A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian Adaptive Randomization Design and Dose Regimen-finding Study With an Open-Label Extension Phase to Evaluate Safety, Tolerability and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Eisai Inc.
- 入组人数
- 856
- 试验地点
- 168
- 主要终点
- Core Study Phase: Change From Baseline in Alzheimer's Disease Composite Score (ADCOMS) at Month 12
研究概览
简要总结
This is a multinational, multicenter, double-blind, placebo-controlled, parallel-group study using a Bayesian design with response adaptive randomization across placebo or 5 active arms of lecanemab to determine clinical efficacy and to explore the dose response of lecanemab using a composite clinical score (ADCOMS). BAN2401-G000-201 Core study is an 18-month study in which 3 dose levels (2.5, 5, and 10 mg/kg) are given biweekly (once every 2 weeks) to separate groups of participants and 2 dose levels (5 and 10 mg/kg) are given monthly (once every 4 weeks) to separate groups of participants. Participants will be from 2 clinical subgroups: mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild Alzheimer's disease dementia. Frequent interim analyses will be conducted to continually update randomization allocation on the basis of the primary clinical endpoint. Any participant who completes the study treatment (Visit 42 [Week 79] of the Core study) or discontinues the Core Study will be eligible to participate in the Extension Phase, provided they meet the Extension Phase inclusion and exclusion criteria. Participants will receive 10 mg/kg biweekly for up to 60 months or until the drug is commercially available in the country, where the subject resides, or until the benefit-to-risk ratio from treatment with lecanemab is no longer considered favorable, whichever comes first. The Follow-up Visit in the Extension Phase will take place 3 months after the last dose of study drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 50 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(Core Study) for Mild Cognitive Impairment due to Alzheimer's Disease
- •- Intermediate likelihood:
- •Subjects who meet the National Institute of Aging - Alzheimer's Association (NIA-AA) core clinical criteria for mild cognitive impairment due to Alzheimer's disease - intermediate likelihood
- •Subjects who have a CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline
- •Subjects who report a history of subjective memory decline with gradual onset and slow progression over the last one year before Screening; MUST be corroborated by an informant
- •Key Inclusion Criteria (Core Study) for Mild Alzheimer's Disease Dementia:
- •Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia
- •Subjects who have a CDR score of 0.5-1.0 and a Memory Box score of 0.5 or greater at Screening and Baseline
- •Inclusion Criteria (Core Study) that must be met by all subjects:
- •Subjects with objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler Memory Scale - IV Logical Memory II (WMS-IV LMII):
- •Less than or equal to 15 for age 50 to 64 years
- •Less than or equal to 12 for age 65 to 69 years
- •Less than or equal to 11 for age 70 to 74 years
- •Less than or equal to 9 for age 75 to 79 years
- •Less than or equal to 7 for age 80 to 90 years
- •Positive amyloid load as indicated by PET or CSF assessment
- •PET assessment of imaging agent uptake into brain
- •CSF assessment of Aβ(1-42)
- •Age between 50 and 90 years, inclusive
- •Mini Mental State Examination (MMSE) score equal to or greater than 22, and equal to or less than 30, at Screening and Baseline
- •Body Mass Index (BMI) greater than 17 and less than 35 at Screening or Baseline
- •Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin assay [ß-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
- •Subjects on acetylcholinesterase inhibitor or memantine therapy or both for AD must be on a stable dose for at least 12 weeks prior to Baseline. Treatment naive subjects can be entered into the study. Unless otherwise stated, subjects must have been on stable doses of all other permitted concomitant medications (ie, non-AD related) for at least 4 weeks prior to Baseline.
- •Subjects must have identified caregivers/informants
- •Subjects must provide written informed consent
- •Inclusion Criteria (Extension Phase):
- •Subjects who have completed Visit 42 (Week 79) of the Core Study or who discontinued study drug during the Core Study due to any of the following reasons:
- •Alzheimer's Related Imaging Abnormality-Edema (ARIA-E)
- •Amyloid related imaging abnormality hemorrhage (ARIA-H) (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
- •Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase
- •Subjects who were APOE4 positive and receiving treatment with lecanemab 10 mg/kg biweekly
- •Any reason for discontinuation not related to prohibited medications, including any AE that was considered not related to study drug, and that was not severe or life-threatening
- •Must continue to have an identified caregiver or informant who is willing and able to provide follow-up information on the subject throughout the course of the Extension Phase
- •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).
- •Must be able to physically attend clinic visits and be willing and able to comply with all aspects of the protocol
排除标准
- •(Core study):
- •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 (TIA), stroke, or seizures within 12 months of Screening
- •Any psychiatric diagnosis or symptoms, (e.g., hallucinations, major depression, or delusions) that could interfere with study procedures in the subject
- •Geriatric Depression Scale (GDS) score ≥8 at Screening
- •Contraindications to MRI scanning, including cardiac pacemaker/ defibrillator, ferromagnetic metal implants, e,g., in skull and cardiac devices other than those approved as safe for use in MR scanners
- •Evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening, or other significant pathological findings on brain MRI at Screening
- •A prolonged QT/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated electrocardiogram (ECG)
- •Certain other specified medical conditions
- •Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately
- •Exclusion Criteria (Extension Phase):
- •Subjects who discontinued from the study drug or from the Core Study for reasons other than the following:
- •ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
- •Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase
- •Subjects who were APOE4 positive and receiving treatment with lecanemab 10 mg/kg biweekly
- •AE that was considered not related to study drug, and that was not severe or life-threatening
- •Females of childbearing potential who do not agree to use a highly effective method of contraception
- •Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.
研究组 & 干预措施
Core Study: Lecanemab 5.0 mg/kg biweekly
5.0 mg/kg biweekly
干预措施: Lecanemab 5.0 mg/kg (Drug)
Core Study: Lecanemab 2.5 mg/kg biweekly
2.5 mg/kg biweekly
干预措施: Lecanemab 2.5 mg/kg (Drug)
Core Study: Lecanemab 10 mg/kg biweekly
10 mg/kg biweekly
干预措施: Lecanemab 10 mg/kg (Drug)
Core Study: Lecanemab 5.0 mg/kg monthly
5.0 mg/kg monthly
干预措施: Lecanemab 5.0 mg/kg (Drug)
Core Study: Lecanemab 10 mg/kg monthly
10 mg/kg monthly
干预措施: Lecanemab 10 mg/kg (Drug)
Core Study: Lecanemab-matched Placebo
Matching placebo biweekly
干预措施: Placebo (Drug)
Extension Phase: Lecanemab 10 mg/kg
All participants who fulfill Extension Phase inclusion and exclusion criteria will have the option to participate in the Extension Phase to receive lecanemab 10 mg/kg biweekly for up to 60 months or until the benefit-to-risk ratio from treatment with lecanemab is no longer considered favorable, whichever comes first. Additionally, participants who have received Extension Phase treatment for at least 18 months may opt to enter the dosing regimen substudy during which they will receive either lecanemab 10 mg/kg once every 4 weeks (Q4W) or once every 3 months (Q3M).
干预措施: Lecanemab 10 mg/kg (Drug)
结局指标
主要结局
Core Study Phase: Change From Baseline in Alzheimer's Disease Composite Score (ADCOMS) at Month 12
时间窗: Core Study Phase: at Month 12
The ADCOMS is a composite score that comprises 4/14 items from the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), 2 items from the Mini Mental State Examination (MMSE), and all items from the Clinical Dementia Rating (CDR). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score means greater impairment. Change from baseline was analyzed using Bayesian analysis. Data presented are posterior mean and posterior standard deviation.
Core Study Phase: Number of Participants With All Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From first dose of the study drug (Week 1) up to 90 days after last dose of study drug (up to 21 months)
A TEAE is defined as an AE that emerged during treatment or within 90 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening (that is, the participant is at immediate risk of death from the adverse event as it occurs, this does not include an event that, has it occurred in a more severe form or is allowed to continue, might have cause death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect (in the child of a participant who is exposed to the study drug).
OLE Phase: Number of Participants With All TEAEs and SAEs
时间窗: From first dose of the study drug (Week 1) up to 30 days after last dose of study drug (up to 61 months)
A TEAE is defined as an AE that emerged during treatment or within 30 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening (that is, the participant is at immediate risk of death from the adverse event as it occurs, this does not include an event that, has it occurred in a more severe form or is allowed to continue, might have cause death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect (in the child of a participant who is exposed to the study drug).
次要结局
- Core Study Phase: Change From Baseline in Cerebrospinal Fluid (CSF) Biomarker Levels at Months 12 and 18(Core Study Phase: at Months 12 and 18)
- Core Study Phase: Change From Baseline at Months 12 and 18 in Brain Amyloid Pathophysiology as Measured by Amyloid Positron Emission Tomography (PET)(Core Study Phase: at Months 12 and 18)
- Core Study Phase: Change From Baseline in ADCOMS at Month 18(Core Study Phase: at Month 18)
- Core Study Phase: Change From Baseline in Clinical Dementia Rating- Sum of Boxes (CDR-SB) at Months 12 and 18(Core Study Phase: at Months 12 and 18)
- Core Study Phase: Change From Baseline in Alzheimer Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at Months 12 and 18(Core Study Phase: at Months 12 and 18)
- Core Study Phase: Change From Baseline in Total Hippocampal Volume at Months 6, 12 and 18(Core Study Phase: at Months 6, 12 and 18)
- Core Study Phase: Change From Baseline in Left and Right Hippocampal Volume at Months 6, 12 and 18(Core Study Phase: at Months 6, 12 and 18)
- Core Study Phase: Change From Baseline in Whole Brain Volume at Months 6, 12 and 18(Core Study Phase: at Months 6, 12 and 18)
- Core Study Phase: Change From Baseline in Total Ventricular Volume at Months 6, 12 and 18(Core Study Phase: at Months 6, 12 and 18)
- OLE Phase: Change From OLE Baseline in Brain Amyloid Levels as Measured by Amyloid PET(OLE Phase: at Months 3, 6, 12, 24, 36 and 48)
- OLE Phase: Change From End of Core Study at the Baseline of OLE Phase in Brain Amyloid Levels as Measured by Amyloid PET(Core Study: Baseline and at Month 18, OLE Phase: Baseline)
- OLE Phase: Percentage of Amyloid Positive Participants Over Time(OLE Phase: Baseline, at Months 3, 6, 12, 24, 36 and 48)