questionnaire administered to the informant, designed to obtain information on the presence of neuropsychiatric symptoms and behaviors in a participant with Alzheimer's disease. Ten areas are assessed: delusions, hallucinations, agitation/aggression, depression, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability and aberrant motor behavior. The NPI total score ranges from 0 to 120. Higher scores indicates greater impairment. | Baseline, Weeks 78 and 106 | 
| Change From Baseline in Amyloid Positron Emission Tomography (PET) Signal at Weeks 78 and 104 | The cerebral amyloid plaque level was measured by amyloid PET imaging. | Baseline, Weeks 78 and 104 | 
| Change From Baseline in Tau PET Signal at Weeks 78 and 104 | The cerebral tau level was measured by tau PET imaging. | Baseline, Weeks 78 and 104 | 
| Change From Baseline in CDR-SB Score at Week 106 | The CDR integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic participant examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. The Sum of boxes scoring methodology (CDR-SB) sums the score for each of the 6 domains and provides a value ranging from 0 to 18 with higher scores indicating greater impairment. Positive change from baseline indicates greater impairment. | Baseline, Week 106 | 
| Change From Baseline in Global Statistical Test (GST) Composite Z-Score | The GST is a composite z-score defined as the average of standardized z-scores of the CDR-SB, ADASCog13, and ADCS-ADL-MCI. A positive change from baseline indicates improvement. | Baseline, Weeks 78 and 106 |