Clinical trial NCT04468659: 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
Official title: AHEAD 3-45 Study: A Placebo-Controlled, Double-Blind, Parallel-Treatment Arm, 216 Week Study With an Extension Phase 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Preclinical Alzheimer's Disease
Early Preclinical Alzheimer's Disease
Keywords: BAN2401
Preclinical Alzheimer's disease
Elevated amyloid
Early preclinical Alzheimer's disease
Intermediate amyloid
A45 Trial
A3 Trial
AHEAD 3-45
Lecanemab
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Alzheimer's Clinical Trials Consortium
name: Biogen
name: National Institute on Aging (NIA)
First posted: 2020-07-13
Enrollment: 1400
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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). This study will also evaluate the long-term safety and tolerability of lecanemab in participants enrolled in the Extension Phase.


Eligibility criteria: Inclusion criteria:

Participants must meet all of the following criteria to be included in this study:

1. 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 plasma biomarker results, PET imaging, or CSF testing
2. Global Clinical Dementia Rating (CDR) score of 0 at screening
3. Mini Mental State Examination score greater than or equal to (\>=) 27 (with educational adjustments) at screening.
4. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at screening of \>=6
5. 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
6. 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
7. Provide written (or electronic, if allowed per country-specific regulations) informed consent
8. Willing and able to comply with all aspects of the protocol

For extension phase :

1. Completed the Core Study, or meet the following progression criteria during the Core Study:

   * Two consecutive CDR visits with Global Scores \> zero when measured at least 6 months apart within the Core Study
   * The principal investigator's confirmation that the participant has clinically declined consistent progression to EAD
2. Must continue to have a study partner who is willing and able to provide follow-up information on the participant throughout the course of the Extension Phase. The study partner must provide separate written informed consent for the Extension Phase. Study partners must continue to have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily functions
3. Provide written informed consent for the Extension Phase. If a participant lacks capacity to consent in the investigator's opinion, the participant's assent should be obtained, if required and in accordance with local laws, regulations, and customs, plus the written informed consent of a legal representative (capacity to consent and the definition of a legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit participants who lack capacity to consent to participate in this study (example, Spain), they will not be enrolled
4. 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:

1. Females who are breastfeeding or pregnant at screening or baseline
2. 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
3. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of screening
4. 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
5. 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
6. Hypersensitivity to any monoclonal antibody treatment
7. 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
8. Bleeding disorder that is not under adequate control (including a platelet count \<50,000 or international normalized ratio \[INR\] \>1.5) at screening
9. 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
10. Known to be human immunodeficiency virus (HIV) positive
11. 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
12. 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
13. 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
14. 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
15. Taking prohibited medications
16. Participation in a clinical study involving:

    * Any anti-amyloid plaque lowering 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 randomization 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
17. Planned surgery during the pre-randomization phase or within 3 months of randomization, which requires general anesthesia

For extension phase:

1. Discontinued from the Core Study or from study treatment
2. Under study drug interruption due to ARIA or other AE at the time of transition to the extension phase

Primary outcomes:
measure: A45 Trial: Change From Baseline in Preclinical Alzheimer Cognitive Composite 5 (PACC5) Score at Week 216
timeFrame: Baseline, Week 216
measure: A3 Trial: Change From Baseline in Amyloid Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216
timeFrame: Baseline, Week 216
Secondary outcomes:
measure: A45 Trial: Change From Baseline in Amyloid Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Weeks 96 and 216
timeFrame: Baseline, Week 96, Week 216
measure: A45 Trial: Change From Baseline in tau Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Weeks 96 and 216
timeFrame: Baseline, Week 96, Week 216
measure: A45 Trial: Change From Baseline in Cognitive Function Index (CFI) at Week 216
timeFrame: Baseline, Week 216
measure: A3 Trial: Change From Baseline in tau Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216
timeFrame: Baseline, Week 216
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Irvine
country: United States
facility: UCI MIND
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: Sharp Mesa Vista Hospital
state: California
city: San Francisco
country: United States
facility: Univeristy of California, San Francisco
state: California
city: Walnut Creek
country: United States
facility: University of California, Davis
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Coral Gables
country: United States
facility: Advanced Clinical Research Network, Corp
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Lady Lake
country: United States
facility: K2 Medical Research - The Villages
state: Florida
city: Maitland
country: United States
facility: K2 Medical Research, Llc
state: Florida
city: Maitland
country: United States
facility: K2 Medical Research
state: Florida
city: Miami Beach
country: United States
facility: Wien Center for Clinical Research
state: Florida
city: Miami
country: United States
facility: Gonzalez MD & Aswad MD Health Sciences
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Orlando
country: United States
facility: Synexus Clinical Research
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Health Byrd Alzheimer Institute
state: Florida
city: The Villages
country: United States
facility: Synexus Clinical Research
state: Florida
city: Wellington
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: Winter Park
country: United States
facility: Charter Research
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Columbus
country: United States
facility: Columbus Memory Center, PC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Fairway
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Woman's Hospital Center for Alzheimer Research and Treatment
state: Massachusetts
city: Plymouth
country: United States
facility: Donald S.Marks, M.D.,P.C.
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan (UMICH)
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: Toms River
country: United States
facility: Advanced Memory Research Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke Health Center
state: North Carolina
city: Matthews
country: United States
facility: AMC Research
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Beachwood
country: United States
facility: Case Western Reserve University/University Hospitals
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Tulsa
country: United States
facility: Central States Research, LLC
state: Oklahoma
city: Portland
country: United States
facility: Summit Research Network, Oregon
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Norristown
country: United States
facility: Keystone Clinical Studies, LLC
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Butler Hospital Memory and Aging Program
state: Rhode Island
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center
state: South Carolina
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, Southwestern MC at Dallas
state: Texas
city: Fort Worth
country: United States
facility: University of North Texas Health Sciences Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist Neurological Institute
state: Texas
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Richmond
country: United States
facility: National Clinical Research, Inc
state: Virginia
city: Seattle
country: United States
facility: University of Washington Memory and Brain Wellness Center
state: Washington
city: Seattle
country: United States
facility: SIBCR
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: CALHN Memory Trials
state: South Australia
city: Ivanhoe
country: Australia
facility: Austin Hospital - Medical and Cognitive Research Unit
state: Victoria
city: Nedlands
country: Australia
facility: Alzheimer's Research Australia
state: Western Australia
city: Hailfax
country: Canada
facility: Centricity Research
state: Nova Scotia
city: New Minas
country: Canada
facility: True North Clinical Research Inc.
state: Nova Scotia
city: New Minas
country: Canada
facility: True North Clinical Research
state: Nova Scotia
city: London
country: Canada
facility: Parkwood Institute Main Building
state: Ontario
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Obu-shi
country: Japan
facility: National Center for Geriatrics and Gerontology
state: Aichi
city: Fukuoka-shi
country: Japan
facility: Fukuoka University Hospital
state: Fukuoka
city: Kobe-shi
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Kamakura-shi
country: Japan
facility: Shonan Kamakura General Hospital
state: Kanagawa
city: Kyoto-shi
country: Japan
facility: Koseikai Takeda Hospital
state: Kyoto
city: Sendai-shi
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Osaka-shi
country: Japan
facility: Medical Corporation Heishinkai OPHAC Hospital
state: Osaka
city: Suita-shi
country: Japan
facility: Medical Corporation Heishinkai OPHAC Hospital
state: Osaka
city: Bunkyo-ku
country: Japan
facility: The University of Tokyo Hospital
state: Tokyo
city: Hachioji -shi
country: Japan
facility: P-One Clinic, Keikokai Medical Corporation
state: Tokyo
city: Itabashi-ku
country: Japan
facility: Tokyo Metropolitan Geriatric Hospital
state: Tokyo
city: Kodaira-shi
country: Japan
facility: National Center of Neurology and Psychiatry
state: Tokyo
city: Shinjuku-Ku
country: Japan
facility: ICR Clinical Research Hospital Tokyo
state: Tokyo
city: Singapore
country: Singapore
facility: National University Hospital
city: Barcelona
country: Spain
facility: Barcelona Beta Brain Research Center
city: Barcelona
country: Spain
facility: Fundació ACE
city: Madrid
country: Spain
facility: Hospital Universitario Quirón Salud Madrid
city: San Sebastian
country: Spain
facility: Fundacion CITA ALZHEIMER
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdeciila
city: Bristol
country: United Kingdom
facility: Bristol Brain Centre
city: Glasgow
country: United Kingdom
facility: Glasgow Memory Clinic
city: London
country: United Kingdom
facility: St Pancras Clinical Research
city: London
country: United Kingdom
facility: Imperial Memory Unit
Study officials:
References: