AHEAD 3-45 Study: A Study to Evaluate Efficacy and Safety of Treatment With Lecanemab in Participants With Preclinical Alzheimer's Disease and Elevated Amyloid and Also in Participants With Early Preclinical Alzheimer's Disease and Intermediate Amyloid

Study Overview
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Brief Summary
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The primary purpose of this study is to determine whether treatment with lecanemab is superior to placebo on change from baseline of the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks of treatment (A45 Trial) and to determine whether treatment with lecanemab is superior to placebo in reducing brain amyloid accumulation as measured by amyloid positron emission tomography (PET) at 216 weeks of treatment (A3 Trial).

Official Title
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AHEAD 3-45 Study: A Placebo-Controlled, Double-Blind, Parallel-Treatment Arm, 216 Week Study to Evaluate Efficacy and Safety of Treatment With BAN2401 in Subjects With Preclinical Alzheimer's Disease and Elevated Amyloid (A45 Trial) and in Subjects With Early Preclinical Alzheimer's Disease and Intermediate Amyloid (A3 Trial)

Conditions
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Preclinical Alzheimer's Disease, Early Preclinical Alzheimer's Disease

Intervention / Treatment
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* Drug: Lecanemab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants must meet all of the following criteria to be included in this study: Male or female, age 55 to 80 years inclusive at the time of informed consent, with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid at Screening or known before Screening to have elevated or intermediate amyloid according to previous PET, cerebrospinal fluid (CSF), or plasma testing • Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity less than (<) 65 years, before screening: First degree relative diagnosed with dementia onset before age 75, or Known to possess at least 1 apolipoprotein E4 variant (APOE4) allele, or Known before screening to have elevated brain amyloid according to previous PET or CSF testing Global Clinical Dementia Rating (CDR) score of 0 at screening Mini Mental State Examination score greater than or equal to (>=) 27 (with educational adjustments) at screening. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at screening of >=6 A45 Trial: Elevated brain amyloid pathology by amyloid PET: defined as approximately greater than (>) 40 Centiloids on screening scan A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: defined as approximately 20 to 40 Centiloids on screening scan Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the participant (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily function Provide written (or electronic, if allowed per country-specific regulations) informed consent Willing and able to comply with all aspects of the protocol Exclusion criteria: Participants who meet any of the following criteria will be excluded from this study: Females who are breastfeeding or pregnant at screening or baseline Females of childbearing potential who: • Within 28 days before study entry, did not use a highly effective method of contraception For sites outside of Europe, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of screening Current or history within the past 2 years of psychiatric diagnosis or symptoms that, in the opinion of the investigator, could interfere with study procedures Contraindications to 3 Tesla magnetic resonance imaging (MRI) scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (example, in-skull and cardiac devices other than those approved as safe for use in MRI scanners), or exhibit other significant pathological findings on brain MRI at Screening Hypersensitivity to any monoclonal antibody treatment Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study Bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5) at screening Results of laboratory tests conducted during screening that are outside the following limits: Thyroid stimulating hormone (TSH) above normal range Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for the testing laboratory (if participant is taking vitamin B12 injections, level should be at or above the LLN for the testing laboratory). A low vitamin B12 is exclusionary, unless the required follow-up labs (homocysteine and methylmalonic acid [MMA]) indicate that it is not physiologically significant Known to be human immunodeficiency virus (HIV) positive Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety Malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participants with treatment cycles completed at least 6 months before screening). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before screening need not be excluded Answer yes to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before screening, at screening, or at baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before screening Known or suspected history of drug or alcohol abuse or dependence within 2 years before screening or a positive urine drug test at screening. Participants who test positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse Taking prohibited medications Participation in a clinical study involving: Any anti-amyloid immunotherapy (example, therapeutic monoclonal antibody or active anti-amyloid vaccine) at any time, unless it can be documented that the participant was randomized to placebo or never received study drug Any immunoglobulin therapy, or vaccine within 6 months before Screening, unless it can be documented that the participant was randomized to placebo or never received study drug Lecanemab Any new chemical entities or investigational drug for AD within 6 months before screening unless it can be documented that the participant received only placebo Any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the participant was in a placebo treatment arm Planned surgery during the pre-randomization phase or within 3 months of randomization, which requires general anesthesia

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 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: A45 Trial: Lecanemab 5 mg/kg + 10 mg/kg<br>Participants will receive lecanemab 5 milligram per kilogram (mg/kg), administered as intravenous (IV) infusion, every two weeks from Week 0 to 6, then 10 mg/kg, administered as IV infusion, every two weeks from Week 8 to 94, and 10 mg/kg, administered as IV infusion, every four weeks from Week 96 to 216. | Drug: Lecanemab<br>* IV infusion.<br>* Other names: BAN2401;|
| Placebo Comparator: A45 Trial: Placebo<br>Participants will receive placebo (0.9 percent [%] sodium chloride solution), administered as IV infusion, every two weeks from Week 0 to 94, then every four weeks from Week 96 to 216. | Drug: Placebo<br>* IV infusion.<br>|
| Experimental: A3 Trial: Lecanemab 5 mg/kg + 10 mg/kg<br>Participants will receive lecanemab 5 mg/kg, administered as IV infusion, every four weeks from Week 0 to 4, then 10 mg/kg, administered as IV infusion, every four weeks from Week 8 to 216. | Drug: Lecanemab<br>* IV infusion.<br>* Other names: BAN2401;|
| Placebo Comparator: A3 Trial: Placebo<br>Participants will receive placebo (0.9% sodium chloride solution), administered as IV infusion, every four weeks from Week 0 to 216. | Drug: Placebo<br>* IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A45 Trial: Change From Baseline in Preclinical Alzheimer Cognitive Composite 5 (PACC5) Score at Week 216 | PACC5(5 components):Free/cued selective reminding test:number of words recalled without cuing/with cuing(0[worst]-96[best recall]);Delayed Paragraph Recall test: recall of 1 short story(25 bits information),immediately after reading and again after delay of 30 minutes (0[worst]-25[best recall]);Digit-symbol substitution test: Participant uses a key to fill in blank squares as fast as possible in 90 seconds(0[none]-91[best performance]);Mini Mental State Score:to evaluate orientation,memory,attention,concentration,naming,repetition,comprehension and ability to create sentence,to copy 2 overlapping pentagons, scored as number of correctly completed items(0[worse]-30[perfect performance]);Category fluency task: participants generate words in 60 second belonging to a semantic category(total score:number of appropriate words generated per task, higher values indicate better performance). | Baseline, Week 216 | 
| A3 Trial: Change From Baseline in Amyloid Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216 |  | Baseline, Week 216 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A45 Trial: Change From Baseline in Amyloid Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Weeks 96 and 216 |  | Baseline, Week 96, Week 216 | 
| A45 Trial: Change From Baseline in tau Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Weeks 96 and 216 |  | Baseline, Week 96, Week 216 | 
| A45 Trial: Change From Baseline in Cognitive Function Index (CFI) at Week 216 | CFI assessment to assess the participant's perceived ability to perform high-level functional tasks in daily life and sense of overall cognitive functional ability. Study participants (18 questions) and their study partners (15 questions) independently rate the participant's abilities. Total score combines participant and study partner scores, with higher scores indicating greater impairment. | Baseline, Week 216 | 
| A3 Trial: Change From Baseline in tau Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216 |  | Baseline, Week 216 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BAN2401, Preclinical Alzheimer's disease, Elevated amyloid, Early preclinical Alzheimer's disease, Intermediate amyloid, A45 Trial, A3 Trial, AHEAD 3-45, Lecanemab