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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2015-000948-42
    Trial protocol
    		 SE   DE   DK   BE   ES   FI   NL   IT  
    Global end of trial date
    20 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2020
    First version publication date
    05 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54861911ALZ2003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02569398
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to determine 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 subjects who were asymptomatic at risk for developing Alzheimer’s dementia.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practices and applicable regulatory requirements. The safety assessments included adverse events, clinical laboratory tests, electrocardiograms, vital signs, physical examination body weight measurements; Magnetic resonance imaging (MRI), centrally read; and physical, neurological, and dermatological examinations and psychometric assessments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 63
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Denmark: 60
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    United Kingdom: 67
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United States: 199
    Worldwide total number of subjects
    557
    EEA total number of subjects
    246
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    86
    From 65 to 84 years
    470
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total of 557 subjects were enrolled in study. Study was early terminated based on experience of significant elevations in liver enzymes in subjects receiving JNJ-54861911 in this study and 54861911ALZ2004 (NCT02406027).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received a single dose of JNJ-54861911 matching placebo tablet orally once daily for up to 24 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of atabecestat matching placebo tablet orally once daily for up to 54 months.

    Arm title
    		 JNJ-54861911 (5 mg)
    Arm description
    		 Subjects received a single dose of JNJ-54861911 5 milligram (mg) tablet orally once daily for up to 24 months (subjects randomized to this group received JNJ-54861911 10 mg prior to protocol amendment 3 and continued to receive JNJ-54861911 5-mg tablets after implementation of protocol Amendment 3; dated: 02-Mar-2016).
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-54861911
    Investigational medicinal product code
    Other name
    Atabecestat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of atabecestat 5 mg tablet orally once daily for up to 54 months.

    Investigational medicinal product name
    JNJ-54861911
    Investigational medicinal product code
    Other name
    Atabecestat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of atabecestat 10 mg tablet orally once daily for up to 54 months.

    Arm title
    		 JNJ-54861911 (25 mg)
    Arm description
    		 Subjects received a single dose of JNJ-54861911 25 mg tablet orally once daily for up to 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-54861911
    Investigational medicinal product code
    Other name
    Atabecestat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of atabecestat 25 mg tablet orally once daily for up to 54 months.

    Number of subjects in period 1
    		Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Started
    185
    189
    183
    Completed
    0
    0
    0
    Not completed
    185
    189
    183
         Consent withdrawn by subject
    43
    43
    30
         Study terminated by sponsor
    130
    131
    134
         Adverse event
    -
    1
    6
         Unspecified
    12
    14
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 matching placebo tablet orally once daily for up to 24 months.

    Reporting group title
    JNJ-54861911 (5 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 5 milligram (mg) tablet orally once daily for up to 24 months (subjects randomized to this group received JNJ-54861911 10 mg prior to protocol amendment 3 and continued to receive JNJ-54861911 5-mg tablets after implementation of protocol Amendment 3; dated: 02-Mar-2016).

    Reporting group title
    JNJ-54861911 (25 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 25 mg tablet orally once daily for up to 24 months.

    Reporting group values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg) Total
    Number of subjects
    		 185 189 183 557
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 33 23 30 86
        From 65 to 84 years
    		 151 166 153 470
        85 years and over
    		 1 0 0 1
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.2 ( 5.81 ) 70.6 ( 5.26 ) 70.5 ( 5.62 ) -
    Title for Gender
    Units: subjects
        Female
    		 108 116 117 341
        Male
    		 77 73 66 216
    Title for Race
    Units: Subjects
        White
    		 167 173 168 508
        Black or African American
    		 2 1 2 5
        Asian
    		 12 11 11 34
        American Indian or Alaska Native
    		 0 1 0 1
        Other
    		 4 3 2 9

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 matching placebo tablet orally once daily for up to 24 months.

    Reporting group title
    JNJ-54861911 (5 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 5 milligram (mg) tablet orally once daily for up to 24 months (subjects randomized to this group received JNJ-54861911 10 mg prior to protocol amendment 3 and continued to receive JNJ-54861911 5-mg tablets after implementation of protocol Amendment 3; dated: 02-Mar-2016).

    Reporting group title
    JNJ-54861911 (25 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 25 mg tablet orally once daily for up to 24 months.

    Primary: Change from Baseline in Preclinical Alzheimer Cognitive Composite (PACC) Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Preclinical Alzheimer Cognitive Composite (PACC) Score at Endpoint (Month 24) [1]
    End point description
    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. Z-score implies how many SD higher or lower score as compared with baseline score with increase signifying improvement. ITT analysis set with subjects in whom PACC change score is non-missing at>=1 post-baseline timepoint.
    End point type
    Primary
    End point timeframe
    Baseline and Endpoint (Month 24)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    74
    73
    64
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.096 ( 1.7261 )
    -0.417 ( 1.8372 )
    -1.096 ( 1.7796 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cognitive Function Index (CFI) Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Cognitive Function Index (CFI) Score at Endpoint (Month 24)
    End point description
    The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument, a subject- 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 subject’s perceived ability to perform high-level functional tasks in daily-life and sense of overall cognitive functional ability. Study subjects and their informants independently rate the subject’s abilities. Total scores range from 0 to 14 (yes=1; no=0; maybe=0.5 for each question) with higher scores indicating greater impairment. Intent to treat (ITT) analysis set included all randomized subjects. Here ‘n’ (number analyzed) was defined as the number of subjects evaluable at specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Month 24)
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    185
    189
    183
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Total CFI Participant score:Month 54(n=28,27,26)
    -0.04 ( 1.866 )
    0.09 ( 1.135 )
    0.75 ( 2.628 )
        Total CFI Informant score:Month 54(n=27,27,26)
    -0.22 ( 1.660 )
    0.30 ( 1.469 )
    0.88 ( 2.475 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living - Prevention Instrument (ADCS-ADLPI) Total Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living - Prevention Instrument (ADCS-ADLPI) Total Score at Endpoint (Month 24)
    End point description
    The Alzheimer's Disease Cooperative Study - Activities of Daily Living -Prevention Instrument (ADCS-ADLPI) is a functional measure composed of 18 items that included 15 activities of daily living rated on a 4-point scale and 3 high level function items. Study subjects and their informants independently rate the subject’s level of ability. 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. ITT analysis set included all randomized subjects. Here ‘n’ (number analyzed) was defined as the number of subjects evaluable at specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Month 24)
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    185
    189
    183
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Total ADL Participant score: (n=124,117,110)
    -0.04 ( 2.975 )
    0.35 ( 2.832 )
    0.15 ( 2.834 )
        Total ADL Informant score (n= 122, 115, 109)
    0.26 ( 4.223 )
    -0.12 ( 3.941 )
    0.24 ( 4.085 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Scale Score at Endpoint (Month 24)
    End point description
    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 subject performance on various subtests, as well as a composite Total Index score for battery. 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. ITT analysis set included. Here 'N' (number of subjects analyzed): subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Month 24)
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    124
    121
    114
    Units: Score on a scale
        arithmetic mean (standard deviation)
    2.0 ( 8.90 )
    -0.9 ( 7.79 )
    -1.7 ( 9.75 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Endpoint (Month 24)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Month 24)
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [2] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    [3] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    [4] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score at Endpoint (Month 24)

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    End point title
    		 Change from Baseline in Neuropsychological Assessment Battery Daily Living Tests (NABDLTs) Score at Endpoint (Month 24)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline and Endpoint (Month 24)
    End point values
    		 Placebo JNJ-54861911 (5 mg) JNJ-54861911 (25 mg)
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [5] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    [6] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    [7] - Study terminated early due to less subjects, limited sample size. Data was not collected/analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 months
    Adverse event reporting additional description
    Safety analysis set included all randomized subjects who have received at least one study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 matching placebo tablet orally once daily for up to 24 months.

    Reporting group title
    JNJ-54861911 (25 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 25 mg tablet orally once daily for up to 24 months.

    Reporting group title
    JNJ-54861911 (5 mg)
    Reporting group description
    		 Subjects received a single dose of JNJ-54861911 5 milligram (mg) tablet orally once daily for up to 24 months (subjects randomized to this group received JNJ-54861911 10 mg prior to protocol amendment 3 and continued to receive JNJ-54861911 5-mg tablets after implementation of protocol Amendment 3; dated: 02-Mar-2016).

    Serious adverse events
    		 Placebo JNJ-54861911 (25 mg) JNJ-54861911 (5 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 185 (4.86%)
    26 / 183 (14.21%)
    18 / 189 (9.52%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Ovarian Tumour
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer Metastatic
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejaculation Failure
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erectile Dysfunction
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthmatic Crisis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Loss of Libido
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 185 (0.00%)
    3 / 183 (1.64%)
    2 / 189 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 185 (0.00%)
    2 / 183 (1.09%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured Ischium
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Lumbar Puncture Syndrome
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical Radiculopathy
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral Radiculopathy
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paralysis Recurrent Laryngeal Nerve
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mechanical Ileus
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 183 (0.55%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 185 (0.00%)
    3 / 183 (1.64%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 185 (0.00%)
    0 / 183 (0.00%)
    1 / 189 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poliomyelitis
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 183 (0.00%)
    0 / 189 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo JNJ-54861911 (25 mg) JNJ-54861911 (5 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 185 (43.24%)
    88 / 183 (48.09%)
    75 / 189 (39.68%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    9 / 185 (4.86%)
    14 / 183 (7.65%)
    9 / 189 (4.76%)
         occurrences all number
    9
    16
    16
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    8 / 185 (4.32%)
    12 / 183 (6.56%)
    9 / 189 (4.76%)
         occurrences all number
    8
    12
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 185 (7.57%)
    16 / 183 (8.74%)
    12 / 189 (6.35%)
         occurrences all number
    16
    19
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 185 (1.62%)
    11 / 183 (6.01%)
    5 / 189 (2.65%)
         occurrences all number
    3
    11
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 185 (3.78%)
    28 / 183 (15.30%)
    15 / 189 (7.94%)
         occurrences all number
    9
    34
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 185 (1.08%)
    6 / 183 (3.28%)
    12 / 189 (6.35%)
         occurrences all number
    2
    7
    13
    Psychiatric disorders
    Abnormal Dreams
         subjects affected / exposed
    1 / 185 (0.54%)
    11 / 183 (6.01%)
    4 / 189 (2.12%)
         occurrences all number
    1
    12
    4
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    9 / 185 (4.86%)
    10 / 183 (5.46%)
    11 / 189 (5.82%)
         occurrences all number
    9
    11
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    27 / 185 (14.59%)
    16 / 183 (8.74%)
    19 / 189 (10.05%)
         occurrences all number
    35
    21
    26
    Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 185 (10.27%)
    12 / 183 (6.56%)
    14 / 189 (7.41%)
         occurrences all number
    22
    20
    19
    Urinary Tract Infection
         subjects affected / exposed
    7 / 185 (3.78%)
    15 / 183 (8.20%)
    8 / 189 (4.23%)
         occurrences all number
    7
    18
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2015
    To add a risk-benefit statement to Section 1.3 (Target Population – Asymptomatic Subjects at Risk for Alzheimer’s Dementia), amend a secondary endpoint, and remove the listing of anticipated events.
    21 Jul 2015
    To add an additional adverse event of special interest to Section 11.10 (Safety Analyses).
    02 Mar 2016
    To reduce the 10-mg treatment to 5-mg of JNJ-54861911, to add additional scales to the study, and to make other required changes which were relevant to the study.
    31 May 2016
    To provide clarification and extra safety precautions to the lumbar puncture procedures (for those subjects who were receiving lumbar punctures for cerebrospinal fluid [CSF] sampling).
    24 Mar 2017
    To add new monitoring guidelines and stopping rules for liver enzymes during the first 3 months of treatment and to provide additional information on the management of elevated liver enzymes, to remove previously prohibited concomitant medications, to remove the stated-choice preference study, to update the frequency of the Alzheimer’s Disease Cooperative Study - Activities of Daily Living-Prevention Instrument (ADCS-ADL-PI), Cognitive Function Indexacute (CFI-a), and Columbia Suicide Severity Rating Scale’s administration, to provide additional information on adverse events of special interest (AESI), and to provide new guidelines for rescreening subjects.
    19 Dec 2017
    1) To add an additional blood draw in an optional substudy to characterize the T-cell response to study drug as a possible mechanism of druginduced hepatic enzyme elevation. This substudy was conducted in a limited set of subjects who experienced hepatic enzyme elevations. 2) To update and clarify 2 exclusion criteria, 3) To broaden criteria for medical professional permitted to perform skin examination, 4) To add the definition of the primary estimand to reflect the recent draft International Conference on Harmonisation (ICH) E9 addendum and the feedback received from health authorities, and 5) Other minor clarifications.
    25 May 2018
    1) Cessation of screening, randomization, and dosing, 2) JNJ 54861911 changed to atabecestat, and 3) other minor editorial updates.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 May 2018
    Due to study termination only about 1/3 of the subjects had PACC data at 6 months. As a result, some imbalances are likely among the remainder who did have post-baseline cognitive data, as small numbers of subjects in treatment arms increase the risk for imbalanced effects. In addition, factors to ensure balanced cognitive abilities were not stratified because larger enrollment numbers were assumed. Another important limitation of the study is the shift in the enrollment population over time, resulting in earlier subjects being more likely to contribute post-baseline data than later ones. Earlier subjects represented different countries, languages and test translations than the total population.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination of study/program due to a change in benefit-risk profile for individuals with early sporadic AD because of elevations in liver enzymes in participants receiving JNJ-54861911.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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