Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease, BAN2401, Lecanemab
Brief summary
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.
Interventions
DRUGLecanemab 2.5 mg/kg
2.5 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion
DRUGLecanemab 5.0 mg/kg
5.0 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion
10 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion.
DRUGPlacebo
biweekly (once every 2 weeks) administered as i.v. infusion
Sponsors
Eisai Inc.
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria (Core Study) for Mild Cognitive Impairment due to Alzheimer's Disease \- Intermediate likelihood: 1. 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 2. Subjects who have a CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline 3. 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: 1. Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia 2. 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: 1. 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): 1. Less than or equal to 15 for age 50 to 64 years 2. Less than or equal to 12 for age 65 to 69 years 3. Less than or equal to 11 for age 70 to 74 years 4. Less than or equal to 9 for age 75 to 79 years 5. Less than or equal to 7 for age 80 to 90 years 2. Positive amyloid load as indicated by PET or CSF assessment 1. PET assessment of imaging agent uptake into brain 2. CSF assessment of Aβ(1-42) 3. Age between 50 and 90 years, inclusive 4. Mini Mental State Examination (MMSE) score equal to or greater than 22, and equal to or less than 30, at Screening and Baseline 5. Body Mass Index (BMI) greater than 17 and less than 35 at Screening or Baseline 6. 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. 7. 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. 8. Subjects must have identified caregivers/informants 9. Subjects must provide written informed consent Inclusion Criteria (Extension Phase): 1. 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: 1. Alzheimer's Related Imaging Abnormality-Edema (ARIA-E) 2. Amyloid related imaging abnormality hemorrhage (ARIA-H) (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage) 3. Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase 4. Subjects who were APOE4 positive and receiving treatment with lecanemab 10 mg/kg biweekly 5. 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 2. 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 3. 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). 4. Must be able to physically attend clinic visits and be willing and able to comply with all aspects of the protocol Key
Exclusion criteria
(Core study): 1. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject's AD 2. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening 3. Any psychiatric diagnosis or symptoms, (e.g., hallucinations, major depression, or delusions) that could interfere with study procedures in the subject 4. Geriatric Depression Scale (GDS) score ≥8 at Screening 5. 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 6. 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 7. A prolonged QT/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated electrocardiogram (ECG) 8. Certain other specified medical conditions 9. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Study Phase: Change From Baseline in Alzheimer's Disease Composite Score (ADCOMS) at Month 12 | 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) | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Amyloid plaque load was identified by PET using 2 tracers (florbetapir and flutemetamol). The imaging uptake was determined via standard uptake value ratio (SUVr) versus a reference region. The SUVr is a quantitative tool and refers to the ratio of the global cortical average as compared to a reference region of choice. Whole cerebellum mask was used as the reference region of choice in this study. PET SUVr values were converted to Centiloid units. Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition. |
| Core Study Phase: Change From Baseline in ADCOMS at Month 18 | Core Study Phase: at Month 18 | The ADCOMS is a composite score that comprises 4/14 items from the ADAS-cog, 2 items from the MMSE, and all items from the 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. |
| 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 | The CDR is a clinical scale that describes 5 degrees of impairment in performance on each of 6 categories of function including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The ratings of degree of impairment obtained on each of the 6 categories of function are synthesized into 1 global rating of dementia CDR score (ranging from 0 to 3). A sum of boxes score provides an additional measure of change where each category has a maximum possible score of 3 points and the total score is a sum of the category scores giving a total possible score of 0 to 18 with higher scores indicating more impairment. |
| 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 | The ADAS-Cog is a cognitive scale which evaluates 14 items- memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope), constructional praxis (copying geometric designs), spoken language, language comprehension, word finding difficulty, ability to remember test instructions, maze, and number cancellation. The total score ranges from 0 to 90. Higher score indicates greater cognitive impairment. |
| 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 | The measurement of the amyloid proteins- Aβ(1-42) (amyloid beta monomer from amino acid 1 to 42), total (t)-tau, and phospho (p)-tau in CSF have been shown to be important biomarkers for alzheimer's disease. |
| 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 | Total hippocampal volume is measured by volumetric magnetic resonance imaging (vMRI). Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total hippocampal volume is calculated by summing up right and left hippocampal volumes. |
| 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 | Left and right hippocampal volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Left and right hippocampal volumes represent a summary measure in the left and right hippocampal regions. |
| 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 | Whole brain volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Whole brain volume represents a summary measure of total brain parenchyma which includes the cerebrum, basal ganglia, diencephalon, and cerebellum. |
| 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 | Total ventricular volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total ventricular volume represents a summary measure of total including right and left lateral ventricles, third ventricle and fourth ventricle of brain. |
| 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 | Amyloid plaque load was identified by PET using 2 tracers (florbetapir and flutemetamol). The imaging uptake was determined via standard uptake value ratio (SUVr) versus a reference region. The SUVr is a quantitative tool and refers to the ratio of the global cortical average as compared to a reference region of choice. Whole cerebellum mask was used as the reference region of choice in this study. PET SUVr values were converted to Centiloid units. Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition. Change from OLE baseline was analyzed using the Mixed Model for Repeated Measures (MMRM) with Core Study treatment group, visit, Core Study treatment group by visit interaction, APOE4 status as fixed effects, and OLE baseline value and Gap duration as covariates. |
| 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 | Amyloid plaque load was identified by PET using 2 tracers (florbetapir and flutemetamol). The imaging uptake was determined via standard uptake value ratio (SUVr) versus a reference region. The SUVr is a quantitative tool and refers to the ratio of the global cortical average as compared to a reference region of choice. Whole cerebellum mask was used as the reference region of choice in this study. PET SUVr values were converted to Centiloid units. Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition. Change from end of core study at the baseline of OLE phase was summarized using change from core study baseline at each visit. |
| OLE Phase: Percentage of Amyloid Positive Participants Over Time | OLE Phase: Baseline, at Months 3, 6, 12, 24, 36 and 48 | Percentage of amyloid positive participants over time was reported. Participants who had Amyloid PET (using Centiloid scales) values greater than or equal to 30.00 were considered as amyloid positive. |
Countries
Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This study has been conducted in two phases: Core Study Phase and an Open-Label Extension (OLE) Phase. Participants took part in the Core study at 149 investigative sites across the North America, Europe and Asia-Pacific. The OLE Phase was conducted at 56 investigative sites across the United States, Europe and Asia-Pacific.
Pre-assignment details
A total of 3267 participants were screened, of which 2411 participants were screen failures, and 856 participants were randomized. Out of 856, 854 participants were treated in Core Study Phase, and 180 participants were enrolled and treated in OLE Phase.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 42 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 816 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Chinese | 0 Participants |
| Race/Ethnicity, Customized Japanese | 0 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized Other Asian | 18 Participants |
| Race/Ethnicity, Customized White | 49 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 245 | 2 / 52 | 0 / 51 | 1 / 92 | 2 / 253 | 0 / 161 | 5 / 180 |
| other Total, other adverse events | 212 / 245 | 46 / 52 | 48 / 51 | 80 / 92 | 237 / 253 | 135 / 161 | 169 / 180 |
| serious Total, serious adverse events | 43 / 245 | 10 / 52 | 4 / 51 | 16 / 92 | 31 / 253 | 25 / 161 | 60 / 180 |
Outcome results
None listed