A Study to Evaluate Safety, Tolerability, and Efficacy of Lecanemab in Subjects With Early Alzheimer's Disease

Alzheimer's Disease Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01767311
• Other study ID #: BAN2401-G000-201
• Secondary ID: 2012-002843-11
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 20, 2012
• Est. completion date: February 20, 2025

Study information

• Verified date: May 2023
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 856
• Est. completion date: February 20, 2025
• Est. primary completion date: February 20, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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 Aß(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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• Lecanemab 2.5 mg/kg
2.5 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion
• Lecanemab 5.0 mg/kg
5.0 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion
• Lecanemab 10 mg/kg
10 mg/kg biweekly (once every 2 weeks) administered as i.v. infusion.
• Lecanemab 5.0 mg/kg
5.0 mg/kg monthly (once every 4 weeks) administered as i.v. infusion. All participants will receive biweekly infusions, participants will have placebo infusion alternating with BAN2401
• Lecanemab 10 mg/kg
10 mg/kg monthly (once every 4 weeks) administered as i.v. infusion. All participants will receive biweekly infusions, participants will have placebo infusion alternating with BAN2401
• Placebo
biweekly (once every 2 weeks) administered as i.v. infusion
• Lecanemab 10 mg/kg
10 mg/kg biweekly (once every 2 weeks), once every 4 weeks (Q4W) or once every 3 months (Q3M) i.v. infusion.

Locations

Country	Name	City	State
Canada	Facility #1	Greenfield Park	Quebec
Canada	Facility #1	Kentville	Nova Scotia
Canada	Facility #1	Kingston	Ontario
Canada	Facility #2	London	Ontario
Canada	Facility #1	Montreal	Quebec
Canada	Facility #1	Ottawa	Ontario
Canada	Facility #1	Peterborough	Ontario
Canada	Facility #1	Québec city
Canada	Facility #1	Toronto	Ontario
Canada	Facility #1	Verdun	Quebec
France	Facility #1	Bron Cedex
France	Facility #1	Paris
France	Facility #1	Paris Cedex 10	Paris
France	Facility #1	Rennes Cedex 9
France	Facility #1	Strasbourg Cedex	Bas Rhin
France	Facility #1	Toulouse	Haute Garonne
France	Facility #1	Villeurbanne
Germany	Facility #1	Berlin
Germany	Facility #2	Berlin
Germany	Facility #3	Berlin
Germany	Facility #1	Guenzburg
Germany	Facility #1	Gunzburg	Baden Wuerttemberg
Germany	Facility #1	Hamburg
Germany	Facility #1	Hannover	Niedersachsen
Germany	Facility #1	Heidelberg
Germany	Facility #1	Hoppegarten	Berlin
Germany	Facility #1	Karlstadt Am Main	Bayern
Germany	Facility #1	Leipzig
Germany	Facility #1	Mannheim
Germany	Facility #1	Mittweida	Sachsen
Germany	Facility #1	Muenchen
Germany	Facility #1	Tuebingen
Italy	Facility #1	Brescia
Italy	Facility #1	Genova
Italy	Facility #1	Milano
Italy	Facility #1	Parma
Italy	Facility #1	Perugia
Italy	Facility #1	Pisa
Italy	Facility #1	Roma
Italy	Facility #2	Roma
Italy	Facility #3	Roma
Japan	Eisai Trial Site #1	Himeji-shi	Hyogo-Ken
Japan	Eisai Trial Site #2	Himeji-shi	Hyogo-Ken
Japan	Eisai Trial Site #3	Himeji-shi	Hyogo-Ken
Japan	Eisai Trial Site #1	Itabashi-ku	Tokyo-To
Japan	Eisai Trial Site #1	Kobe-shi	Hyogo-Ken
Japan	Eisai Trial Site #1	Kurashiki-shi	Okayama-Ken
Japan	Eisai Trial Site #1	Kyoto-shi	Kyoto-Fu
Japan	Eisai Trial Site #1	Nishinomiya-shi	Hyogo-Ken
Japan	Eisai Trial Site #1	Osaka-shi	Osaka-Fu
Japan	Eisai Trial Site #1	Otake-shi	Hiroshima-Ken
Japan	Eisai Trial Site #1	Saitama-shi	Saitama-Ken
Japan	Eisai Trial Site #1	Shinjuku-ku	Tokyo-To
Japan	Eisai Trial Site #2	Shinjuku-ku	Tokyo-To
Korea, Republic of	Facility #1	Busan	Gyeongsangnam-do
Korea, Republic of	Facility #1	Seongnam-si	Gyeonggi-do
Korea, Republic of	Facility #2	Seoul
Korea, Republic of	Facility #3	Seoul
Korea, Republic of	Facility #4	Seoul
Netherlands	Facility #1	Amsterdam
Spain	Facility #1	Alicante
Spain	Facility #1	Barakaldo	Vizcaya
Spain	Facility #1	Barcelona
Spain	Facility #1	Madrid
Spain	Facility #2	Madrid
Spain	Facility #1	San Sebastian	Guipuzcoa
Spain	Facility #1	Sant Cugat Del Vallés	Barcelona
Spain	Facility #1	Sevilla
Sweden	Facility #1	Malmö
Sweden	Facility #1	Mölndal
Sweden	Facility #1	Stockholm
Sweden	Facility #1	Uppsala
United Kingdom	Facility #1	Bath
United Kingdom	Facility #1	Glasgow	Renfrewshire
United Kingdom	Facility #1	Isleworth	Middlesex
United Kingdom	Facility #1	London	Greater London
United Kingdom	Facility #2	London
United Kingdom	Facility #1	Swindon
United States	Facility #1	Abington	Pennsylvania
United States	Facility #1	Albany	New York
United States	Facility #1	Amherst	New York
United States	Facility #1	Ann Arbor	Michigan
United States	Facility #1	Atlanta	Georgia
United States	Facility #2	Atlanta	Georgia
United States	Facility #1	Atlantis	Florida
United States	Facility #1	Austin	Texas
United States	Facility #1	Bennington	Vermont
United States	Facility #1	Birmingham	Alabama
United States	Facility #1	Boca Raton	Florida
United States	Facility #2	Boca Raton	Florida
United States	Facility #1	Boston	Massachusetts
United States	Facility #2	Boston	Massachusetts
United States	Facility #1	Bradenton	Florida
United States	Facility #1	Burlington	Massachusetts
United States	Facility #1	Carson	California
United States	Facility #1	Centerville	Ohio
United States	Facility #1	Charlotte	North Carolina
United States	Facility #1	Chicago	Illinois
United States	Facility #1	Columbus	Georgia
United States	Facility #1	Dallas	Texas
United States	Facility #2	Dallas	Texas
United States	Facility #1	Decatur	Georgia
United States	Facility #1	Deerfield Beach	Florida
United States	Facility #1	Delray Beach	Florida
United States	Facility #1	Denver	Colorado
United States	Facility #1	East Lansing	Michigan
United States	Facility #1	East Providence	Rhode Island
United States	Facility #1	Eatontown	New Jersey
United States	Facility #1	Elk Grove Village	Illinois
United States	Facility #1	Elkhart	Indiana
United States	Facility #1	Farmington Hills	Michigan
United States	Facility #1	Fort Myers	Florida
United States	Facility #1	Hallandale Beach	Florida
United States	Facility #1	Hialeah	Florida
United States	Facility #1	Houston	Texas
United States	Facility #1	Indianapolis	Indiana
United States	Facility #1	Jenkintown	Pennsylvania
United States	Facility #1	Knoxville	Tennessee
United States	Facility #1	Lake Worth	Florida
United States	Facility #1	Lansing	Michigan
United States	Facility #1	Latham	New York
United States	Facility #1	Leesburg	Florida
United States	Facility #2	Leesburg	Florida
United States	Facility #1	Lexington	Kentucky
United States	Facility #1	Lomita	California
United States	Facility #1	Long Beach	California
United States	Facility #1	Los Alamitos	California
United States	Facility #1	Los Angeles	California
United States	Facility #2	Los Angeles	California
United States	Facility #3	Los Angeles	California
United States	Facility #1	Miami	Florida
United States	Facility #2	Miami	Florida
United States	Facility #3	Miami	Florida
United States	Facility #1	Miami Springs	Florida
United States	Facility #1	Milwaukee	Wisconsin
United States	Facility #1	Naples	Florida
United States	Facility #1	New Haven	Connecticut
United States	Facility #2	New Haven	Connecticut
United States	Facility #1	New York	New York
United States	Facility #2	New York	New York
United States	Facility #1	Newton	Massachusetts
United States	Facility #1	Ocala	Florida
United States	Facility #1	Oklahoma City	Oklahoma
United States	Facility #2	Oklahoma City	Oklahoma
United States	Facility #1	Orange	California
United States	Facility #1	Orlando	Florida
United States	Facility #1	Oxnard	California
United States	Facility #1	Palm Beach Gardens	Florida
United States	Facility #1	Phoenix	Arizona
United States	Facility #1	Portland	Oregon
United States	Facility #2	Portland	Oregon
United States	Facility #1	Richmond	Virginia
United States	Facility #1	Rochester	New York
United States	Facility #2	Rochester	New York
United States	Facility #1	Saint Louis	Missouri
United States	Facility #1	Saint Petersburg	Florida
United States	Facility #1	San Antonio	Texas
United States	Facility #2	San Antonio	Texas
United States	Facility #3	San Antonio	Texas
United States	Facility #1	San Diego	California
United States	Facility #1	Sunrise	Florida
United States	Facility #1	Tampa	Florida
United States	Facility #2	Tampa	Florida
United States	Facility #3	Tampa	Florida
United States	Facility #1	The Villages	Florida
United States	Facility #1	Toms River	New Jersey
United States	Facility #1	Tucson	Arizona
United States	Facility #1	West Bloomfield	Michigan
United States	Facility #1	Wichita	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Biogen

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Core Study: Change from Baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months		Baseline and 12 months
Primary	Core Study and Extension Phase: Safety will be assessed by monitoring and recording all adverse events (AEs) and serious adverse events (SAEs)	Safety assessments will consist of monitoring and recording all AEs and SAEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); safety magnetic resonance imaging (MRI); and performance of physical examinations.	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	Core Study: Change from Baseline at 18 Months in Brain Amyloid Pathophysiology as Measured by Amyloid Positron Emission Tomography (PET)		Baseline and 18 Months
Secondary	Core Study: Change from Baseline in the ADCOMS at 18 Months		Baseline and 18 Months
Secondary	Core Study: Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) at 18 Months		Baseline and 18 Months
Secondary	Core Study: Change from Baseline in Alzheimer Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 18 Months		Baseline and 18 Months
Secondary	Core Study: Change from Baseline in Cerebrospinal fluid (CSF) Biomarkers (Aß[1-42], t-tau, and p-tau) at 18 Months		Baseline and 18 Months
Secondary	Core Study: Change from Baseline in Total Hippocampal Volume at 18 Months as Measured by Volumetric Magnetic Resonance Imaging (vMRI)		Baseline and 18 months
Secondary	Core Study: Change from Baseline at 12 Months in Brain Amyloid Pathophysiology as Measured by Amyloid PET		Baseline and 12 Months
Secondary	Core Study: Change from baseline at 12 months on clinical status for the following assessments: ADCOMS, CDR-SB, and ADAS-cog		Baseline and 12 Months
Secondary	Core Study: Change from Baseline in CSF Biomarkers (Aß[1-42], t-tau, and p-tau) at 12 Months		Baseline and 12 Months
Secondary	Core Study: Change from Baseline in Total Hippocampal Volume at 6 and 12 Months as Measured by vMRI		Baseline, 6 and 12 Months
Secondary	Core Study: Change from Baseline in Left and Right Hippocampal Volume at 6, 12, and 18 Months as Measured by vMRI		Baseline and 6, 12 and 18 Months
Secondary	Core Study: Change from Baseline in Whole Brain Volume at 6, 12, and 18 Months as Measured by vMRI		Baseline and 6, 12 and 18 Months
Secondary	Core Study: Change from Baseline in Total Ventricular Volume at 6, 12, and 18 Months as Measured by vMRI		Baseline and 6, 12 and 18 Months
Secondary	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		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]
Secondary	Extension Phase: Change from end of Core Study in Brain Amyloid Levels as Measured by Amyloid PET at the Baseline of Extension Phase		End of Core Study (Month 18) up to Baseline of Extension Phase
Secondary	Extension Phase: Percentage of Amyloid Positive Participants Over Time		Extension Phase: Baseline up to 60 months