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    Clinical Trial Results:
    A multi-centre, double-blind, parallel-group, randomized controlled study to investigate the efficacy, safety and tolerability of orally administered BI 409306 during a 12-week treatment period compared to placebo in patients with Alzheimer’s Disease

    Summary
    EudraCT number
    2013-005031-24
    Trial protocol
    DE   IT   PT   ES   BE   AT   NL   GB  
    Global end of trial date
    09 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Oct 2018
    First version publication date
    24 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1289.5
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02240693
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, 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
    20 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety, and tolerability of different doses of BI 409306 compared with placebo in treatment of prodromal Alzheimer’s disease (AD)
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 160
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Spain: 85
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    504
    EEA total number of subjects
    414
    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)
    78
    From 65 to 84 years
    402
    85 years and over
    24

    Subject disposition

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    Recruitment
    Recruitment details
    A multi-centre, double-blind, parallel-group, randomized controlled study to investigate the efficacy, safety and tolerability of orally administered BI 409306 during a 12-week treatment period compared to placebo in patients with Alzheimer’s Disease

    Pre-assignment
    Screening details
    For this trial, patients were randomised at 36 sites in 11 countries. Following an initial Screening Visit and a single blinded 2-week placebo run-in period, patients who qualified according to the in- and exclusion criteria were randomised to one of the five treatment groups

    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
    This trial incorporated a double-blind, double-dummy trial design

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BI 409306 10 milligram (mg) once daily (QD)
    Arm description
    Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 409306
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg BI 409306 once daily for 12 weeks

    Arm title
    BI 409306 25 mg QD
    Arm description
    Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 409306
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg BI 409306 once daily for 12 weeks

    Arm title
    BI 409306 50 mg QD
    Arm description
    Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 409306
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg BI 409306 once daily for 12 weeks

    Arm title
    BI 409306 25 mg twice daily (BID)
    Arm description
    Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 409306
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg BI 409306 twice daily for 12 weeks

    Arm title
    Placebo matching BI 409306
    Arm description
    Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks
    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
    Placebo matching 10 mg/25 mg/ 50 mg BI 409306 QD/BID for 12 weeks

    Number of subjects in period 1 [1]
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Started
    22
    21
    21
    21
    43
    Completed
    22
    21
    17
    20
    42
    Not completed
    0
    0
    4
    1
    1
         Other than specified
    -
    -
    2
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    2
    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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 409306 10 milligram (mg) once daily (QD)
    Reporting group description
    Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg QD
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 50 mg QD
    Reporting group description
    Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg twice daily (BID)
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.

    Reporting group title
    Placebo matching BI 409306
    Reporting group description
    Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks

    Reporting group values
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306 Total
    Number of subjects
    22 21 21 21 43 128
    Age categorical
    Units: Subjects
    Age Continuous
    Age at the time of signing informed consent form is presented. Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
    Units: years
        arithmetic mean (standard deviation)
    72.3 ± 5.4 74.1 ± 8.1 73.3 ± 5.1 71.9 ± 6.0 72.2 ± 6.5 -
    Sex: Female, Male
    Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
    Units: Subjects
        Female
    10 12 8 13 28 71
        Male
    12 9 13 8 15 57
    Race (NIH/OMB)
    Race data is presented below; Ethnicity was not reported in this trial
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0
        Asian
    0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0
        Black or African American
    0 0 0 0 0 0
        White
    22 21 21 21 43 128
        More than one race
    0 0 0 0 0 0
        Unknown or Not Reported
    0 0 0 0 0 0
    Neuropsychological Test Battery (NTB) Total
    Baseline cognitive assessment data- NTB total z-score. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests.
    Units: Unit on scale
        arithmetic mean (standard deviation)
    0.07 ± 0.70 0.02 ± 0.75 -0.02 ± 0.72 -0.02 ± 0.61 -0.03 ± 0.63 -

    End points

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    End points reporting groups
    Reporting group title
    BI 409306 10 milligram (mg) once daily (QD)
    Reporting group description
    Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg QD
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 50 mg QD
    Reporting group description
    Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg twice daily (BID)
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.

    Reporting group title
    Placebo matching BI 409306
    Reporting group description
    Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks

    Subject analysis set title
    Pooled BI 409306
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.

    Subject analysis set title
    Pooled BI 409306
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.

    Primary: Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment.

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    End point title
    Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment.
    End point description
    Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. Least Squares Mean is actually an adjusted mean change from baseline. The full analysis set (FAS): FAS includes all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one post-baseline on-treatment primary endpoint NTB or secondary endpoint assessment. Observed cases (OC).
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306 Pooled BI 409306
    Number of subjects analysed
    20 [1]
    19 [2]
    16 [3]
    18 [4]
    39 [5]
    73 [6]
    Units: Unit on scale
        least squares mean (standard error)
    0.35 ± 0.061
    0.20 ± 0.063
    0.26 ± 0.065
    0.32 ± 0.064
    0.27 ± 0.043
    0.29 ± 0.031
    Notes
    [1] - FAS (OC)
    [2] - FAS (OC)
    [3] - FAS (OC)
    [4] - FAS (OC)
    [5] - FAS (OC)
    [6] - FAS (OC)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.3236 [8]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.074
         upper limit
    0.223
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.075
    Notes
    [7] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [8] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 25 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.3694 [10]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    0.082
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Notes
    [9] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [10] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 50 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.8374 [12]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.171
         upper limit
    0.139
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.078
    Notes
    [11] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [12] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.5484 [14]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.106
         upper limit
    0.199
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.077
    Notes
    [13] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
    [14] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    Placebo matching BI 409306 v Pooled BI 409306
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.7905 [16]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.092
         upper limit
    0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Notes
    [15] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
    [16] - p-value was nominal and not adjusted.

    Secondary: Change from baseline in ADCS-MCI-ADL (Alzheimer's Disease Cooperative Study/Activities of Daily Living for patients with mild cognitive impairment) total score after 12-week treatment

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    End point title
    Change from baseline in ADCS-MCI-ADL (Alzheimer's Disease Cooperative Study/Activities of Daily Living for patients with mild cognitive impairment) total score after 12-week treatment
    End point description
    Alzheimer's Disease Cooperative Study/Activities of Daily Living (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. Each item has a score range varying from 0-3 to 0-5. The sum score can range from 0 to 78. Higher scores indicate better function. Least Squares Mean is actually an adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Number of subjects analysed
    19 [17]
    18 [18]
    20 [19]
    17 [20]
    37 [21]
    Units: Unit on scale
        least squares mean (standard error)
    0.24 ± 0.896
    1.79 ± 0.921
    -0.10 ± 0.875
    0.80 ± 0.947
    0.38 ± 0.642
    Notes
    [17] - FAS
    [18] - FAS
    [19] - FAS
    [20] - FAS
    [21] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    = 0.8973 [23]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.33
         upper limit
    2.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.102
    Notes
    [22] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
    [23] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 25 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.2141 [25]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    3.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.122
    Notes
    [24] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
    [25] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 50 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.6553 [27]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.64
         upper limit
    1.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.085
    Notes
    [26] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [27] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.7166 [29]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.85
         upper limit
    2.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.144
    Notes
    [28] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [29] - p-value was nominal and not adjusted.

    Secondary: Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment

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    End point title
    Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment
    End point description
    Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) is obtained through semi-structured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). Least Squares Mean is actually an adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Number of subjects analysed
    21 [30]
    19 [31]
    16 [32]
    18 [33]
    40 [34]
    Units: Unit on scale
        least squares mean (standard error)
    0.0 ± 0.19
    0.4 ± 0.20
    -0.1 ± 0.22
    0.1 ± 0.21
    0.1 ± 0.14
    Notes
    [30] - FAS
    [31] - FAS
    [32] - FAS
    [33] - FAS
    [34] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.9491 [36]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.49
         upper limit
    0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [35] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [36] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 25 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    = 0.1699 [38]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [37] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [38] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 50 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.4948 [40]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [39] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [40] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. Kenward−Roger was used to model degrees of freedom.
    Comparison groups
    BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    = 0.7548 [42]
    Method
    Mixed Model Repeated Measurement (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [41] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [42] - p-value was nominal and not adjusted.

    Secondary: Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment

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    End point title
    Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment
    End point description
    Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) is an 11-item cognitive subscale that objectively measures memory, language, orientation, and praxis with a total score range of 0 to 70. Least Squares Mean is actually an adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 weeks
    End point values
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Number of subjects analysed
    19 [43]
    17 [44]
    19 [45]
    19 [46]
    38 [47]
    Units: Unit on scale
        least squares mean (standard error)
    0.98 ± 0.885
    0.62 ± 0.935
    0.12 ± 0.875
    -1.27 ± 0.875
    1.24 ± 0.619
    Notes
    [43] - FAS
    [44] - FAS
    [45] - FAS
    [46] - FAS
    [47] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.8137 [49]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    1.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.081
    Notes
    [48] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [49] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 25 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    = 0.5801 [51]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.84
         upper limit
    1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.12
    Notes
    [50] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [51] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 50 mg QD v Placebo matching BI 409306
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority [52]
    P-value
    = 0.2978 [53]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.25
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.072
    Notes
    [52] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [53] - p-value was nominal and not adjusted.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
    Comparison groups
    BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    P-value
    = 0.0209 [55]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.64
         upper limit
    -0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.072
    Notes
    [54] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
    [55] - p-value was nominal and not adjusted.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study medication until 7 days after last administration of BI 409306, up to 16 weeks.
    Adverse event reporting additional description
    The treated set (TS) used (all patients who were randomised and treated with at least one dose of trial medication.) for safety assessment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    BI 409306 10 milligram (mg) once daily (QD)
    Reporting group description
    Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg QD
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 50 mg QD
    Reporting group description
    Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.

    Reporting group title
    BI 409306 25 mg twice daily (BID)
    Reporting group description
    Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.

    Reporting group title
    Placebo matching BI 409306
    Reporting group description
    Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.

    Serious adverse events
    BI 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    1 / 43 (2.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 43 (2.33%)
         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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 43 (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 409306 10 milligram (mg) once daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg twice daily (BID) Placebo matching BI 409306
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 22 (54.55%)
    13 / 21 (61.90%)
    14 / 21 (66.67%)
    13 / 21 (61.90%)
    22 / 43 (51.16%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
    4 / 21 (19.05%)
    0 / 21 (0.00%)
    4 / 43 (9.30%)
         occurrences all number
    3
    0
    4
    0
    5
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 21 (14.29%)
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 43 (0.00%)
         occurrences all number
    3
    4
    2
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 21 (19.05%)
    3 / 21 (14.29%)
    0 / 21 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    2
    4
    3
    0
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    0 / 21 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2014
    Amendment 1 introduced changes to inclusion criteria #7 and #8, to be in accordance with ICH-GCP. The option of consent by a legal representative was deleted throughout the CTP.Based on scientific advice from external experts, the cut-offs for the MMSE were changed and a cut-off for the global CDR-score was introduced to more appropriately describe the target population. The amendment introduced changes to exclusion criterion #13: The acceptable methods of birth control for female patients of child-bearing potential were changed based on authority feedback. An additional exclusion criterion concerning birth control for male patients was added. Relevant CYP2C19 inducers were added to the list of restricted concomitant medication. Amendment 1 added the option of doing the neuropsychological assessments of Visit 3 on the day before, i.e. on the last day of the screening period, to increase feasibility. The change was made based on feedback from investigators. Based on feedback from authorities, Visit 4 was changed to be a clinic visit. Serology was added, to be done in case of reported liver injury. Several changes were introduced to align the CTP with project standards: - The follow-up period was extended to 4 weeks - Exclusion criterion #10 was updated to include DSM-V - The wording on reporting of visual AEs was moved and changed - The instructions for assessment of safety laboratory parameters were reworded; - Vitamin B12 and Folate were added. - Transmitting ECGs to the vendor was introduced, instead of electronic storage at the site only. - The instructions for neuropsychological assessments were reworded.
    03 Aug 2015
    Amendment 3 specified the definition of eligible patients further. According to feedback from the investigators, patients with prodromal AD usually ask for treatment and sometimes take available AD medication, despite the fact that there are no treatments registered for prodromal AD. In order to avoid unnecessary limitation to the recruitment, patients who previously took AD treatment were allowed to enter the trial. The restrictions for intake of drugs for treatment of AD during trial participation were updated accordingly, to clarify that patients who took AD treatment previously were not allowed to use these treatments during the trial. The number of neuropsychological scales was reduced to reduce patient burden during the visits. This did not have an impact on primary and secondary analyses, as many items of the removed scales were still part of the remaining assessments. The amendment allowed use of strong or moderate CYP3A4 inhibitors as a clinical trial did not show an impact on exposure to BI 409306 after CYP3A4 inhibition. To allow patients with a contraindication for MRI to enter the trial, the use of a CCT to exclude other disorders causing prodromal AD was allowed. The analysis models for secondary endpoints with different number of data collection visits were clarified. Text clarifications were also implemented.

    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.
    Additional combined primary and/or secondary endpoints are defined and analyzed for trial 1289.5 and 1289.7, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02240693
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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