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    Clinical Trial Results:
    A Randomized, Two-Period, Double-Blind Placebo-Controlled and Open-Label, Multicenter Extension Study to Determine the Long-Term Safety and Tolerability of JNJ-54861911 in Subjects in the Early Alzheimer’s Disease Spectrum

    Summary
    EudraCT number
    		 2014-004274-41
    Trial protocol
    		 BE   SE   DE   ES   FR   NL  
    Global end of trial date
    28 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2019
    First version publication date
    11 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    54861911ALZ2004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02406027
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202 South, 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
    28 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety and tolerability of atabecestat in subjects in the early Alzheimer's disease (AD) spectrum who had completed a Phase 1b or Phase 2 clinical trial with atabecestat (for example, study 54861911ALZ2002), who were willing to continue their assigned treatment.
    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. Safety evaluations included monitoring of adverse events (AEs), clinical laboratory parameters (chemistry, hematology, urinalysis), vital signs, electrocardiograms (ECG), neurological, physical examination, amyloid related imaging abnormalities [ARIA]-edema or effusion [E] and ARIA-hemosiderin [H]); suicidality risk assessment (Columbia Suicide Severity Rating Scale [C-SSRS]); dermatologic and ophthalmologic examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 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
    Belgium: 13
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Sweden: 12
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    19
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 07 July 2015 to 28 June 2018. Subjects who completed their treatment period as described under parent protocol in study 54861911ALZ2002 (NCT02260674) or any ongoing/future Phase 1b or Phase 2 atabecestat clinical study were enrolled in this study.

    Pre-assignment
    Screening details
    		 A Total of 90 subjects were enrolled into period 1 (double-blind treatment phase). Of 90 subjects, 77 subjects completed period 1 and went on to receive active atabecestat treatment during period 2. All 77 subjects discontinued study.

    Period 1
    Period 1 title
    Double-blind Treatment Phase (Period 1)
    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
    		 Double-blind Treatment Phase (Period 1): Placebo
    Arm description
    		 Subjects received placebo matched to atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.
    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 placebo matched to atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Arm title
    		 Double-blind Treatment Phase (Period 1): Atabecestat 10 mg
    Arm description
    		 Subjects received 10 milligram (mg) of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat, 10 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Arm title
    		 Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Arm description
    		 Subjects received 25 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat, 25 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Number of subjects in period 1
    		Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Started
    35
    29
    26
    Completed
    29
    26
    22
    Not completed
    6
    3
    4
         Consent withdrawn by subject
    2
    1
    1
         Physician decision
    3
    -
    1
         Adverse event, non-fatal
    -
    2
    1
         Subject refused further study treatment
    1
    -
    1
    Period 2
    Period 2 title
    Open-label (Period 2)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg
    Arm description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat, 5 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who were receiving placebo in the Double-blind treatment phase, received the 5 mg atabecestat once daily until registration of atabecestat or any safety issue in Open-label phase.

    Arm title
    		 OL Phase (Period 2): Placebo to Atabecestat 25 mg
    Arm description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat, 25 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who were receiving placebo in the Double-blind treatment phase, received 25 mg atabecestat once daily until registration of atabecestat or any safety issue in Open-label phase.

    Arm title
    		 OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg
    Arm description
    		 Subjects who were receiving atabecestat 10 mg in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat 5 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who were receiving atabecestat 10 mg in the Double-blind treatment phase, received 5 mg atabecestat once daily until registration of atabecestat or any safety issue in Open-label phase.

    Arm title
    		 OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Arm description
    		 Subjects who were receiving atabecestat 25 mg in the Double-blind treatment phase continued to receive 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atabecestat 25 mg
    Investigational medicinal product code
    Other name
    JNJ-54861911
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who were receiving atabecestat 25 mg in the Double-blind treatment phase continued to receive 25 mg atabecestat once daily until registration of atabecestat or any safety issue in Open-label phase.

    Number of subjects in period 2
    		Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg OL Phase (Period 2): Placebo to Atabecestat 25 mg OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Started
    15
    14
    26
    22
    Completed
    0
    0
    0
    0
    Not completed
    15
    14
    26
    22
         Consent withdrawn by subject
    2
    4
    -
    2
         Physician decision
    -
    -
    1
    1
         At spouse request with PI agrement
    -
    -
    1
    -
         Adverse event, non-fatal
    2
    2
    -
    -
         Study terminated by sponsor
    11
    7
    24
    19
         Subject not Compliant to Study Procedure
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-blind Treatment Phase (Period 1): Placebo
    Reporting group description
    		 Subjects received placebo matched to atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 10 mg
    Reporting group description
    		 Subjects received 10 milligram (mg) of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Reporting group description
    		 Subjects received 25 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group values
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg Total
    Number of subjects
    		 35 29 26 90
    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)
    		 6 5 8 19
        From 65 to 84 years
    		 29 24 18 71
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.4 ( 5.15 ) 71.4 ( 7.04 ) 67.9 ( 8.87 ) -
    Title for Gender
    Units: subjects
        Female
    		 19 16 12 47
        Male
    		 16 13 14 43

    End points

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    End points reporting groups
    Reporting group title
    Double-blind Treatment Phase (Period 1): Placebo
    Reporting group description
    		 Subjects received placebo matched to atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 10 mg
    Reporting group description
    		 Subjects received 10 milligram (mg) of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Reporting group description
    		 Subjects received 25 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.
    Reporting group title
    Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg
    Reporting group description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Placebo to Atabecestat 25 mg
    Reporting group description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg
    Reporting group description
    		 Subjects who were receiving atabecestat 10 mg in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Reporting group description
    		 Subjects who were receiving atabecestat 25 mg in the Double-blind treatment phase continued to receive 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subjects who received study drug without regard to possibility of causal relationship. TEAEs were events between administration of study drug and up to 3 years that were absent before treatment or that worsened relative to pre-treatment state. An serious adverse event (SAE) is 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. Safety analysis set included all subjects who received at least 1 dose of study drug in the study (during Period 1 and 2).
    End point type
    Primary
    End point timeframe
    Up to 3 years
    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
    		 Double-blind Treatment Phase (Period 1): Placebo Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg Double-blind Treatment Phase (Period 1): Atabecestat 10 mg OL Phase (Period 2): Placebo to Atabecestat 25 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Number of subjects analysed
    35
    15
    29
    14
    26
    26
    22
    Units: Subjects
        Number of Subjects with TEAEs
    22
    10
    15
    11
    21
    19
    16
        Number of Subjects with Serious TEAEs
    3
    2
    4
    4
    4
    0
    1
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Amyloid Beta (ABeta) (1-37, 1-38, 1-40, 1-42) Levels

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    End point title
    		 Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Amyloid Beta (ABeta) (1-37, 1-38, 1-40, 1-42) Levels
    End point description
    The CSF samples were obtained for measuring levels of different ABeta fragments such as ABeta 1-37, ABeta 1-38, ABeta 1-40, ABeta 1-42. ABeta fragments of different length were produced by cleavage of the amyloid precursor protein (APP) by beta-secretase (BACE) and the gamma-secretase complex in the brain and excreted into CSF. Subjects were classified as 'Asymptomatic at Risk (AAR)' and 'Prodormal'. The Double-blind (DB) Safety Analysis Set included all subjects who received study treatment during Period 1. Here ‘n’ (number of subjects analysed) signifies those subjects who were evaluable for this endpoint at a given time point. For Arithmetic Mean and Standard Deviation (SD), 99999 indicates that data was not assessable as no subject was analysed for this endpoint at specified timepoints. For CSF ABeta 1-37 AAR at Week 52, 99999 indicates that SD could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    Baseline, Double-blind (DB) Day 1 and DB Week 52
    End point values
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Number of subjects analysed
    35
    29
    26
    Units: Percent change
    arithmetic mean (standard deviation)
        CSF ABeta 1-37: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-37: AAR: DB Week 52, n=4, 1, 1
    -9.9 ( 7.32 )
    -65.4 ( 99999 )
    -90.0 ( 99999 )
        CSF ABeta 1-37: Prodromal: DB Day 1, n=3, 0,0
    6.1 ( 10.09 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-37: Prodromal: DB Week 52, n=8, 8, 5
    -8.8 ( 17.75 )
    -62.0 ( 11.02 )
    -65.9 ( 23.16 )
        CSF ABeta 1-38: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-38: AAR: DB Week 52, n=4, 3, 2
    -9.3 ( 7.02 )
    -42.9 ( 17.49 )
    -83.5 ( 4.84 )
        CSF ABeta 1-38: Prodromal: DB Day 1, n=3, 0, 0
    10.2 ( 15.41 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-38: Prodromal: DB Week 52, n=10, 9, 10
    -9.7 ( 16.52 )
    -58.6 ( 10.21 )
    -70.4 ( 23.53 )
        CSF ABeta 1-40: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-40: AAR: DB Week 52, n=4, 3, 2
    -9.7 ( 6.12 )
    -46.2 ( 18.22 )
    -84.6 ( 5.43 )
        CSF ABeta 1-40: Prodromal: DB Day 1, n=3, 0, 0
    8.6 ( 17.19 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-40: Prodromal: DB Week 52, n=12, 9, 10
    -14.5 ( 20.48 )
    -60.7 ( 13.52 )
    -72.8 ( 22.30 )
        CSF ABeta 1-42: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-42: AAR: DB Week 52, n=4, 3, 2
    -10.1 ( 7.81 )
    -39.6 ( 24.28 )
    -76.7 ( 11.01 )
        CSF ABeta 1-42: Prodromal: DB Day 1, n=3, 0, 0
    8.0 ( 7.44 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF ABeta 1-42: Prodromal: DB Week 52, n=12, 9, 10
    -15.0 ( 20.51 )
    -52.5 ( 11.60 )
    -57.6 ( 31.42 )
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Soluble Amyloid Precursor Protein (sAPP) Fragments (sAPP-alpha and sAPP-beta) Levels

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    End point title
    		 Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Soluble Amyloid Precursor Protein (sAPP) Fragments (sAPP-alpha and sAPP-beta) Levels
    End point description
    The CSF samples were obtained for measuring levels of different soluble amyloid precursor protein (sAPP) fragments (sAPP-alpha, sAPP-beta). Subjects were classified as 'Asymptomatic at Risk (AAR)' and 'Prodormal'. The DB Safety Analysis Set included all subjects who received study treatment during Period 1. Here ‘n’ (number of subjects analysed) signifies those subjects who were evaluable for this endpoint at a given time point. For Arithmetic Mean and Standard Deviation (SD), 99999 indicates that data was not assessable as no subject was analysed for this endpoint at specified timepoints. For CSF sAPP-alpha and sAPP-Beta AAR at Week 52, 99999 indicates that Standard Deviation could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Day 1 and DB Week 52
    End point values
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Number of subjects analysed
    35
    29
    26
    Units: Percent change
    arithmetic mean (standard deviation)
        CSF sAPP-alpha: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF sAPP-alpha: AAR: DB Week 52, n=4, 3, 1
    -4.7 ( 12.78 )
    50.1 ( 13.67 )
    77.8 ( 99999 )
        CSF sAPP-alpha: Prodromal: DB Day 1, n=3, 0, 0
    0.9 ( 24.97 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF sAPP-alpha: Prodromal: DB Week 52, n=12, 9, 11
    -11.2 ( 14.01 )
    60.2 ( 24.03 )
    85.1 ( 39.35 )
        CSF sAPP-Beta: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF sAPP-Beta: AAR: DB Week 52, n=4, 3, 1
    -10.8 ( 8.44 )
    -57.5 ( 8.06 )
    -90.8 ( 99999 )
        CSF sAPP-Beta: Prodromal: DB Day 1, n=3, 0, 0
    0.4 ( 18.93 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF sAPP-Beta: Prodromal: DB Week 52, n=12, 9, 11
    -11.7 ( 14.47 )
    -63.5 ( 5.19 )
    -73.0 ( 21.79 )
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Plasma Amyloid Beta (ABeta) (1-38, 1-40, 1-42) Levels

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    End point title
    		 Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Plasma Amyloid Beta (ABeta) (1-38, 1-40, 1-42) Levels
    End point description
    Plasma samples were obtained for measuring levels of different ABeta fragments such as ABeta 1-38, ABeta 1-40, and ABeta 1-42. ABeta fragments of different length are produced by cleavage of the APP by beta-secretase (BACE) and the gamma-secretase complex in the different peripheral tissues, including white blood cells and can be measured in Plasma. Subjects were classified as 'Asymptomatic at Risk (AAR)' and 'Prodormal'. The DB Safety Analysis Set included all subjects who received study treatment during Period 1. Here ‘n’ (number of subjects analysed) signifies those subjects who were evaluable for this endpoint at a given time point. For Arithmetic Mean and Standard Deviation (SD), 99999 indicates that data was not assessable as no subject was analysed for this endpoint at specified timepoint. For Plasma ABeta 1-38 AAR at Week 52, ABeta 1-40 and 1-42 AAR at Day 1, 99999 indicates that SD could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Day 1, DB Week 24, and DB Week 52
    End point values
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Number of subjects analysed
    35
    29
    26
    Units: Percent change
    arithmetic mean (standard deviation)
        Plasma ABeta 1-38: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-38: AAR: DB Week 24, n=2, 0, 0
    -9.9 ( 0.83 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-38: AAR: DB Week 52, n=1, 0, 0
    -5.3 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-38: Prodromal: DB Day 1, n=4, 0, 3
    -5.0 ( 10.07 )
    99999 ( 99999 )
    -6.6 ( 13.56 )
        Plasma ABeta 1-38:Prodromal: DB Week 24, n=4,0,0
    3.0 ( 24.32 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-38:Prodromal: DB Week 52, n=3,0,0
    20.3 ( 35.48 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-40: AAR: DB Day 1, n=1, 1, 4
    19.2 ( 99999 )
    -4.9 ( 99999 )
    4.7 ( 40.27 )
        Plasma ABeta 1-40: AAR: DB Week 24, n=5, 4, 4
    -2.3 ( 12.38 )
    -75.2 ( 10.16 )
    -82.6 ( 5.59 )
        Plasma ABeta 1-40: AAR: DB Week 52, n=5, 4, 4
    0.0 ( 10.85 )
    -74.9 ( 6.76 )
    -80.8 ( 7.60 )
        Plasma ABeta 1-40:Prodromal: DB Day 1, n=12,3,7
    2.9 ( 15.48 )
    25.8 ( 66.03 )
    -24.2 ( 41.31 )
        Plasma ABeta 1-40:Prodromal:DB Week 24, n=21,16,14
    8.6 ( 18.57 )
    -68.6 ( 8.20 )
    -82.5 ( 7.38 )
        Plasma ABeta 1-40:Prodromal:DB Week 52, n=18,15,13
    10.5 ( 17.09 )
    -70.9 ( 9.24 )
    -75.3 ( 22.15 )
        Plasma ABeta 1-42: AAR: DB Day 1, n=1, 0, 0
    -5.9 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-42: AAR: DB Week 24, n=3, 0, 0
    -7.3 ( 9.33 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-42: AAR: DB Week 52, n=3, 0, 0
    -6.0 ( 2.69 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-42:Prodromal:DB Day 1, n=4,0,0
    -1.9 ( 5.54 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-42:Prodromal:DB Week 24, n=8,0,0
    15.9 ( 17.15 )
    99999 ( 99999 )
    99999 ( 99999 )
        Plasma ABeta 1-42:Prodromal:DB Week 52, n=6,0,0
    5.1 ( 17.68 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Tau Protein and Phosphorylated Tau (p-Tau) Protein Level

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    End point title
    		 Double-blind Treatment Phase (Period 1): Percent Change from Baseline in Cerebrospinal Fluid (CSF) Tau Protein and Phosphorylated Tau (p-Tau) Protein Level
    End point description
    The CSF samples were obtained for measuring levels of Tau protein and phosphorylated (p)-tau protein. The DB Safety Analysis Set included all subjects who received study treatment during Period 1. Here ‘n’ (number of subjects analysed) signifies those subjects who were evaluable for this endpoint at a given time point. For Arithmetic Mean and Standard Deviation (SD), 99999 indicates that data was not assessable as no subject was analysed for this endpoint at specified timepoint. For CSF Tau Protein and p-Tau Protein AAR at Week 52, 99999 indicates that SD could not be calculated for a single subject.
    End point type
    Secondary
    End point timeframe
    Baseline, DB Day 1 and DB Week 52
    End point values
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Number of subjects analysed
    35
    29
    26
    Units: Percent change
    arithmetic mean (standard deviation)
        CSF Tau Protein: AAR: DB Day 1, n=0, 0, 0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF Tau Protein: AAR: DB Week 52, n=4, 3, 1
    -1.4 ( 14.10 )
    3.2 ( 15.04 )
    22.4 ( 99999 )
        CSF Tau Protein: Prodromal:DB Day 1, n=3,0,0
    6.1 ( 6.82 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF Tau Protein: Prodromal:DB Week 52, n=12,9,11
    13.6 ( 45.55 )
    2.1 ( 13.82 )
    1.4 ( 8.20 )
        CSF p-Tau Protein: AAR:DB Day 1, n=0,0,0
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF p-Tau Protein: AAR:DB Week 52, n=4,3,1
    -4.6 ( 6.47 )
    -4.9 ( 1.40 )
    8.3 ( 99999 )
        CSF p-Tau Protein: Prodromal:DB Day 1, n=3,0,0
    -0.6 ( 7.81 )
    99999 ( 99999 )
    99999 ( 99999 )
        CSF p-Tau Protein: Prodromal: Week 52, n=12,9,11
    2.2 ( 12.93 )
    -2.7 ( 10.52 )
    -2.6 ( 8.52 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3 years
    Adverse event reporting additional description
    Safety analysis set included all subjects who received study treatment during Period 1 and 2.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Double-blind Treatment Phase (Period 1): Placebo
    Reporting group description
    		 Subjects received placebo matched to atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 10 mg
    Reporting group description
    		 Subjects received 10 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Double-blind Treatment Phase (Period 1): Atabecestat 25 mg
    Reporting group description
    		 Subjects received 25 mg of atabecestat orally, once daily from Day 1 up to Week 52 in the Double-blind treatment phase.

    Reporting group title
    Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg
    Reporting group description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Placebo to Atabecestat 25 mg
    Reporting group description
    		 Subjects who were receiving placebo in the Double-blind treatment phase, received 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg
    Reporting group description
    		 Subjects who were receiving atabecestat 10 mg in the Double-blind treatment phase, received 5 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Reporting group title
    OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Reporting group description
    		 Subjects who were receiving atabecestat 25 mg in the Double-blind treatment phase continued to receive 25 mg atabecestat orally, once daily until registration of atabecestat or any safety issue in Open-label phase.

    Serious adverse events
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg OL Phase (Period 2): Placebo to Atabecestat 25 mg OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 29 (13.79%)
    4 / 26 (15.38%)
    2 / 15 (13.33%)
    4 / 14 (28.57%)
    0 / 26 (0.00%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns Third Degree
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic Disorder
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Urinary
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric Obstruction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot Deformity
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-blind Treatment Phase (Period 1): Placebo Double-blind Treatment Phase (Period 1): Atabecestat 10 mg Double-blind Treatment Phase (Period 1): Atabecestat 25 mg Open-label (OL) Phase (Period 2): Placebo to Atabecestat 5 mg OL Phase (Period 2): Placebo to Atabecestat 25 mg OL Phase (Period 2): Atabecestat 10 mg to Atabecestat 5 mg OL Phase (Period 2): Atabecestat 25 mg to Atabecestat 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 35 (48.57%)
    11 / 29 (37.93%)
    14 / 26 (53.85%)
    10 / 15 (66.67%)
    11 / 14 (78.57%)
    12 / 26 (46.15%)
    11 / 22 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 26 (7.69%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    Skin Papilloma
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    Delirium
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    2 / 15 (13.33%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    1
    Depressive Symptom
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    2
    Nightmare
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    2 / 15 (13.33%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    3 / 14 (21.43%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    Intraocular Pressure Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 26 (7.69%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Transaminases Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    Weight Decreased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    0
    Periorbital Haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tendon Rupture
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Nervous system disorders
    Complex Regional Pain Syndrome
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    2 / 14 (14.29%)
    3 / 26 (11.54%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    1
    0
    2
    4
    1
    Tension Headache
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Ear and labyrinth disorders
    Ear Discomfort
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    6 / 35 (17.14%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 26 (7.69%)
    1 / 22 (4.55%)
         occurrences all number
    6
    0
    2
    0
    0
    2
    2
    Dry Eye
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Eye Pruritus
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Keratitis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Lacrimation Increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Macular Fibrosis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Vitreous Floaters
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    2 / 14 (14.29%)
    1 / 26 (3.85%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    1
    1
    2
    2
    1
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Inguinal Hernia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Actinic Keratosis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    2
    1
    1
    0
    Hair Colour Changes
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Nail Discolouration
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    2
    0
    1
    0
    1
    Seborrhoeic Dermatitis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 26 (3.85%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    4
    Muscle Spasms
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    Infections and infestations
    Abscess Neck
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Bacterial Blepharitis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    2
    1
    0
    1
    0
    Candida Infection
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    1
    Dermatophytosis of Nail
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 29 (6.90%)
    2 / 26 (7.69%)
    1 / 15 (6.67%)
    3 / 14 (21.43%)
    3 / 26 (11.54%)
    1 / 22 (4.55%)
         occurrences all number
    2
    3
    2
    1
    4
    3
    1
    Pneumonia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 26 (0.00%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 26 (7.69%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 26 (3.85%)
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2015
    The overall reason for the amendment #1 was to clarify that subjects who had progressed to dementia (Clinical Dementia Rating Scale [CDR] greater than or equal to [>=]1) in the parent protocol (54861911ALZ2002) would not be enrolled in Study 54861911ALZ2004. In addition, in the case where the subject progressed to a dementia state during the study, the subject may have remained in the study, provided that the investigator judged that the potential benefits of treatment for this subject clearly outweighed the known and foreseeable risks and consent for continued participation was obtained from a representative determined in accordance with the local law.
    08 Apr 2016
    The overall reason for the amendment #2 was to reduce the 10 mg treatment to 5 mg of atabecestat for Treatment Period 2, to increase the frequency of hematology and chemistry assessments in the study, and other required changes which were relevant to the study.
    26 Oct 2016
    The overall reason for the amendment #4 was to specify that hepatic enzyme elevations were to be classified as “adverse drug reactions” (ADRs) and to clarify the reporting of those events that were considered serious. Additionally, the text was modified and updated related to dermatologic and ophthalmologic/Optical coherence tomography (OCT) examinations. The text related to re-consenting subjects who experienced cognitive decline was updated and clarified in sections regarding the informed consent process. An overall risk-benefit assessment was added in the protocol.
    27 Mar 2017
    The overall reason for the amendment #5 was 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.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    28 Jun 2018
    Study was early terminated by the Sponsor.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The major limitation of this study was early termination of the study/program by the sponsor, which resulted in small numbers of subjects in groups, precluding meaningful interpretation of some of the analyses.
    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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