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    Clinical Trial Results:
    A phase II randomized, double-blinded, placebo-controlled parallel group trial to examine the efficacy and safety of BI 425809 once daily with adjunctive Computerized Cognitive Training over 12 week treatment period in patients with schizophrenia

    Summary
    EudraCT number
    		 2018-002740-82
    Trial protocol
    		 GB  
    Global end of trial date
    04 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2023
    First version publication date
    15 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1346-0038
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03859973
    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
    07 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to provide proof of concept (PoC) data to assess the effect oncognition of oral once daily administration of iclepertin given for 12 weeks in patients with schizophrenia on stable antipsychotic treatment and adjunctive Computerised Cognitive Training (CCT). Other objectives of this trial were to explore endpoints to assess functioning and well-being of patients with schizophrenia and to evaluate safety and pharmacokinetics (PK) of iclepertin.
    Protection of trial subjects
    An individual patient was to be withdrawn from trial treatment if: - The patient wanted to withdraw from trial treatment or trial participation, without the need to justify the decision - The patient needed to take concomitant drugs that interfered with the investigational product or were restricted - The patient could no longer be treated with trial medication for other medical reasons (such as surgery, AEs, other diseases, or pregnancy) o If a patient became pregnant during the trial, the trial medication was to be stopped, the patient was to be discontinued from the trial and the patient was to be followed up until birth or otherwise termination of the pregnancy o For further information, including the process for follow-up on the outcome of the pregnancy - The patient had repeatedly shown to be non-compliant with important trial procedures and, in the opinion of both the investigator and sponsor representative, was not willing or able to stick to the trial requirements in the future - The patient exhibited suicidality, in the clinical judgement of the investigator or according to criteria below: o Any suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour) o Any suicidal ideation of type 4 or 5 in the Columbia-Suicide Severity Rating Scale (C-SSRS) (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent) - Hb level <100 g/L (10 g/dL) AND absolute drop of >20 g/L (2 g/dL) since baseline (Visit 2); or - The patient developed anaemia with symptoms of anaemia such as dizziness, fatigue, pallor, shortness of breath, etc. as determined by the investigator - The patient needed to stop all current antipsychotic medications - The patient’s disease state dramatically worsened, in clinical judgement of investigator - The patient experienced severe or serious symptomatic infection with SARS-CoV-2
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2019
    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
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 317
    Worldwide total number of subjects
    406
    EEA total number of subjects
    36
    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)
    406
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled in the trial once informed consent had been signed. Patients underwent computerised cognitive training (CCT) run-in for 2 weeks during the screening period. Patients compliant with the CCT run-in procedure and suitable after screening were randomised to the 12-week treatment period assigned at a ratio of 1:1 to 1 of 2 arms.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

    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, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    Patients, investigators, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial was to remain blinded with regard to the randomised treatment assignments (trial drug arms) until after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BI 425809 10 mg + Computerized Cognitive Training
    Arm description
    		 Patients administered once daily (in the morning) two tablets of 5 milligram (mg) of BI 425809 (total BI 425809 dose= 10 mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).
    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
    Patients administered once daily (in the morning) two tablets of 5 milligram (mg) of BI 425809 (total BI 425809 dose= 10 mg) orally for 12 weeks.

    Arm title
    		 Placebo + Computerized Cognitive Training
    Arm description
    		 Patients administered once daily (in the morning) two tablets of Placebo matching BI 425809 5 milligram (mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching BI 425809 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered once daily (in the morning) two tablets of Placebo matching BI 425809 5 milligram (mg) orally for 12 weeks.

    Number of subjects in period 1 [1]
    		BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Started
    99
    101
    Completed
    79
    75
    Not completed
    20
    26
         Consent withdrawn by subject
    8
    9
         Adverse event, non-fatal
    3
    5
         Other reason than listed
    3
    2
         COVID−19 related, not due to AE
    3
    4
         Lost to follow-up
    2
    3
         Protocol deviation
    1
    3
    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: Out of 406 screened participants only 200 were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 425809 10 mg + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) two tablets of 5 milligram (mg) of BI 425809 (total BI 425809 dose= 10 mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Reporting group title
    Placebo + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) two tablets of Placebo matching BI 425809 5 milligram (mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Reporting group values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training Total
    Number of subjects
    		 99 101 200
    Age categorical
    Treated Set (TS) includes all patients in RS who were treated with at least 1 dose of the trial regimen (including both trial drug and CCT).
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 99 101 200
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Treated Set (TS) includes all patients in RS who were treated with at least 1 dose of the trial regimen (including both trial drug and CCT).
    Units: years
        arithmetic mean (standard deviation)
    		 37.9 ( 8.1 ) 38.5 ( 7.7 ) -
    Sex: Female, Male
    Treated Set (TS) includes all patients in RS who were treated with at least 1 dose of the trial regimen (including both trial drug and CCT).
    Units: Participants
        Female
    		 34 30 64
        Male
    		 65 71 136
    Ethnicity (NIH/OMB)
    Treated Set (TS) includes all patients in RS who were treated with at least 1 dose of the trial regimen (including both trial drug and CCT).
    Units: Subjects
        Hispanic or Latino
    		 12 16 28
        Not Hispanic or Latino
    		 87 85 172
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Treated Set (TS) includes all patients in RS who were treated with at least 1 dose of the trial regimen (including both trial drug and CCT).
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 4 5 9
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 44 40 84
        White
    		 47 51 98
        More than one race
    		 2 2 4
        Unknown or Not Reported
    		 2 0 2
    Baseline MCCB neurocognitive composite T−score
    Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) neurocognitive composite T-score assesses 6 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving. MCCB neurocognitive T-scores in the general population have a mean of 50 and standard deviation of 10. A higher T-score indicates better cognition. Treated Set (TS). For one patient in the treated set MCCB neurocognitive T-Score at baseline was not measured.
    Units: T-score
        arithmetic mean (standard deviation)
    		 33.5 ( 12.0 ) 34.0 ( 11.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    BI 425809 10 mg + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) two tablets of 5 milligram (mg) of BI 425809 (total BI 425809 dose= 10 mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Reporting group title
    Placebo + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) two tablets of Placebo matching BI 425809 5 milligram (mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Primary: Change from baseline in neurocognitive function as measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of treatment

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    End point title
    		 Change from baseline in neurocognitive function as measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of treatment
    End point description
    MCCB neurocognitive composite T-score assesses 6 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving. MCCB neurocognitive T-scores in the general population have a mean of 50 and standard deviation of 10. A higher T-score indicates better cognition. Change from baseline in MCCB neurocognitive composite T-score at Week 12 was modelled based on a restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (screening, baseline, week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group, and continuous covariate of change from screening to baseline value. The Least Squares Mean (95 % Confidence Interval) at Week 12 is reported. Full Analysis Set (FAS).
    End point type
    Primary
    End point timeframe
    At screening (28 days prior to first drug drug administration), at baseline and at Weeks 6 and 12 after first drug administration.
    End point values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Number of subjects analysed
    88
    86
    Units: T-score
        least squares mean (confidence interval 95%)
    1.580 (0.370 to 2.790)
    2.466 (1.246 to 3.686)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (screening, baseline, week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group, and continuous covariate of change from screening to baseline value.
    Comparison groups
    BI 425809 10 mg + Computerized Cognitive Training v Placebo + Computerized Cognitive Training
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.3101
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.866
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.605
         upper limit
    		 0.833
    Notes
    [1] - Point estimate=Least Square Mean of (BI 425809 10 mg + Computerized Cognitive Training) - Least Square Mean of (Placebo + Computerized Cognitive Training)

    Secondary: Change from baseline in cognitive function as measured by the overall MCCB composite T score (including social cognition) after 12 weeks of treatment

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    End point title
    		 Change from baseline in cognitive function as measured by the overall MCCB composite T score (including social cognition) after 12 weeks of treatment
    End point description
    MCCB cognitive score comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. MCCB cognitive T-scores in the general population have a mean of 50 and standard deviation of 10. A higher T-score indicates better cognition. Change from baseline in MCCB overall composite T-score was modelled using a restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (screening, baseline, week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group, and continuous covariate of change from screening to baseline value. The Least Squares Mean (95 % Confidence Interval) at Week 12 is reported.
    End point type
    Secondary
    End point timeframe
    At screening (28 days prior to first drug drug administration), at baseline and at Weeks 6 and 12 after first drug administration.
    End point values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Number of subjects analysed
    88 [2]
    86 [3]
    Units: T-score
        least squares mean (confidence interval 95%)
    1.184 (-0.031 to 2.398)
    2.235 (1.011 to 3.459)
    Notes
    [2] - Full Analysis Set (FAS).
    [3] - Full Analysis Set (FAS).
    Statistical analysis title
    		 Statistican analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (screening, baseline, week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group, and continuous covariate of change from screening to baseline value.
    Comparison groups
    BI 425809 10 mg + Computerized Cognitive Training v Placebo + Computerized Cognitive Training
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2309 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.778
         upper limit
    		 0.676
    Notes
    [4] - Point estimate= Least Square Mean of (BI 425809 10 mg + Computerized Cognitive Training) - Least Square Mean of (Placebo + Computerized Cognitive Training)

    Secondary: Change from baseline in the effect of cognitive deficit on day-to-day functioning as measured by SCoRS total score after 12 weeks of treatment

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    End point title
    		 Change from baseline in the effect of cognitive deficit on day-to-day functioning as measured by SCoRS total score after 12 weeks of treatment
    End point description
    Schizophrenia Cognition Rating Scale (SCoRS) is a 20-item interview-based assessment of cognitive deficits and the degree to which they affect day-to-day functioning. Each item is rated on a 4-point scale. SCoRS total score is between 20 and 80 where higher score values represent greater degree of impairment in day-to-day functions due to cognitive deficits. The composite score was the average of non-missing responses. If five or more of the 20 items were missing, the composite score was missing for that participant at the visit. Change from baseline in SCoRS total score after 12 weeks of treatment was modelled using an Analysis of Covariance (ANCOVA) which included the following fixed effects: categorical factor of planned treatment, continuous covariate of baseline value, categorical factor of age group. FAS includes all patients in treated set (TS) who had non-missing baseline and at least 1 non-missing post-baseline on-treatment measurement of the primary efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    At baseline and at 12 weeks after first drug administration.
    End point values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Number of subjects analysed
    82 [5]
    75 [6]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -2.495 (-3.724 to -1.266)
    -3.072 (-4.358 to -1.787)
    Notes
    [5] - Only patients with non-missing results at Week 12 are reported.
    [6] - Only patients with non-missing results at Week 12 are reported.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis of Covariance (ANCOVA) which included the following fixed effects: categorical factor of planned treatment, continuous covariate of baseline value, categorical factor of age group.
    Comparison groups
    BI 425809 10 mg + Computerized Cognitive Training v Placebo + Computerized Cognitive Training
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.5237
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.577
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.207
         upper limit
    		 2.362
    Notes
    [7] - Point estimate= Least Square Mean of (BI 425809 10 mg + Computerized Cognitive Training) - Least Square Mean of (Placebo + Computerized Cognitive Training)

    Secondary: Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after 12 weeks of treatment

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    End point title
    		 Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after 12 weeks of treatment
    End point description
    PANSS was used to evaluate broad psychopathology associated with schizophrenia disease state. The PANSS has 30 items. Each is rated from 1 to 7 points. The total factor score is the summation of the actual points for each item, leading the total score ranging from 30 to 210; a higher score indicates a worse disease condition. Change from baseline in PANNS total score after 12 weeks of treatment was modelled based on a restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (baseline, Week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group. The Least Squares Mean (95 % Confidence Interval) at Week 12 is reported. Full Analysis Set (FAS).
    End point type
    Secondary
    End point timeframe
    At baseline and at Weeks 6 and 12 after first drug administration.
    End point values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Number of subjects analysed
    88
    85 [8]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -2.749 (-4.732 to -0.765)
    -2.080 (-4.104 to -0.055)
    Notes
    [8] - One patient in the FAS was excluded due to lack of post-baseline PANSS total score values.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML) based approach using a mixed model with repeated measurements (MMRM) which included the following fixed effects: categorical factor of planned treatment, visit (baseline, Week 6 and Week 12), planned treatment by visit interaction, continuous covariate of baseline value, baseline by visit interaction, categorical factor of age group.
    Comparison groups
    BI 425809 10 mg + Computerized Cognitive Training v Placebo + Computerized Cognitive Training
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.642
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.669
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.51
         upper limit
    		 2.172
    Notes
    [9] - Point estimate= Least Square Mean of (BI 425809 10 mg + Computerized Cognitive Training) - Least Square Mean of (Placebo + Computerized Cognitive Training)

    Secondary: Percentage of patients with any Adverse Event (AE) and with serious adverse events (SAEs)

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    End point title
    		 Percentage of patients with any Adverse Event (AE) and with serious adverse events (SAEs)
    End point description
    Percentage of patients with any Adverse Event (AE) and with serious adverse events (SAEs) is reported. Percentages were rounded to one decimal place. Treated Set (TS) includes all patients in randomized set (RS) who were treated with at least 1 dose of the trial regimen (including both trial drug and computerized cognitive training (CCT)).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug administration until four weeks after the last dose of study drug administration, up to 16 weeks.
    End point values
    		 BI 425809 10 mg + Computerized Cognitive Training Placebo + Computerized Cognitive Training
    Number of subjects analysed
    99
    101
    Units: percentage of participants
    number (not applicable)
        Any adverse event
    39.4
    56.4
        Serious adverse events
    1.0
    2.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug administration until four weeks after the last dose of study drug administration, up to 16 weeks.
    Adverse event reporting additional description
    Treated Set (TS) includes all patients in randomized set (RS) who were treated with at least 1 dose of the trial regimen (including both trial drug and computerized cognitive training (CCT)).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) two tablets of 5 milligram (mg) of Placebo matching BI 425809 orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Reporting group title
    BI 425809 10 mg + Computerized Cognitive Training
    Reporting group description
    		 Patients administered once daily (in the morning) orally two tablets of 5 milligram (mg) of BI 425809 (total BI 425809 dose= 10 mg) orally for 12 weeks. Concomitantly patients received non-pharmacological adjunctive computerized cognitive training (CCT).

    Serious adverse events
    		 Placebo + Computerized Cognitive Training BI 425809 10 mg + Computerized Cognitive Training
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 99 (1.01%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Computerized Cognitive Training BI 425809 10 mg + Computerized Cognitive Training
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 101 (15.84%)
    9 / 99 (9.09%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 101 (10.89%)
    7 / 99 (7.07%)
         occurrences all number
    14
    9
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 101 (5.94%)
    3 / 99 (3.03%)
         occurrences all number
    7
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2018
    Global Amendment 1, dated 21 Dec 2018 (prior to enrolment of the first patient; Independent Ethics Committee/Institutional review board (IEC/IRB) approval required): Proof of clinical concept (PoCC) was changed to proof of concept (PoC) to reflect exploratory nature of the trial. Exclusion criterion no. 24 was amended to remove exception for benzodiazepines (they were not included in the urine drug screen. New exclusion criterion no. 28 was added to exclude patients with an allergy to BI 425809 (iclepertin) and/or any of the excipients (including lactose) or placebo ingredients.
    02 Oct 2019
    Global Amendment 2, dated 02 Oct 2019 (IEC/IRB approval required): The following measures were introduced to minimise CCT exposure prior to randomisation: 1) Assessment of laboratory results was ideally done prior to start of CCT run-in; 2) CCT run-in was to be stopped once compliance was established; 3) CCT run-in was not to be repeated for re-screened patients. Screening Period was allowed to be extended up to 10 days (for total 38 days) in case cannabis re-testing per exclusion criterion 24 was performed, and time frame for cannabis re-testing was removed from Exclusion Criterion 24. Exclusion Criterion 19 was amended to exclude patients with known history of human immunodeficiency virus (HIV) infection based on review of medical history. The need for CCT sessions to be minimum 10 consecutive minutes in order to be included in weekly accrual time was removed. Sites were to determine the reason if the number of doses taken was greater than 100%. The MATRICS Consensus Cognitive Battery (MCCB) assessments at Visit 4 and(e)EoT Visit had to be started at the same time of the day as at Visit 2 (+/- 60 min).
    21 Jul 2020
    Global Amendment 3, dated 21 Jul 2020 (IEC/IRB approval required): Schizophrenia Cognition Rating Scale (SCoRS) assessment was added to Visit 1 (Screening). Additional follow up for patients with hemoglobin (Hb) decrease >20 g/L (2 g/dL) since baseline (Visit 2) or leading to symptoms of anaemia (e.g. dyspnoea, dizziness, etc.). The following inclusion criteria were re-phrased: 1) Criterion 4 to remove specific psychotropic medications and refer to them as examples; 2) Criterion 6 to allow randomisation of patients who did not meet the CCT run-in compliance threshold pending a documented discussion between the investigator and the Clinical Trial Manager (CTM) or Clinical Trial Lead(CTL); 3) Criterion 7 to remove the requirement to comply with at-home CCT exercises (to avoid overlap with Criterion 6). The following changes were made to address the COVID-19 pandemic: 1) New exclusion criterion 29 for patients with known active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the last 30 days prior to randomisation; 2) Additional criterion for discontinuation of trial treatment for patients that experienced severe or serious symptomatic infection with SARS-CoV-2.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    Patient involvement in the trial began in June 2019 and completed in November 2022, which included the period during which the COVID-19 pandemic was occurring globally. The trial was at the stage of recruitment when the pandemic occurred. Enrolment, randomisation, and site initiations for the trial were put on hold at all sites in March 2020 and re-started at different times in different countries depending on the local situation.
    -

    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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