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

Eisai

Status and phase: Enrolling; Phase 3

Conditions: Preclinical Alzheimer's Disease; Early Preclinical Alzheimer's Disease

Treatments: Drug: Lecanemab; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT04468659

R01AG054029 (U.S. NIH Grant/Contract)

2020-004244-28 (EudraCT Number)

R01AG061848 (U.S. NIH Grant/Contract)

BAN2401-G000-303

Details and patient eligibility

About

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.

Enrollment: 1,400 estimated patients

Sex: All

Ages: 55 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,400 participants in 6 patient groups, including a placebo group

A45 Trial: Lecanemab 5 mg/kg + 10 mg/kg (Core Study)

Experimental group

Description:

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 in core study.

Treatment:

Drug: Lecanemab

A45 Trial: Placebo (Core Study)

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

A3 Trial: Lecanemab 5 mg/kg + 10 mg/kg (Core Study)

Experimental group

Description:

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 in core study.

Treatment:

Drug: Lecanemab

A3 Trial: Placebo (Core Study)

Placebo Comparator group

Description:

Participants will receive placebo (0.9% sodium chloride solution), administered as IV infusion, every four weeks from Week 0 to 216.

Treatment:

Drug: Placebo

A45 Trial: Lecanemab 10 mg/kg (Extension Phase)

Experimental group

Description:

Participants progressing to early Alzheimer's disease (EAD) during the core study (progressors) will receive lecanemab 10 mg/kg, administered as IV infusion, every two weeks after transition to the extension phase through to at least Week 216 from randomization in the core study. Participants completing the core study (completers) will enter extension phase and will receive lecanemab 10 mg/kg, administered as IV infusion, every two weeks for up to Week 312. Eligible participants receiving placebo in core study will continue to extension phase.

Treatment:

Drug: Lecanemab

A3 Trial: Lecanemab 10 mg/kg (Extension Phase)

Experimental group

Description:

Participants progressing to EAD during the core study (progressors) will receive lecanemab 10 mg/kg, administered as IV infusion, every two weeks after transition to the extension phase through to at least Week 216 from randomization in the core study. Participants completing the core study (completers) will enter extension phase and will receive lecanemab 10 mg/kg, administered as IV infusion, every two weeks for up to Week 312. Eligible participants receiving placebo in core study will continue to extension phase.

Treatment:

Drug: Lecanemab