An Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia (EARLY)

A Phase 2b/3 Randomized, Double-blind, Placebo-Controlled, Parallel Group, Multicenter Study Investigating the Efficacy and Safety of JNJ-54861911 in Subjects Who Are Asymptomatic At Risk for Developing Alzheimer's Dementia

The purpose of this study is to evaluate whether treatment with atabecestat slows cognitive decline compared with placebo treatment, as measured by a composite cognitive measure, the Preclinical Alzheimer Cognitive Composite (PACC), in amyloid-positive participants who are asymptomatic at risk for developing Alzheimer's dementia.

Study Overview

• Status: Terminated
• Conditions: Asymptomatic Amyloid-positive
• Intervention / Treatment: Drug: Atabecestat, 5 mg; Drug: Atabecestat, 25 mg; Drug: Placebo

Detailed Description

This is a randomized (study drug assigned by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), multi-center (more than one hospital or medical school team work on a medical research study), placebo-controlled, parallel-group study in participants who are asymptomatic and at risk for developing Alzheimer's dementia. The study will consist of a Screening Phase (approximately 90 days), treatment Phase (54 months) and follow-up Phase (7 to 28 days). In treatment Phase eligible Participants will be randomized to receive study drug or placebo once daily for up to 4.5 years. The maximum study duration for a participant will be 58 months. Participants' safety will be monitored throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 557
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
  • Brisbane, Australia
  • Darlinghurst, Australia
  • East Gosford, Australia
  • Heidelberg, Australia
  • Herston, Australia
  • Subiaco, Australia
  • Tarren Point, Australia
  • Waratah, Australia
• Belgium
  • Antwerpen, Belgium
  • Baudour, Belgium
  • Brussel, Belgium
  • Edegem, Belgium
  • Liège, Belgium
  • Mons, Belgium
• Canada
  • Gatineau, Canada
  • Toronto, Canada
• Denmark
  • Aalborg, Denmark
  • Ballerup, Denmark
  • København Ø, Denmark
  • Rødovre, Denmark
• Finland
  • Kuopio N/a, Finland
  • Turku, Finland
• Germany
  • Berlin, Germany
  • Essen, Germany
  • Halle, Germany
  • Homburg, Germany
  • Kiel, Germany
  • Mannheim, Germany
  • Mittweida, Germany
  • Stuttgart, Germany
  • ULM, Germany
• Japan
  • Chiba-shi, Japan
  • Fukuoka-shi, Japan
  • Hachioji-shi, Japan
  • Iizuka-shi, Japan
  • Osaka-shi, Japan
  • Shibuya-ku, Japan
  • Shinjuku-ku, Japan
  • Shirakawa, Japan
  • Tokyo, Japan
• Mexico
  • Chihuahua, Mexico
  • Monterrey, Mexico
  • San Luis Potosi, Mexico
  • Tlalnepantla de Baz, Mexico
• Netherlands
  • Amsterdam, Netherlands
  • Breda, Netherlands
  • Utrecht, Netherlands
  • s-Hertogenbosch, Netherlands
• Spain
  • Barcelona, Spain
  • Getxo, Spain
  • Madrid, Spain
  • Manresa, Spain
  • San Sebastian, Spain
  • Terrassa, Spain
  • Valencia, Spain
• Sweden
  • Mölndal, Sweden
• United Kingdom
  • Birmingham, United Kingdom
  • Glasgow, United Kingdom
  • Guildford, United Kingdom
  • London, United Kingdom
  • Newcastle upon Tyne, United Kingdom
  • Plymouth, United Kingdom
  • Swindon, United Kingdom
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
    • Sun City, Arizona, United States
  • California
    • Downey, California, United States
    • La Jolla, California, United States
    • Newport Beach, California, United States
    • Orange, California, United States
    • San Diego, California, United States
  • Connecticut
    • New Haven, Connecticut, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Delray Beach, Florida, United States
    • Fort Myers, Florida, United States
    • Jacksonville, Florida, United States
    • Lake Worth, Florida, United States
    • Melbourne, Florida, United States
    • Miami Beach, Florida, United States
    • Ocoee, Florida, United States
    • Orlando, Florida, United States
    • Ormond Beach, Florida, United States
    • Tampa, Florida, United States
    • The Villages, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Columbus, Georgia, United States
    • Decatur, Georgia, United States
  • Illinois
    • Arlington Heights, Illinois, United States
    • Chicago, Illinois, United States
    • Elk Grove Village, Illinois, United States
  • Indiana
    • Elkhart, Indiana, United States
    • Indianapolis, Indiana, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Kansas
    • Westwood, Kansas, United States
  • Kentucky
    • Lexington, Kentucky, United States
  • Louisiana
    • Baton Rouge, Louisiana, United States
  • Maine
    • Bangor, Maine, United States
  • Massachusetts
    • Boston, Massachusetts, United States
    • Plymouth, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
    • Kalamazoo, Michigan, United States
  • Mississippi
    • Hattiesburg, Mississippi, United States
  • Missouri
    • Saint Louis, Missouri, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • New York
    • Amherst, New York, United States
    • New York, New York, United States
    • Orangeburg, New York, United States
    • Rochester, New York, United States
    • Staten Island, New York, United States
    • Syracuse, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
    • Raleigh, North Carolina, United States
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Cleveland, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Willow Grove, Pennsylvania, United States
  • Rhode Island
    • Providence, Rhode Island, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Tennessee
    • Cordova, Tennessee, United States
    • Nashville, Tennessee, United States
  • Texas
    • Houston, Texas, United States
    • San Antonio, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Virginia
    • Charlottesville, Virginia, United States
  • Washington
    • Seattle, Washington, United States
    • Spokane, Washington, United States
  • Wisconsin
    • Madison, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have a global Clinical Dementia Rating Scale- (CDR) score of '0' at Screening
• Participants 60 to 64 years of age must also have 1 of the following 3 conditions: a) a positive family history for dementia (minimum of 1 first degree relative), b) a previously known apolipoprotein E, ε4 allele (APOE ɛ4) genotype, c) a previously known biomarker status demonstrating elevated amyloid accumulation in cerebrospinal fluid (CSF) or positron emission tomography (PET)
• Participant must be able to read and write and must have adequate hearing and visual acuity to complete the psychometric tests. The legally acceptable representative must also be able to read and write
• Participants must have evidence of amyloid accumulation by means of either: a) low Cerebrospinal Fluid (CSF) ABeta 1-42 levels at Screening; b) a positive amyloid positron emission tomography (PET) scan at Screening (depending on the site's PET capability) by visual read
• Participant must be otherwise healthy for their age group or medically stable with or without medication on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at Screening or at Baseline

Exclusion Criteria:

• Participant is receiving an acetylcholinesterase (AChE) inhibitor and/or memantine at any time during Screening or Day 1 predose
• Participant has evidence of any brain diseases, other than potential very early signs of Alzheimer's Dementia (AD) (example. mild hippocampal atrophy) or typical age-related changes (e.g. mild white matter hyperintensity on magnetic resonance imaging [MRI]) or any other abnormality (e.g. folic acid/Vitamin B12 deficiency) that could explain a possible cognitive deficit (including, but not limited to vascular encephalopathy or large strokes (as imaged by cerebral MRI)
• Participant has any contraindications for MRI (example, prostheses, implants, claustrophobia, pacemaker)
• Participant has met criteria for dementia or has a brain disorder that can cause dementia
• Participant has evidence of familial autosomal dominant AD (mutation identified in the family and/or participant prior to randomization)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Participants will receive one atabecestat, 5 milligram (mg) tablet orally once daily up to 54 months.	Drug: Atabecestat, 5 mg; One atabecestat, 5 mg tablet orally once daily up to 54 months.
Experimental: Group 2; Participants will receive one atabecestat, 25 mg tablet orally once daily up to 54 months.	Drug: Atabecestat, 25 mg; One atabecestat, 25 mg tablet orally once daily up to 54 months.
Experimental: Group 3; Participants will receive one matching placebo tablet orally once daily up to 54 months.	Drug: Placebo; One matching placebo tablet orally once daily up to 54 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Preclinical Alzheimer Cognitive Composite (PACC) Score at Endpoint (Month 24)	PACC has 4 components: Free and Cued Selective Reminding Test (0 (worst)-48 (best recall); Delayed Paragraph Recall test (Range 0 (worst)-25 (best recall); Wechsler Adult Intelligence scale: (ranges 0 [none]-135 [best performance]) and Mini Mental State Examination (Range 0 [worst] - 30 [best performance]). Component scores are transformed using an established normalization method into z-scores. Each of 4 component change scores is divided by baseline sample standard deviation (SD) of that component. These z scores are summed to form the composite score. Thus, a change of 1 baseline standard deviation on each component would correspond to a 4-point change on the composite. A z-score of 0 is equal to the mean and implies how many SD higher or lower score as compared with baseline score, with increase signifying improvement.	Baseline and Endpoint (Month 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Cognitive Function Index (CFI) Score at Endpoint (Month 24)	The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument, a participant- and informant-reported outcome measure developed by the Alzheimer's Disease Cooperative Study (ADCS). This assessment includes 15 questions (14 of which contribute to the total score, and 1 additional unscored item) that assess the participant's perceived ability to perform high-level functional tasks in daily-life and sense of overall cognitive functional ability. Study participants and their informants independently rate the participant's abilities. A participant-reported and an informant-reported total score is calculated which ranges from 0 to 14 (yes=1; no=0; maybe=0.5 for each question) with higher scores indicating greater impairment.	Baseline and Endpoint (Month 24)
Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living - Prevention Instrument (ADCS-ADLPI) Total Score at Endpoint (Month 24)	The Alzheimer's Disease Cooperative Study - Activities of Daily Living -Prevention Instrument (ADCS-ADLPI) is a functional measure composed of 18 items that includes 15 activities of daily living rated on a 4-point scale and 3 high level function items. Study participants and their informants independently rate the participant's level of ability (with no difficulty = 3, with some difficulty = 2, with a lot of difficulty = 1, did not do/don't know = 0). Informants are additionally asked to evaluate whether activities were completed less often, required more time to complete, and if any errors were made performing the task. High-level function items are rated as "yes" or "no". The scores range from 0 to 45 with higher scores indicating less impairment. The total score is the sum of the scores of the 15 activities of daily living questions (range: 0-45) with higher scores indicating less impairment.	Baseline and Endpoint (Month 24)
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Score at Endpoint (Month 24)	RBANS is 20 to 25 minute battery developed for cognitive assessment, detection, and characterization of dementia. RBANS includes 12 subtests that measure following 5 indices: (1)Attention Index, composed of Digit Span and Coding; (2)Language Index, consisting of Picture Naming and Semantic Fluency subtests; (3)Visuospatial/Construction Index, made up of Figure Copy and Line Orientation subtests; (4)Immediate Memory Index, composed of List Learning and Story Memory subtests, and (5)Delayed Memory Index, consisting of List Recall, List Recognition, Story Recall, and Figure Recall subtests. Completion of RBANS yields 5 index scores based on participant performance on various subtests, as well as a composite Total Index score for battery. Total index scores range from 40 to 160, and are normalized to a mean of 100 and standard deviation (SD) of 15. Higher scores indicate less impairment.	Baseline and Endpoint (Month 24)
Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Endpoint (Month 24)	The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18. Higher score indicates severe impairment.	Baseline and Endpoint (Month 24)
Change From Baseline in Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score at Endpoint (Month 24)	The Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score represent a series of performance based measures covering 5 domains (Attention, Memory, Language, Spatial, and Executive function). These are valid, clinically meaningful measures that objectively assess functional deficits. Participant performance scores on NAB subtests are summed, and then normalized to yield an index score. Index scores can range from less than or equal to (< =) 55 to greater than or equal to (> =) 145, and are normalized to a mean of 100 and standard deviation of 15. Higher scores indicate less impairment.	Baseline and Endpoint (Month 24)

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, Rafii MS, Streffer J, Shi Y, Karcher K, Raghavan N, Tymofyeyev Y, Bogert J, Brashear HR, Novak G, Thipphawong J, Saad ZS, Kolb H, Rofael H, Sanga P, Romano G. Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):293-301. doi: 10.1001/jamaneurol.2020.4857.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2015
• Primary Completion (Actual): December 20, 2018
• Study Completion (Actual): December 20, 2018

Study Registration Dates

• First Submitted: October 5, 2015
• First Submitted That Met QC Criteria: October 5, 2015
• First Posted (Estimate): October 6, 2015

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: February 3, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Dementia; Alzheimer disease; Atabecestat
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Dementia; Alzheimer Disease
• Other Study ID Numbers: CR107373; 2015-000948-42 (EudraCT Number); 54861911ALZ2003 (Other Identifier: Janssen Research & Development, LLC)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No