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

• ClinicalTrials.gov Identifier: NCT02569398
• Recruitment Status: Terminated
• First Posted: October 6, 2015
• Results First Posted: February 10, 2020
• Last Update Posted: February 10, 2020
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: October 5, 2015
• First Posted Date: October 6, 2015
• Results First Submitted Date: December 20, 2019
• Results First Posted Date: February 10, 2020
• Last Update Posted Date: February 10, 2020
• Actual Study Start Date: October 29, 2015
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2020)

Change From Baseline in Preclinical Alzheimer Cognitive Composite (PACC) Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.

Original Primary Outcome Measures (submitted: October 5, 2015)

Change from Baseline in Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) to Month 54 [ Time Frame: Up to Month 54 ]

The ADCS-PACC is composed of 4 measures [Free and Cued Selective Reminding Test, Delayed Paragraph Recall, Wechsler Adult Intelligence Scale (WAIS)-IV Coding and Mini Mental State Examination (MMSE) Total Score] that are weighted towards episodic memory and includes a timed executive function test and a global cognitive screening test. Each component score will be transformed into z scores. These z-scores will then be summed to form the composite. Higher scores indicate better performance.

Current Secondary Outcome Measures (submitted: February 3, 2020)

• Change From Baseline in Cognitive Function Index (CFI) Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.
• Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living - Prevention Instrument (ADCS-ADLPI) Total Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.
• Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.
• Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.
• Change From Baseline in Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score at Endpoint (Month 24) [ Time Frame: Baseline and 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.

Original Secondary Outcome Measures (submitted: October 5, 2015)

• Change from Baseline in Cognitive Function Index (CFI) to Month 54 [ Time Frame: Up to Month 54 ]
  Cognitive Function Index (CFI) is a 15 point rating scale that assess the Participants perceived ability to perform high-level functional tasks in daily-life and sense of overall cognitive functional ability. The higher scores indicates greater impairment.
• Change from Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCSADLPI) Total Score to Month 54 [ Time Frame: Up to Month 54 ]
  The Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCSADLPI) is a questionnaire related to activities of daily living and to physical functioning. The scores range from 0 to 45 with higher scores indicating less impairment.
• Change from Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Score to Month 51 [ Time Frame: Up to Month 51 ]
  The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) rating scale is used to assess the cognitive assessment, detection, and characterization of dementia. The scores range from 40 to 160, and are normalized to a mean of 100 and standard deviation of 15. Higher scores indicating less impairment.
• Change from Baseline in Clinical Dementia RatingSum of Boxes (CDRSB) Score to Month 54 [ Time Frame: Up to Month 54 ]
  The Clinical Dementia RatingSum of Boxes (CDRSB) scores ranging from 0 to 18. The CDR assesses 3 domains of cognition (memory, orientation, judgment/problem solving) and 3 domains of function (community affairs, home/hobbies, personal care) using semistructured interviews of both the study participant and an informant carried out by a trained rater. The Higher CDRSB scores indicate greater impairment.
• Change from Baseline in Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score to Month 54 [ Time Frame: Up to Month 54 ]
  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). 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.
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Month 58 ]
  An AE was any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
• Trough Plasma Concentration (Ctrough) of JNJ-54861911 [ Time Frame: Up to Month 54 ]
  The Ctrough is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
• Area Under the Plasma Concentration-Time Curve From 0 to tau Hours After Dosing (AUCtau) [ Time Frame: Up to Month 54 ]
  The AUCtau is the area under the plasma concentration-time curve from time zero to tau hours (time tau is the dosing interval).
• Change in mean Cerebral Fibrillar Amyloid Accumulation [ Time Frame: Up to Month 54 ]
  The accumulation of cerebral fibrillar amyloid will be measured by amyloid positron emission tomography (PET) imaging.
• Change From Baseline of Neurodegeneration by Assessing Changes in Imaging Biomarkers [ Time Frame: Up to Month 54 ]
  Neurodegeneration will be assessed based on changes in imaging biomarkers.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia
• Official Title: 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
• Brief Summary: 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.
• 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
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Asymptomatic Amyloid-positive

Intervention

• Drug: Atabecestat, 5 mg
  One atabecestat, 5 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.
• Drug: Placebo
  One matching placebo tablet orally once daily up to 54 months.

Study Arms

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

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 3, 2020): 557
• Original Estimated Enrollment (submitted: October 5, 2015): 1650
• Actual Study Completion Date: December 20, 2018
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Denmark, Finland, Germany, Japan, Mexico, Netherlands, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: France, Italy, Switzerland

Administrative Information

• NCT Number: NCT02569398
• Other Study ID Numbers: CR107373; 2015-000948-42 ( EudraCT Number ); 54861911ALZ2003 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: February 2020