Clinical trial NCT01767311: A Study to Evaluate Safety, Tolerability, and Efficacy of Lecanemab in Subjects With Early Alzheimer's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
BAN2401
Lecanemab
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biogen
First posted: 2013-01-14
Enrollment: 856
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Exclusion Criteria (Extension Phase):

1. Subjects who discontinued from the study drug or from the Core Study for reasons other than the following:

   1. ARIA-E
   2. 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. AE that was considered not related to study drug, and that was not severe or life-threatening
2. Females of childbearing potential who do not agree to use a highly effective method of contraception
3. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.

Primary outcomes:
measure: Core Study: Change from Baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months
timeFrame: Baseline and 12 months
measure: Core Study and Extension Phase: Safety will be assessed by monitoring and recording all adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From the time the participant signs the informed consent form until 3 months after the last dose of study drug or through the last visit, whichever is longer; up to 78 months
Secondary outcomes:
measure: Core Study: Change from Baseline at 18 Months in Brain Amyloid Pathophysiology as Measured by Amyloid Positron Emission Tomography (PET)
timeFrame: Baseline and 18 Months
measure: Core Study: Change from Baseline in the ADCOMS at 18 Months
timeFrame: Baseline and 18 Months
measure: Core Study: Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) at 18 Months
timeFrame: Baseline and 18 Months
measure: Core Study: Change from Baseline in Alzheimer Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 18 Months
timeFrame: Baseline and 18 Months
measure: Core Study: Change from Baseline in Cerebrospinal fluid (CSF) Biomarkers (Aβ[1-42], t-tau, and p-tau) at 18 Months
timeFrame: Baseline and 18 Months
measure: Core Study: Change from Baseline in Total Hippocampal Volume at 18 Months as Measured by Volumetric Magnetic Resonance Imaging (vMRI)
timeFrame: Baseline and 18 months
measure: Core Study: Change from Baseline at 12 Months in Brain Amyloid Pathophysiology as Measured by Amyloid PET
timeFrame: Baseline and 12 Months
measure: Core Study: Change from baseline at 12 months on clinical status for the following assessments: ADCOMS, CDR-SB, and ADAS-cog
timeFrame: Baseline and 12 Months
measure: Core Study: Change from Baseline in CSF Biomarkers (Aβ[1-42], t-tau, and p-tau) at 12 Months
timeFrame: Baseline and 12 Months
measure: Core Study: Change from Baseline in Total Hippocampal Volume at 6 and 12 Months as Measured by vMRI
timeFrame: Baseline, 6 and 12 Months
measure: Core Study: Change from Baseline in Left and Right Hippocampal Volume at 6, 12, and 18 Months as Measured by vMRI
timeFrame: Baseline and 6, 12 and 18 Months
measure: Core Study: Change from Baseline in Whole Brain Volume at 6, 12, and 18 Months as Measured by vMRI
timeFrame: Baseline and 6, 12 and 18 Months
measure: Core Study: Change from Baseline in Total Ventricular Volume at 6, 12, and 18 Months as Measured by vMRI
timeFrame: Baseline and 6, 12 and 18 Months
measure: Change From Baselines in Brain Amyloid Levels as Measured by Amyloid PET at 3 months (Visit 50 [Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], Cohort 2), 12 months and Annually Thereafter in the Extension Phase
timeFrame: Extension Phase: Baseline, 3 months (Visit 50 [Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], Cohort 2), 12 months and annually thereafter in the Extension Phase up to Visit 174 [Extension Week 261]
measure: Extension Phase: Change from end of Core Study in Brain Amyloid Levels as Measured by Amyloid PET at the Baseline of Extension Phase
timeFrame: End of Core Study (Month 18) up to Baseline of Extension Phase
measure: Extension Phase: Percentage of Amyloid Positive Participants Over Time
timeFrame: Extension Phase: Baseline up to 60 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Facility #1
state: Alabama
city: Phoenix
country: United States
facility: Facility #1
state: Arizona
city: Tucson
country: United States
facility: Facility #1
state: Arizona
city: Carson
country: United States
facility: Facility #1
state: California
city: Lomita
country: United States
facility: Facility #1
state: California
city: Long Beach
country: United States
facility: Facility #1
state: California
city: Los Alamitos
country: United States
facility: Facility #1
state: California
city: Los Angeles
country: United States
facility: Facility #1
state: California
city: Los Angeles
country: United States
facility: Facility #2
state: California
city: Los Angeles
country: United States
facility: Facility #3
state: California
city: Orange
country: United States
facility: Facility #1
state: California
city: Oxnard
country: United States
facility: Facility #1
state: California
city: San Diego
country: United States
facility: Facility #1
state: California
city: Denver
country: United States
facility: Facility #1
state: Colorado
city: New Haven
country: United States
facility: Facility #1
state: Connecticut
city: New Haven
country: United States
facility: Facility #2
state: Connecticut
city: Atlantis
country: United States
facility: Facility #1
state: Florida
city: Boca Raton
country: United States
facility: Facility #1
state: Florida
city: Boca Raton
country: United States
facility: Facility #2
state: Florida
city: Bradenton
country: United States
facility: Facility #1
state: Florida
city: Deerfield Beach
country: United States
facility: Facility #1
state: Florida
city: Delray Beach
country: United States
facility: Facility #1
state: Florida
city: Fort Myers
country: United States
facility: Facility #1
state: Florida
city: Hallandale Beach
country: United States
facility: Facility #1
state: Florida
city: Hialeah
country: United States
facility: Facility #1
state: Florida
city: Lake Worth
country: United States
facility: Facility #1
state: Florida
city: Leesburg
country: United States
facility: Facility #1
state: Florida
city: Leesburg
country: United States
facility: Facility #2
state: Florida
city: Miami Springs
country: United States
facility: Facility #1
state: Florida
city: Miami
country: United States
facility: Facility #1
state: Florida
city: Miami
country: United States
facility: Facility #2
state: Florida
city: Miami
country: United States
facility: Facility #3
state: Florida
city: Naples
country: United States
facility: Facility #1
state: Florida
city: Ocala
country: United States
facility: Facility #1
state: Florida
city: Orlando
country: United States
facility: Facility #1
state: Florida
city: Palm Beach Gardens
country: United States
facility: Facility #1
state: Florida
city: Saint Petersburg
country: United States
facility: Facility #1
state: Florida
city: Sunrise
country: United States
facility: Facility #1
state: Florida
city: Tampa
country: United States
facility: Facility #3
state: Florida
city: Tampa
country: United States
facility: Facility #1
state: Florida
city: Tampa
country: United States
facility: Facility #2
state: Florida
city: The Villages
country: United States
facility: Facility #1
state: Florida
city: Atlanta
country: United States
facility: Facility #2
state: Georgia
city: Atlanta
country: United States
facility: Facility #1
state: Georgia
city: Columbus
country: United States
facility: Facility #1
state: Georgia
city: Decatur
country: United States
facility: Facility #1
state: Georgia
city: Chicago
country: United States
facility: Facility #1
state: Illinois
city: Elk Grove Village
country: United States
facility: Facility #1
state: Illinois
city: Elkhart
country: United States
facility: Facility #1
state: Indiana
city: Indianapolis
country: United States
facility: Facility #1
state: Indiana
city: Wichita
country: United States
facility: Facility #1
state: Kansas
city: Lexington
country: United States
facility: Facility #1
state: Kentucky
city: Boston
country: United States
facility: Facility #1
state: Massachusetts
city: Boston
country: United States
facility: Facility #2
state: Massachusetts
city: Burlington
country: United States
facility: Facility #1
state: Massachusetts
city: Newton
country: United States
facility: Facility #1
state: Massachusetts
city: Ann Arbor
country: United States
facility: Facility #1
state: Michigan
city: East Lansing
country: United States
facility: Facility #1
state: Michigan
city: Farmington Hills
country: United States
facility: Facility #1
state: Michigan
city: Lansing
country: United States
facility: Facility #1
state: Michigan
city: West Bloomfield
country: United States
facility: Facility #1
state: Michigan
city: Saint Louis
country: United States
facility: Facility #1
state: Missouri
city: Eatontown
country: United States
facility: Facility #1
state: New Jersey
city: Toms River
country: United States
facility: Facility #1
state: New Jersey
city: Albany
country: United States
facility: Facility #1
state: New York
city: Amherst
country: United States
facility: Facility #1
state: New York
city: Latham
country: United States
facility: Facility #1
state: New York
city: New York
country: United States
facility: Facility #1
state: New York
city: New York
country: United States
facility: Facility #2
state: New York
city: Rochester
country: United States
facility: Facility #1
state: New York
city: Rochester
country: United States
facility: Facility #2
state: New York
city: Charlotte
country: United States
facility: Facility #1
state: North Carolina
city: Centerville
country: United States
facility: Facility #1
state: Ohio
city: Oklahoma City
country: United States
facility: Facility #1
state: Oklahoma
city: Oklahoma City
country: United States
facility: Facility #2
state: Oklahoma
city: Portland
country: United States
facility: Facility #2
state: Oregon
city: Portland
country: United States
facility: Facility #1
state: Oregon
city: Abington
country: United States
facility: Facility #1
state: Pennsylvania
city: Jenkintown
country: United States
facility: Facility #1
state: Pennsylvania
city: East Providence
country: United States
facility: Facility #1
state: Rhode Island
city: Knoxville
country: United States
facility: Facility #1
state: Tennessee
city: Austin
country: United States
facility: Facility #1
state: Texas
city: Dallas
country: United States
facility: Facility #1
state: Texas
city: Dallas
country: United States
facility: Facility #2
state: Texas
city: Houston
country: United States
facility: Facility #1
state: Texas
city: San Antonio
country: United States
facility: Facility #1
state: Texas
city: San Antonio
country: United States
facility: Facility #2
state: Texas
city: San Antonio
country: United States
facility: Facility #3
state: Texas
city: Bennington
country: United States
facility: Facility #1
state: Vermont
city: Richmond
country: United States
facility: Facility #1
state: Virginia
city: Milwaukee
country: United States
facility: Facility #1
state: Wisconsin
city: Kentville
country: Canada
facility: Facility #1
state: Nova Scotia
city: Kingston
country: Canada
facility: Facility #1
state: Ontario
city: London
country: Canada
facility: Facility #2
state: Ontario
city: Ottawa
country: Canada
facility: Facility #1
state: Ontario
city: Peterborough
country: Canada
facility: Facility #1
state: Ontario
city: Toronto
country: Canada
facility: Facility #1
state: Ontario
city: Greenfield Park
country: Canada
facility: Facility #1
state: Quebec
city: Montreal
country: Canada
facility: Facility #1
state: Quebec
city: Verdun
country: Canada
facility: Facility #1
state: Quebec
city: Québec city
country: Canada
facility: Facility #1
city: Strasbourg Cedex
country: France
facility: Facility #1
state: Bas Rhin
city: Toulouse
country: France
facility: Facility #1
state: Haute Garonne
city: Paris Cedex 10
country: France
facility: Facility #1
state: Paris
city: Bron Cedex
country: France
facility: Facility #1
city: Paris
country: France
facility: Facility #1
city: Rennes Cedex 9
country: France
facility: Facility #1
city: Villeurbanne
country: France
facility: Facility #1
city: Gunzburg
country: Germany
facility: Facility #1
state: Baden Wuerttemberg
city: Karlstadt Am Main
country: Germany
facility: Facility #1
state: Bayern
city: Hoppegarten
country: Germany
facility: Facility #1
state: Berlin
city: Hannover
country: Germany
facility: Facility #1
state: Niedersachsen
city: Mittweida
country: Germany
facility: Facility #1
state: Sachsen
city: Berlin
country: Germany
facility: Facility #1
city: Berlin
country: Germany
facility: Facility #2
city: Berlin
country: Germany
facility: Facility #3
city: Guenzburg
country: Germany
facility: Facility #1
city: Hamburg
country: Germany
facility: Facility #1
city: Heidelberg
country: Germany
facility: Facility #1
city: Leipzig
country: Germany
facility: Facility #1
city: Mannheim
country: Germany
facility: Facility #1
city: Muenchen
country: Germany
facility: Facility #1
city: Tuebingen
country: Germany
facility: Facility #1
city: Brescia
country: Italy
facility: Facility #1
city: Genova
country: Italy
facility: Facility #1
city: Milano
country: Italy
facility: Facility #1
city: Parma
country: Italy
facility: Facility #1
city: Perugia
country: Italy
facility: Facility #1
city: Pisa
country: Italy
facility: Facility #1
city: Roma
country: Italy
facility: Facility #1
city: Roma
country: Italy
facility: Facility #2
city: Roma
country: Italy
facility: Facility #3
city: Otake-shi
country: Japan
facility: Eisai Trial Site #1
state: Hiroshima-Ken
city: Himeji-shi
country: Japan
facility: Eisai Trial Site #1
state: Hyogo-Ken
city: Himeji-shi
country: Japan
facility: Eisai Trial Site #2
state: Hyogo-Ken
city: Himeji-shi
country: Japan
facility: Eisai Trial Site #3
state: Hyogo-Ken
city: Kobe-shi
country: Japan
facility: Eisai Trial Site #1
state: Hyogo-Ken
city: Nishinomiya-shi
country: Japan
facility: Eisai Trial Site #1
state: Hyogo-Ken
city: Kyoto-shi
country: Japan
facility: Eisai Trial Site #1
state: Kyoto-Fu
city: Kurashiki-shi
country: Japan
facility: Eisai Trial Site #1
state: Okayama-Ken
city: Osaka-shi
country: Japan
facility: Eisai Trial Site #1
state: Osaka-Fu
city: Saitama-shi
country: Japan
facility: Eisai Trial Site #1
state: Saitama-Ken
city: Itabashi-ku
country: Japan
facility: Eisai Trial Site #1
state: Tokyo-To
city: Shinjuku-ku
country: Japan
facility: Eisai Trial Site #1
state: Tokyo-To
city: Shinjuku-ku
country: Japan
facility: Eisai Trial Site #2
state: Tokyo-To
city: Seongnam-si
country: Korea, Republic of
facility: Facility #1
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Facility #1
state: Gyeongsangnam-do
city: Seoul
country: Korea, Republic of
facility: Facility #2
city: Seoul
country: Korea, Republic of
facility: Facility #3
city: Seoul
country: Korea, Republic of
facility: Facility #4
city: Amsterdam
country: Netherlands
facility: Facility #1
city: Sant Cugat Del Vallés
country: Spain
facility: Facility #1
state: Barcelona
city: San Sebastian
country: Spain
facility: Facility #1
state: Guipuzcoa
city: Barakaldo
country: Spain
facility: Facility #1
state: Vizcaya
city: Alicante
country: Spain
facility: Facility #1
city: Barcelona
country: Spain
facility: Facility #1
city: Madrid
country: Spain
facility: Facility #1
city: Madrid
country: Spain
facility: Facility #2
city: Sevilla
country: Spain
facility: Facility #1
city: Malmö
country: Sweden
facility: Facility #1
city: Mölndal
country: Sweden
facility: Facility #1
city: Stockholm
country: Sweden
facility: Facility #1
city: Uppsala
country: Sweden
facility: Facility #1
city: London
country: United Kingdom
facility: Facility #1
state: Greater London
city: Isleworth
country: United Kingdom
facility: Facility #1
state: Middlesex
city: Glasgow
country: United Kingdom
facility: Facility #1
state: Renfrewshire
city: Bath
country: United Kingdom
facility: Facility #1
city: London
country: United Kingdom
facility: Facility #2
city: Swindon
country: United Kingdom
facility: Facility #1
Study officials:
References:
citation: Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RYK, Lannfelt L, Bradley H, Rabe M, Koyama A, Reyderman L, Berry DA, Berry S, Gordon R, Kramer LD, Cummings JL. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 2021 Apr 17;13(1):80. doi: 10.1186/s13195-021-00813-8.