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    Clinical Trial Results:
    A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer’s Disease Dementia (Extension of Study AZES, The AMARANTH Study)

    Summary
    EudraCT number
    2016-003440-36
    Trial protocol
    HU   DE   PL   ES   BE   GB   FR   IT   RO  
    Global end of trial date
    02 Oct 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    05 Jan 2020
    First version publication date
    27 Jun 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Revision to Full Data Set

    Trial information

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    Trial identification
    Sponsor protocol code
    I8D-MC-AZFD
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02972658
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 16557
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Sponsor organisation name
    AstraZeneca UK Limited
    Sponsor organisation address
    Charter Way, Macclesfield, Cheshire, United Kingdom, SK10 2NA
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, AstraZeneca UK Limited, 44 1625-58-2828,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, AstraZeneca UK Limited, 44 1625-58-2828,
    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
    02 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study is an extension of study I8D-MC-AZES (NCT02245737), the AMARANTH study. The purpose of this study is to evaluate the effectiveness of the study drug lanabecestat in participants with early Alzheimer's disease dementia at the time of entry into study I8D-MC-AZES.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Mar 2017
    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
    Spain: 60
    Country: Number of subjects enrolled
    United Kingdom: 46
    Country: Number of subjects enrolled
    United States: 94
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Romania: 2
    Worldwide total number of subjects
    421
    EEA total number of subjects
    211
    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)
    96
    From 65 to 84 years
    325
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants who completed feeder study (AZES (NCT02245737)) were enrolled in this study.

    Pre-assignment
    Screening details
    Participants who were randomized in Study AZES to either 20 mg or 50 mg of lanabecestat continued on the treatment allocation from the feeder study. Participants randomized to placebo in Study AZES were randomized in a blinded fashion, 1:1 ratio, to either lanabecestat 20 mg or 50 mg daily (QD), administered orally.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AZES Placebo/AZFD Lanabecestat 20 mg
    Arm description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 20 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814, AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg film-coated tablets of lanabecestat administered orally once a day.

    Arm title
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg
    Arm description
    Participants who received lanabecestat 20 mg in the feeder study (AZES) were randomized to receive lanabecestat 20 mg. 1 participant was incorrectly marked as "Completed" rather than study terminated by Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814, AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg film-coated tablets of lanabecestat administered orally once a day.

    Arm title
    AZES Placebo/AZFD Lanabecestat 50 mg
    Arm description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814, AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg film-coated tablets of lanabecestat administered orally once a day.

    Arm title
    AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Arm description
    Participants who received lanabecestat 50 mg in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanabecestat
    Investigational medicinal product code
    Other name
    LY3314814, AZD3293
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg film-coated tablets of lanabecestat administered orally once a day.

    Number of subjects in period 1
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Started
    76
    139
    75
    131
    Received at least 1 Dose of Study drug
    76
    139
    74
    131
    Completed
    0
    1
    0
    0
    Not completed
    76
    138
    75
    131
         Withdrawal due to Caregiver Circumstance
    1
    1
    1
    -
         Adverse event, serious fatal
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    3
    -
    2
         Progressive Disease
    -
    1
    -
    1
         Other-selected by Investigator
    1
    1
    -
    -
         Consent withdrawn by subject
    4
    4
    1
    6
         Sponsor Decision
    70
    127
    72
    119
         Lost to follow-up
    -
    1
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZES Placebo/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 20 mg.

    Reporting group title
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received lanabecestat 20 mg in the feeder study (AZES) were randomized to receive lanabecestat 20 mg. 1 participant was incorrectly marked as "Completed" rather than study terminated by Sponsor.

    Reporting group title
    AZES Placebo/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.

    Reporting group title
    AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received lanabecestat 50 mg in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.

    Reporting group values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg Total
    Number of subjects
    76 139 75 131 421
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Details are from AZES baseline.
    Units: years
        arithmetic mean (standard deviation)
    70.7 ± 6.6 69.8 ± 7.8 71.1 ± 6.6 70.1 ± 6.7 -
    Gender categorical
    Units: Subjects
        Female
    35 76 40 75 226
        Male
    41 63 35 56 195
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    7 4 4 3 18
        Not Hispanic or Latino
    62 115 54 114 345
        Unknown or Not Reported
    7 20 17 14 58
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    7 23 10 16 56
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 2 1 0 3
        White
    64 104 51 106 325
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    5 10 13 9 37
    Region of Enrollment
    Units: Subjects
        Puerto Rico
    0 1 0 0 1
        Romania
    1 1 0 0 2
        Hungary
    1 0 0 0 1
        United States
    23 35 13 23 94
        Japan
    6 14 5 14 39
        United Kingdom
    8 17 8 13 46
        Spain
    10 21 8 21 60
        Canada
    6 8 5 14 33
        South Korea
    1 7 3 2 13
        Belgium
    5 2 0 4 11
        Poland
    6 8 6 14 34
        France
    4 9 12 8 33
        Australia
    3 13 8 6 30
        Germany
    2 3 7 12 24
    ADAS-Cog13 (13-item Alzheimer’s Disease Assessment Scale)
    ADAS-Cog13, a 13-item rating scale, measured the severity of cognitive dysfunction in persons with Alzheimer's disease (AD). Scores ranged from 0 to 85, with a higher score indicating worse cognitive functioning. Details are from AZES baseline.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    27.9 ± 8.3 29.6 ± 7.8 27.0 ± 7.5 27.1 ± 7.5 -

    End points

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    End points reporting groups
    Reporting group title
    AZES Placebo/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 20 mg.

    Reporting group title
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received lanabecestat 20 mg in the feeder study (AZES) were randomized to receive lanabecestat 20 mg. 1 participant was incorrectly marked as "Completed" rather than study terminated by Sponsor.

    Reporting group title
    AZES Placebo/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.

    Reporting group title
    AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received lanabecestat 50 mg in the feeder study (AZES) were randomized to receive lanabecestat 50 mg.

    Primary: Change From Baseline Analysis on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)

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    End point title
    Change From Baseline Analysis on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) [1]
    End point description
    ADAS-Cog13 is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 (apolipoprotein E4) status, AChEI (acetylcholinesterase inhibitor) use at baseline, age at baseline, and pooled country. Analysis Population Description (APD): All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.
    End point type
    Primary
    End point timeframe
    AZES Baseline through AZFD Week 26
    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: Because the feeder study AZES was stopped for futility, the original primary efficacy analysis (Delayed Start analysis) was replaced with MMRM analysis across AZES and AZFD. No comparisons between treatment groups were made.
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    139
    75
    131
    Units: Units on a scale
        least squares mean (standard error)
    9.61 ± 1.60
    9.25 ± 1.21
    8.41 ± 1.65
    10.41 ± 1.25
    No statistical analyses for this end point

    Secondary: Change From Baseline in Delayed Start Analysis on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)

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    End point title
    Change From Baseline in Delayed Start Analysis on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)
    End point description
    The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. APD: All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADCS-iADL measure.
    End point type
    Secondary
    End point timeframe
    AZES Baseline through AZFD Week 26
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    139
    74
    129
    Units: Units on a scale
        least squares mean (standard error)
    -9.19 ± 1.47
    -8.45 ± 1.10
    -7.37 ± 1.51
    -7.48 ± 1.14
    No statistical analyses for this end point

    Secondary: Change From Baseline in Delayed Start Analysis on the Functional Activities Questionnaire (FAQ) Score

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    End point title
    Change From Baseline in Delayed Start Analysis on the Functional Activities Questionnaire (FAQ) Score
    End point description
    FAQ is a 10-item, caregiver-questionnaire and was administered to the study partner and asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now =1; Never did but could do now =0; Normal =0; Has difficulty but does by self =1; Requires assistance =2; Dependent =3). FAQ scale is 0 to 30, with higher scores indicating greater impairment. LS Mean was determined by MMRM. APD: All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for FAQ score.
    End point type
    Secondary
    End point timeframe
    AZES Baseline through AZFD Week 26
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    137
    74
    130
    Units: Units on a scale
        least squares mean (standard error)
    6.28 ± 0.98
    7.09 ± 0.76
    6.73 ± 1.01
    6.91 ± 0.79
    No statistical analyses for this end point

    Secondary: Change From Baseline in Delayed Start Analysis on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score

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    End point title
    Change From Baseline in Delayed Start Analysis on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score
    End point description
    The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS- Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with with higher scores indicating greater impairment. LS Mean was determined by MMRM with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. APD: All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for iADRS.
    End point type
    Secondary
    End point timeframe
    AZES Baseline through AZFD Week 26
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    138
    72
    123
    Units: Units on a scale
        least squares mean (standard error)
    -18.85 ± 2.58
    -17.57 ± 1.97
    -15.37 ± 2.76
    -18.37 ± 2.09
    No statistical analyses for this end point

    Secondary: Change From Baseline in Delayed Start Analysis on the Mini-Mental Status Examination (MMSE)

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    End point title
    Change From Baseline in Delayed Start Analysis on the Mini-Mental Status Examination (MMSE)
    End point description
    The MMSE is an instrument used to assess a participant's cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with a higher score indicating better cognitive performance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. APD: All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for MMSE.
    End point type
    Secondary
    End point timeframe
    AZES Baseline through AZFD Week 26
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    139
    75
    131
    Units: Units on a scale
        least squares mean (standard error)
    -5.84 ± 0.71
    -5.73 ± 0.54
    -4.72 ± 0.72
    -5.25 ± 0.56
    No statistical analyses for this end point

    Secondary: Delayed Start Analysis on the ADAS-Cog13

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    End point title
    Delayed Start Analysis on the ADAS-Cog13
    End point description
    ADAS-Cog13 (13-item version of ADAS Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 (apolipoprotein E4) status, AChEI (acetylcholinesterase inhibitor) use at baseline, age at baseline, and pooled country. APD: All AZFD participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.
    End point type
    Secondary
    End point timeframe
    AZES Baseline through AZFD Week 52
    End point values
    AZES Placebo/AZFD Lanabecestat 20 mg AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Number of subjects analysed
    76
    139
    75
    131
    Units: Units on a scale
        least squares mean (standard error)
    16.64 ± 3.45
    12.40 ± 2.25
    16.79 ± 2.47
    15.05 ± 2.06
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up To 156 Weeks
    Adverse event reporting additional description
    All AZFD participants who received at least one dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received Lanabecestat 20 mg in the feeder study (AZES) received Lanabecestat 20 mg in AZFD.

    Reporting group title
    AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received Lanabecestat 50 mg in the feeder study (AZES) received Lanabecestat 50 mg in AZFD.

    Reporting group title
    AZES Placebo/AZFD Lanabecestat 20 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) received Lanabecestat 20 mg in AZFD.

    Reporting group title
    AZES Placebo/AZFD Lanabecestat 50 mg
    Reporting group description
    Participants who received placebo in the feeder study (AZES) received Lanabecestat 50 mg in AZFD.

    Serious adverse events
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg AZES Placebo/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 139 (5.76%)
    7 / 131 (5.34%)
    3 / 76 (3.95%)
    5 / 74 (6.76%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    radiation proctitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    electrocardiogram repolarisation abnormality
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    weight decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    breast cancer in situ
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    breast cancer metastatic
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    laryngeal squamous cell carcinoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 131 (0.00%)
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    bradycardia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    ischaemic stroke
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    optic neuritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    neuropsychiatric symptoms
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    colitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    enteritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    oesophageal motility disorder
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    diverticulitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    0 / 131 (0.00%)
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 131 (0.76%)
    0 / 76 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AZES Lanabecestat 20 mg/AZFD Lanabecestat 20 mg AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg AZES Placebo/AZFD Lanabecestat 20 mg AZES Placebo/AZFD Lanabecestat 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 139 (16.55%)
    17 / 131 (12.98%)
    11 / 76 (14.47%)
    8 / 74 (10.81%)
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    7 / 139 (5.04%)
    5 / 131 (3.82%)
    4 / 76 (5.26%)
    3 / 74 (4.05%)
         occurrences all number
    8
    8
    4
    3
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    8 / 139 (5.76%)
    6 / 131 (4.58%)
    2 / 76 (2.63%)
    2 / 74 (2.70%)
         occurrences all number
    8
    6
    2
    2
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 131 (1.53%)
    4 / 76 (5.26%)
    0 / 74 (0.00%)
         occurrences all number
    3
    2
    4
    0
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    8 / 139 (5.76%)
    5 / 131 (3.82%)
    1 / 76 (1.32%)
    3 / 74 (4.05%)
         occurrences all number
    10
    7
    1
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Feb 2018
    Amendment (a): Amended to -Extend the study additional year from original protocol. -Provided Clarification of when temporary discontinuation would be considered due to vasogenic edema.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was stopped after an independent assessment concluded that the feeder study AZES was futile. Because of this, the originally planned delayed-start analysis for this study was not performed.
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