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    Clinical Trial Results:
    A multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy and safety of orally administered BI 425809 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.

    Summary
    EudraCT number
    		 2015-005438-24
    Trial protocol
    		 AT   HU   NO   FI   GR   GB   ES   FR   IT  
    Global end of trial date
    11 Oct 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Dec 2020
    First version publication date
    24 Oct 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of NCT Number in section Trial Information / Additional Trial Identifier.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1346.23
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02788513
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.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
    19 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial was to assess safety, tolerability, and efficacy of different doses of BI 425809 compared with Placebo in patients with cognitive impairment due to Alzheimer's Disease.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required. For two subjects in the Adults (18-64 years) it does not reflect their true age. Their actual age is unknown. Subjects counted for Afghanistan does not reflect their true country. Their actual country is unknown.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 30
    Country: Number of subjects enrolled
    Canada: 69
    Country: Number of subjects enrolled
    Finland: 32
    Country: Number of subjects enrolled
    France: 114
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Greece: 52
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Japan: 70
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 67
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 221
    Country: Number of subjects enrolled
    Afghanistan: 2
    Worldwide total number of subjects
    851
    EEA total number of subjects
    489
    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)
    147
    From 65 to 84 years
    666
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy and safety of orally administered BI 425809 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer’s Disease.

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility prior to participation. Subjects attended a specialist site which ensured that they strictly met all eligibility criteria. Subjects were not to be allocated to a treatment group if any of the criteria were violated. One subject was randomized by error via Interactive Response Technology but never took a drug.

    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
    Blinding implementation details
    Double-blind trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 mg BI 425809
    Arm description
    		 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 425809
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Arm title
    		 5 mg BI 425809
    Arm description
    		 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 425809
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Arm title
    		 10 mg BI 425809
    Arm description
    		 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 425809
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Arm title
    		 25 mg BI 425809
    Arm description
    		 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 425809
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Arm title
    		 Placebo group
    Arm description
    		 Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
    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
    Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Number of subjects in period 1 [1]
    		2 mg BI 425809 5 mg BI 425809 10 mg BI 425809 25 mg BI 425809 Placebo group
    Started
    123
    122
    122
    123
    120
    Completed
    114
    114
    114
    117
    115
    Not completed
    9
    8
    8
    6
    5
         Consent withdrawn by subject
    3
    -
    2
    3
    1
         Adverse event, non-fatal
    5
    8
    4
    2
    2
         Decision by the study team
    -
    -
    -
    -
    1
         Lost to follow-up
    1
    -
    -
    -
    1
         Subject decided to stop taking treatment
    -
    -
    1
    -
    -
         Protocol deviation
    -
    -
    1
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject was screened/randomized by error via Interactive Response Technology (IRT) but never took a drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2 mg BI 425809
    Reporting group description
    		 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    5 mg BI 425809
    Reporting group description
    		 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    10 mg BI 425809
    Reporting group description
    		 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    25 mg BI 425809
    Reporting group description
    		 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    Placebo group
    Reporting group description
    		 Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group values
    		 2 mg BI 425809 5 mg BI 425809 10 mg BI 425809 25 mg BI 425809 Placebo group Total
    Number of subjects
    		 123 122 122 123 120 610
    Age categorical
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 22 23 8 18 23 94
        From 65-84 years
    		 97 90 107 101 92 487
        85 years and over
    		 4 9 7 4 5 29
    Age Continuous
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: years
        arithmetic mean (standard deviation)
    		 72.3 ± 7.5 72.5 ± 8.2 74.4 ± 6.9 72.9 ± 7.7 72.4 ± 7.9 -
    Sex: Female, Male
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: Participants
        Female
    		 68 62 66 64 64 324
        Male
    		 55 60 56 59 56 286
    Ethnicity (NIH/OMB)
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: Subjects
        Hispanic or Latino
    		 17 22 11 16 20 86
        Not Hispanic or Latino
    		 101 98 106 103 94 502
        Unknown or Not Reported
    		 5 2 5 4 6 22
    Race (NIH/OMB)
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 11 10 12 14 11 58
        Native Hawaiian or Other Pacific Islander
    		 0 2 1 1 2 6
        Black or African American
    		 10 5 4 3 8 30
        White
    		 97 103 100 102 93 495
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 5 2 5 3 6 21
    ADASCOG baseline cognitive assessment data
    Treated set (TS): The TS included all randomized subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for demographics, baseline characteristics and safety analyses.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 18.8 ± 7.9 18.8 ± 7.4 19.6 ± 7.8 19.6 ± 7.3 18.2 ± 8.0 -

    End points

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    End points reporting groups
    Reporting group title
    2 mg BI 425809
    Reporting group description
    		 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    5 mg BI 425809
    Reporting group description
    		 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    10 mg BI 425809
    Reporting group description
    		 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    25 mg BI 425809
    Reporting group description
    		 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    Placebo group
    Reporting group description
    		 Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Subject analysis set title
    2 mg BI 425809
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Subject analysis set title
    5 mg BI 425809
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Subject analysis set title
    10 mg BI 425809
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Subject analysis set title
    25 mg BI 425809
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Subject analysis set title
    Placebo group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Primary: Change from baseline in ADAS-Cog11 (Alzheimer's Disease Assessment Scale-Cognitive subscale 11 item) total score after 12 weeks of treatment

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    End point title
    		 Change from baseline in ADAS-Cog11 (Alzheimer's Disease Assessment Scale-Cognitive subscale 11 item) total score after 12 weeks of treatment
    End point description
    ADAS-Cog11 is a 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. Negative change is an improvement from BL. MCPmod + MMRM combination is used for primary analysis. MMRM included fixed, categorical covariates of treatment, visit, BL Mini Mental State Examination (>=20, <20) and treatment-by-visit interaction, as well as the continuous fixed covariates of BL and BL-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis. Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication, had a BL and at least one corresponding post-BL on-treatment efficacy assessment for any efficacy EP. FAS is used for efficacy analysis.
    End point type
    Primary
    End point timeframe
    On day 1 (visit 2, baseline) and day 85 (end of trial)
    End point values
    		 2 mg BI 425809 5 mg BI 425809 10 mg BI 425809 25 mg BI 425809 Placebo group
    Number of subjects analysed
    121
    120
    121
    119
    118
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.026 ± 4.864
    0.175 ± 4.471
    0.699 ± 4.313
    -0.174 ± 4.044
    0.138 ± 4.939
    Statistical analysis title
    		 MCPMod Beta model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.9931 [2]
    Method
    		 MCPMod Beta model fit.
    Confidence interval
    Notes
    [1] - Model assumption: 75% of max effect is achieved at 2 mg, 87.5% at 5 mg, 25% at 25 mg, max effect achieved at 10 mg of BI 425809, scalar parameter = 26
    [2] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 MCPMod Emax model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.9225 [4]
    Method
    		 MCPMod Emax model fit.
    Confidence interval
    Notes
    [3] - Model assumption: 20% of the maximum effect is achieved at 2 mg
    [4] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 MCPMod Sigmoidal Emax model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.9287 [6]
    Method
    		 MCPMod Sigmoidal Emax model fit.
    Confidence interval
    Notes
    [5] - Model assumption: 25% of max effect achieved at 5 mg and 75% of max effect achieved at 10 mg of BI 425809
    [6] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 MCPMod linear model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.7646 [8]
    Method
    		 MCPMod linear model fit.
    Confidence interval
    Notes
    [7] - No assumption needed
    [8] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 MCPMod linear in log model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.9335 [10]
    Method
    		 MCPMod linear in log model fit.
    Confidence interval
    Notes
    [9] - No assumption needed
    [10] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 MCPMod logistic model fit
    Statistical analysis description
    Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
    Comparison groups
    2 mg BI 425809 v 5 mg BI 425809 v 10 mg BI 425809 v 25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.8199 [12]
    Method
    		 MCPMod logistic model fit.
    Confidence interval
    Notes
    [11] - Model assumption: 10% of max effect achieved at 5 mg and 50% of max effect achieved at 10 mg of BI 425809
    [12] - An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
    Statistical analysis title
    		 Mixed model repeated measures (MMRM)
    Statistical analysis description
    MMRM is descripted is in the description section.
    Comparison groups
    2 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.934 [13]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 1.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Notes
    [13] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Mixed model repeated measures (MMRM)
    Statistical analysis description
    MMRM is descripted is in the description section.
    Comparison groups
    5 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6041 [14]
    Method
    		 MMRM
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Notes
    [14] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Mixed model repeated measures (MMRM)
    Statistical analysis description
    MMRM is described in the description section.
    Comparison groups
    10 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1926 [15]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Notes
    [15] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Mixed model repeated measures (MMRM)
    Statistical analysis description
    MMRM is described in the description section.
    Comparison groups
    25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9739 [16]
    Method
    		 MMRM
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58
    Notes
    [16] - p-values are nominal without multiplicity adjustment.

    Secondary: Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative Study/Activities of Daily Living) score after 12 weeks of treatment

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    End point title
    		 Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative Study/Activities of Daily Living) score after 12 weeks of treatment
    End point description
    Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative Study/Activities of Daily Living) score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.
    End point type
    Secondary
    End point timeframe
    On day 1 (visit 2, baseline) and day 85 (end of trial)
    End point values
    		 2 mg BI 425809 5 mg BI 425809 10 mg BI 425809 25 mg BI 425809 Placebo group
    Number of subjects analysed
    113
    111
    110
    116
    111
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.283 ± 6.805
    0.577 ± 5.852
    -1.145 ± 4.764
    -1.828 ± 7.034
    0.261 ± 4.842
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    2 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.979 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 1.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76
    Notes
    [17] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    5 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.521 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Notes
    [18] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    10 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.047 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.04
         upper limit
    		 -0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Notes
    [19] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.005 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.65
         upper limit
    		 -0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76
    Notes
    [20] - p-values are nominal without multiplicity adjustment.

    Secondary: Clinician's Interview-Based Impression of Change (CIBIC+) score after 12 weeks of treatment

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    End point title
    		 Clinician's Interview-Based Impression of Change (CIBIC+) score after 12 weeks of treatment
    End point description
    Clinician's Interview-Based Impression of Change (CIBIC+) score after 12 weeks of treatment is presented. Clinician's Interview-Based Impression of Change (CIBIC+) and Clinical Interview-Based Impression of Severity (CIBIS) scales are based on semi-structured interview covering domains of function and cognition. They additionally require the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (scores 1, 2 and 3 = improvement, 4 = no change, 5, 6 and 7 = deterioration). Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.
    End point type
    Secondary
    End point timeframe
    On day 1 (visit 2, baseline) and day 85 (end of trial)
    End point values
    		 2 mg BI 425809 5 mg BI 425809 10 mg BI 425809 25 mg BI 425809 Placebo group
    Number of subjects analysed
    114
    112
    110
    116
    112
    Units: score on a scale
        arithmetic mean (standard deviation)
    4.000 ± 0.941
    4.080 ± 0.773
    4.209 ± 0.679
    4.224 ± 0.781
    4.080 ± 0.829
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    2 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.343 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [21] - Mini Mental State Examination (MMSE)
    [22] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    5 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.645 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [23] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    10 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.448 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [24] - p-values are nominal without multiplicity adjustment.
    Statistical analysis title
    		 Analysis of Covariance (ANCOVA)
    Statistical analysis description
    Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
    Comparison groups
    25 mg BI 425809 v Placebo group
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.34 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [25] - p-values are nominal without multiplicity adjustment.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks.
    Adverse event reporting additional description
    Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    BI 5mg BI 425809
    Reporting group description
    		 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    BI 2mg BI 425809
    Reporting group description
    		 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    BI 25mg BI 425809
    Reporting group description
    		 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    Placebo group
    Reporting group description
    		 Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Reporting group title
    BI 10mg BI 425809
    Reporting group description
    		 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.

    Serious adverse events
    		 BI 5mg BI 425809 BI 2mg BI 425809 BI 25mg BI 425809 Placebo group BI 10mg BI 425809
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 122 (3.28%)
    5 / 123 (4.07%)
    4 / 123 (3.25%)
    5 / 120 (4.17%)
    4 / 122 (3.28%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic neoplasm
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 122 (0.82%)
    2 / 123 (1.63%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Dementia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Drug-induced liver injury
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Torticollis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 123 (0.81%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    1 / 123 (0.81%)
    0 / 120 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoglycaemia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    1 / 120 (0.83%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BI 5mg BI 425809 BI 2mg BI 425809 BI 25mg BI 425809 Placebo group BI 10mg BI 425809
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 122 (18.03%)
    17 / 123 (13.82%)
    19 / 123 (15.45%)
    12 / 120 (10.00%)
    14 / 122 (11.48%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 122 (7.38%)
    4 / 123 (3.25%)
    6 / 123 (4.88%)
    2 / 120 (1.67%)
    3 / 122 (2.46%)
         occurrences all number
    11
    5
    8
    4
    3
    Headache
         subjects affected / exposed
    10 / 122 (8.20%)
    6 / 123 (4.88%)
    5 / 123 (4.07%)
    5 / 120 (4.17%)
    7 / 122 (5.74%)
         occurrences all number
    12
    7
    9
    6
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 122 (0.82%)
    6 / 123 (4.88%)
    8 / 123 (6.50%)
    2 / 120 (1.67%)
    2 / 122 (1.64%)
         occurrences all number
    1
    8
    11
    2
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 122 (5.74%)
    3 / 123 (2.44%)
    3 / 123 (2.44%)
    3 / 120 (2.50%)
    3 / 122 (2.46%)
         occurrences all number
    9
    4
    3
    3
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2017
    The amendment introduced a new concept to detect efficacy signals in executive function and memory of the heterogeneous AD patient population in this trial. This included the deletion of the CDR from the main inclusion criteria, a change from ADAS-Cog13 to ADAS-Cog11 as primary endpoint, the deletion of CDR-SB (Clinical Dementia Rating Sum of Boxes) from the secondary endpoints, and the addition CIBIC+ as secondary endpoints and further cognitive tests (COWAT, VFT; Coding and Digit span). Lower Hb levels were allowed per inclusion criteria. The possibility to introduce Vitamin B12 and folate treatments was introduced if values were found below lower limit of normal at Visit 1. The Amendment added Visit 0 to allow comfortable time window for imaging, review of inclusion and exclusion criteria, and concomitant medications.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Sep 2016
    Following the identification of a new major metabolite, BI 761036, BI communicated a voluntary hold of the Phase II to relevant competent authorities on 16 Sep 2016, which was formalised as full clinical hold by FDA on 26 Oct 2016. The clinical hold was removed by FDA on 21 Nov 2017 and the trial was re-initiated.
    21 Nov 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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