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

Preclinical Alzheimer's Disease Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04468659
• Other study ID #: BAN2401-G000-303
• Secondary ID: R01AG054029R01AG
• Status: Recruiting
• Phase: Phase 3
• Start date: July 14, 2020
• Est. completion date: February 15, 2029

Study information

• Verified date: January 2024
• Source: Eisai Inc.
• Contact: Eisai Medical Information
• Phone: +1-888-274-2378
• Email: esi_medinfo[@]eisai.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1400
• Est. completion date: February 15, 2029
• Est. primary completion date: February 15, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Amyloidosis
• Early Preclinical Alzheimer's Disease
• Preclinical Alzheimer's Disease

Intervention

Drug:
• Lecanemab
IV infusion.
• Placebo
IV infusion.

Locations

Country	Name	City	State
Australia	CALHN Memory Trials	Adelaide	South Australia
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Austin Hospital - Medical and Cognitive Research Unit	Ivanhoe	Victoria
Australia	Australian Alzheimer's Research Foundation	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Canada	Parkwood Institute Main Building	London	Ontario
Canada	McGill University / Jewish General Hospital Memory Clinic	Montreal	Quebec
Canada	True North Clinical Research Inc.	New Minas	Nova Scotia
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto Memory Program	Toronto	Ontario
Japan	Eisai Trial Site #4	Bunkyo-ku	Tokyo
Japan	Eisai Trial Site #9	Fukuoka-shi	Fukuoka
Japan	Eisai Trial Site #1	Hachioji -shi	Tokyo
Japan	Eisai Trial Site #7	Itabashi-ku	Tokyo
Japan	Eisai Trial Site #10	Kamakura-shi	Kanagawa
Japan	Eisai Trial Site #13	Kobe-shi	Hyogo
Japan	Eisai Trial Site #8	Kodaira-shi	Tokyo
Japan	Eisai Trial Site #11	Kyoto-shi	Kyoto
Japan	Eisai Trial Site #2	Obu-shi	Aichi
Japan	Eisai Trial Site #6	Osaka-shi	Osaka
Japan	Eisai Trial Site #5	Sendai-shi	Miyagi
Japan	Eisai Trial Site #3	Shinjuku-Ku	Tokyo
Japan	Eisai Trial Site #12	Suita-shi	Osaka
Netherlands	Brain Research Center	Amsterdam
Singapore	National University Hospital	Singapore
Spain	Barcelona Beta Brain Research Center	Barcelona
Spain	Fundació ACE	Barcelona
Spain	Hospital Universitario Quirón Salud Madrid	Madrid
Spain	Fundacion CITA ALZHEIMER	San Sebastian
Spain	Hospital Universitario Marqués de Valdeciila	Santander
Sweden	Memory Clinic, Skåne University Hospital	Malmo
Sweden	Memory Clinic Sahlgrenska University Hospital	Molndal
Sweden	Karolinska University Hospital	Stockholm
United Kingdom	Bristol Brain Centre	Bristol
United Kingdom	Glasgow Memory Clinic	Glasgow
United Kingdom	Imperial Memory Unit	London
United Kingdom	St Pancras Clinical Research	London
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	University of Michigan (UMICH)	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Case Western Reserve University/University Hospitals	Beachwood	Ohio
United States	University of Alabama, Birmingham	Birmingham	Alabama
United States	Boston University	Boston	Massachusetts
United States	Brigham and Woman's Hospital Center for Alzheimer Research and Treatment	Boston	Massachusetts
United States	Ralph H. Johnson VA Medical Center	Charleston	South Carolina
United States	Roper St. Francis Healthcare	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Cleveland	Ohio
United States	Columbus Memory Center, PC	Columbus	Georgia
United States	Ohio State University	Columbus	Ohio
United States	Advanced Clinical Research Network, Corp	Coral Gables	Florida
United States	Neurology Clinic, P.C.	Cordova	Tennessee
United States	University of Texas, Southwestern MC at Dallas	Dallas	Texas
United States	Brain Matters Research	Delray Beach	Florida
United States	Duke Health Center	Durham	North Carolina
United States	University of Kansas	Fairway	Kansas
United States	University of North Texas Health Sciences Center	Fort Worth	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	Houston Methodist Neurological Institute	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	UCI MIND	Irvine	California
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	K2 Medical Research	Maitland	Florida
United States	AMC Research	Matthews	North Carolina
United States	Gonzalez MD & Aswad MD Health Sciences	Miami	Florida
United States	Wien Center for Clinical Research	Miami Beach	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Eastern Virginia Medical School	Norfolk	Virginia
United States	Keystone Clinical Studies, LLC	Norristown	Pennsylvania
United States	Renstar Medical Research	Ocala	Florida
United States	Synexus Clinical Research	Orlando	Florida
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Banner Alzheimer's Institute	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Donald S.Marks, M.D.,P.C.	Plymouth	Massachusetts
United States	Progressive Medical Research	Port Orange	Florida
United States	Oregon Health & Science University	Portland	Oregon
United States	Summit Research Network, Oregon	Portland	Oregon
United States	Butler Hospital Memory and Aging Program	Providence	Rhode Island
United States	Rhode Island Hospital	Providence	Rhode Island
United States	National Clinical Research, Inc	Richmond	Virginia
United States	Mayo Clinic, Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Washington University	Saint Louis	Missouri
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Sharp Mesa Vista Hospital	San Diego	California
United States	Univeristy of California, San Francisco	San Francisco	California
United States	SIBCR	Seattle	Washington
United States	University of Washington Memory and Brain Wellness Center	Seattle	Washington
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	University of South Florida - Health Byrd Alzheimer Institute	Tampa	Florida
United States	Synexus Clinical Research	The Villages	Florida
United States	Advanced Memory Research Institute of New Jersey	Toms River	New Jersey
United States	Central States Research, LLC	Tulsa	Oklahoma
United States	University of California, Davis	Walnut Creek	California
United States	Georgetown University	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia
United States	Alzheimer's Research and Treatment Center	Wellington	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Charter Research	Winter Park	Florida

Sponsors (4)

Lead Sponsor	Collaborator
Eisai Inc.	Alzheimer's Clinical Trials Consortium, Biogen, National Institute on Aging (NIA)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Japan,  Netherlands,  Singapore,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	A3 Trial: Change From Baseline in Amyloid Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216		Baseline, Week 216
Secondary	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
Secondary	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
Secondary	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
Secondary	A3 Trial: Change From Baseline in tau Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at Week 216		Baseline, Week 216