Efficacy and Safety Evaluation of Lecanemab in Early Alzheimer's Disease: A Placebo-Controlled, Double-Blind, Parallel-Group Study with Open-Label Extension

Trial ID: 2024-510887-22-00
Protocol: BAN2401-G000-301
Sponsor: Eisai Limited

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Diseases & Conditions

Dementia Alzheimer's type Prodromal Alzheimer's disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of BAN2401 in subjects with early Alzheimer's disease (EAD) by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months of treatment. This is clinically relevant as it aims to assess the potential of BAN2401 to slow cognitive decline in patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia.

Secondary objectives include: - Determining whether BAN2401 is superior to placebo in reducing brain amyloid levels as measured by amyloid positron emission tomography (PET) using Centiloids at 18 months. - Evaluating the efficacy of BAN2401 by determining its superiority compared with placebo on the change from baseline in the AD Assessment Scale–Cognitive Subscale14 (ADAS-cog14) at 18 months of treatment. - Assessing the efficacy of BAN2401 by determining its superiority compared with placebo on the change from baseline in the AD composite score (ADCOMS) at 18 months of treatment. - Evaluating the efficacy of BAN2401 by determining its superiority compared with placebo on the change from baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL) at 18 months of treatment.

Participants

The clinical trial involves a total of **1558 participants** diagnosed with **mild cognitive impairment due to Alzheimer's disease** or mild Alzheimer's disease dementia. The study population includes both male and female subjects aged between **50 and 90 years**. Participants were selected based on specific inclusion criteria, including a **body mass index (BMI)** greater than 17 and less than 35, and a stable dose of any approved Alzheimer's disease treatment, if applicable, for at least 12 weeks prior to the baseline. Additionally, participants must have a **positive biomarker for brain amyloid pathology** and an **MMSE score** between 22 and 30 at screening and baseline. The trial also requires participants to have an identified study partner who can provide support and follow-up information throughout the study. The population includes individuals who are considered vulnerable, and the trial does not restrict participation based on lifestyle factors such as diet or physical activity. The selection process ensures that participants meet the necessary clinical criteria to evaluate the efficacy and safety of BAN2401 in early Alzheimer's disease.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **Lecanemab**, a **monoclonal antibody**, in subjects with early Alzheimer's disease, specifically those with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia. The study is structured as a randomized, double-blind, placebo-controlled trial with a parallel-group design, followed by an open-label extension phase. The core study duration is 18 months, with an additional extension phase to assess long-term safety and efficacy. Participants will receive **Lecanemab** as a **concentrate for solution for infusion** administered via intravenous use, with a maximum daily dose of 10 mg/kg over a treatment period of up to 48 weeks.

The trial includes several key study visits. The initial inclusion visit, or screening, will determine participant eligibility based on criteria such as age, cognitive impairment, and biomarker status for brain amyloid pathology. Following successful screening, participants will be randomized to receive either the investigational product or placebo. Regular follow-up visits will occur throughout the 18-month core study to monitor changes in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) and other cognitive assessments. The end-of-study visit will evaluate the primary endpoint, which is the change from baseline in the CDR-SB. Secondary endpoints include changes in amyloid PET imaging, ADAS-cog14, and other cognitive measures.

Participant involvement is expected to last for the entire duration of the core study, approximately 18 months, with the possibility of continuing into the extension phase. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of **Lecanemab** in the target population, contributing to the understanding of its potential as a treatment for early Alzheimer's disease.

Treatment

The clinical trial involves the administration of **Lecanemab**, a monoclonal antibody, as the experimental medication. Lecanemab is provided in the pharmaceutical form of a **concentrate for solution for infusion**. The active substance, lecanemab, is derived from a protein of other origin. The medication is administered via the **intravenous route**. The dosing regimen for Lecanemab is set at a maximum daily dose of 10 mg/kg, with the same maximum total dose amount. The treatment period extends up to 48 weeks. The product is not formulated for pediatric use and is not classified as an orphan drug. The sponsor product code for Lecanemab is BAN2401, and it is manufactured by EISAI LTD.

In this study, a **placebo** is used as the comparator treatment. The trial is designed as a placebo-controlled, double-blind, parallel-group study with an open-label extension phase. The primary objective is to evaluate the efficacy of BAN2401 in subjects with early Alzheimer's disease by comparing it to the placebo based on changes in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) over an 18-month treatment period. The extension phase aims to assess the long-term safety and tolerability of BAN2401, as well as the maintenance of its effects over time.

Efficacy

The efficacy of BAN2401 in subjects with early Alzheimer's disease will be assessed by evaluating the change from baseline in the **Clinical Dementia Rating–Sum of Boxes (CDR-SB)** at 18 months of treatment. This primary endpoint will determine the superiority of BAN2401 compared to placebo. The CDR-SB is a validated scale used to quantify the severity of symptoms of dementia, providing a comprehensive measure of cognitive and functional performance.

Secondary endpoints include changes from baseline in amyloid PET using Centiloids for brain amyloid levels, ADAS-cog14, ADCOMS, and ADCS MCI-ADL at 18 months. These measures will provide additional insights into the cognitive and functional effects of BAN2401. The amyloid PET assessment will be used to evaluate changes in brain amyloid levels, which are indicative of Alzheimer's disease progression.

The schedule for measuring these efficacy parameters includes assessments at baseline and at the 18-month mark. Data collection will involve the use of standardized and validated tools to ensure accuracy and reliability. The analysis will focus on comparing the changes in these parameters between the BAN2401 and placebo groups to determine the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis; MCI due to AD–intermediate likelihood: Meet NIA-AA core clinical criteria for MCI due to AD–intermediate likelihood.
Diagnosis; MCI due to AD–intermediate likelihood: A global CDR score of 0.5 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
Diagnosis; MCI due to AD–intermediate likelihood: Report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; must be corroborated by an informant.
Diagnosis; Mild AD dementia: Meet NIA-AA core clinical criteria for probable AD dementia.
Diagnosis; Mild AD dementia: A global CDR score of 0.5 to 1.0 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Objective impairment in episodic memory as indicated by at least 1 SD below age-adjusted mean in the WMS-IV LMII, as follows a. ≤15 for age 50-64 years b. ≤12 for age 65-69 years c. ≤11 for age 70-74 years d. ≤9 for age 75-79 years e. ≤7 for age 80-90 years
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following: a. PET assessment of imaging agent uptake into brain. Note: amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility. b. CSF assessment of t-tau/Aβ[1-42] NOTE1: Subjects who are on anticoagulant therapy may not participate in CSF assessments. NOTE2: Subjects may consent to both the PET and CSF assessments, but to confirm eligibility, a positive amyloid result is needed in only 1 of the 2 procedures (ie, the subject will be eligible even if 1 of the 2 results does not meet its eligibility criterion). Subjects who consent to amyloid PET or CSF at Screening for the purposes of eligibility are not required to participate in the amyloid PET, tau PET, or CSF longitudinal substudies. Use of a historical amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility provided the subject had not participated in any clinical studies involving anti-amyloid therapies subsequent to the PET assessment. Historical PET will not suffice for the baseline assessment if the subject wishes to consent to the amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor to confirm amyloid positivity.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Male or female subjects aged ≥50, ≤90 years, at the time of informed consent.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: MMSE score greater than or equal to 22 at Screening and Baseline and less than or equal to 30 at Screening and Baseline.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: BMI >17 and <35 at Screening.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: If receiving an approved AD treatment, such as AChEIs, or memantine, or both for AD, must be on a stable dose for at least 12 weeks prior to Baseline. Treatment-naïve subjects for AD can be entered into the study. Unless otherwise stated, subjects must have been on stable doses of all other (ie, non-AD-related) permitted concomitant medications for at least 4 weeks prior to Baseline. Use of memantine will not be allowed for Japanese subjects.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must provide separate written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that the study partner can reliably fulfill the study requirements. A permanent study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. If in doubt about whether a subject's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. Study partners need to participate in person for visits where clinical assessment of CDR (global and CDR-SB), EQ-5D-5L, QOL-AD, ADCS MCIADL and Zarit Burden Interview take place.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Provide written informed consent. If a subject lacks capacity to consent in the investigator's opinion, the subject's assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study (eg Germany and Spain), they will not be enrolled.
Diagnosis; Key Inclusion Criteria that must be met by all subjects: Willing and able to comply with all aspects of the protocol.
Extension: See protocol for full details.

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Exclusion Criteria

Females who are breastfeeding or pregnant at screening or Baseline.
Females of childbearing potential who: a. Within 28 days before study entry, did not use a highly effective method of contraception b. Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after study drug discontinuation.
Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject's AD.
History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
Any psychiatric diagnosis or symptoms that could interfere with study procedures in the subject.
GDS score greater than or equal to 8 at Screening.
Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants.
Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD.
Other significant pathological findings on brain MRI at Screening - see protocol for further details.
Hypersensitivity to BAN2401 or any of the excipients, or 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.
Subjects with a bleeding disorder that is not under adequate control (including a platelet count <50,000 or INR >1.5 for subjects who are not on anticoagulant treatment. Subjects who are on anticoagulant therapy should have their anticoagulant status optimized and be on a stable dose for 4 weeks before Screening. Subjects who are on anticoagulant therapy are not permitted to participate in CSF assessments.
Have TSH above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all subjects whether or not they are taking thyroid supplements.
Abnormally low serum vitamin B12 levels for the testing laboratory.
Known to be HIV positive.
Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the investigator require further investigation.
Subjects with malignant neoplasms within 3 years of Screening.
Answer "yes" to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, 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. Subjects who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if in the clinical opinion of the investigator, this is due to the subject taking prior/concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.
Any other medical conditions which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments.
Subjects who are taking prohibited medications.
Participation in a clinical study involving any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening, unless it can be documented that the subject was randomized to placebo.
Participation in a clinical study involving any anti-amyloid therapies (including any monoclonal antibody therapies and any BACE inhibitor therapies) unless it can be documented that the subject only received placebo.
Subjects who have any known prior exposure to BAN2401.
Subjects who were dosed in a clinical study involving any new chemical entities for AD within 6 months prior to Screening unless it can be documented that the subject was in a placebo treatment arm.
Participated in 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 subject was in a placebo treatment arm.
Planned surgery which requires general anesthesia that would take place during the study.
Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately. Extension: See protocol for full details.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	01 Aug 2019	61
Germany	Not Recruiting	01 Aug 2019	36
Italy	Not Recruiting	01 Aug 2019	79
Spain	Not Recruiting	01 Aug 2019	142
Sweden	Not Recruiting	01 Aug 2019	30