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    Clinical Trial Results:
    Add-on spironolactone for the treatment of schizophrenia.

    Summary
    EudraCT number
    		 2014-001968-35
    Trial protocol
    		 DE  
    Global end of trial date
    11 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2024
    First version publication date
    02 Feb 2023
    Other versions
    Summary report(s)
    		 CSR-SPIRO

    Trial information

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    Trial identification
    Sponsor protocol code
    SPIROTREAT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Klinikum der Universität München, vertreten durch den Vorstand
    Sponsor organisation address
    Marchioninistraße 15, München , Germany, 81377
    Public contact
    PD Dr. rer nat. Peter Zill , Klinikum der Universität München - AöR vertreten durch den Vorstand des Bereichs Humanmedizin, 0049 89 4400 52741, Peter.Zill@med.uni-muenchen.de
    Scientific contact
    Prof. Dr. med. Alkomiet Hasan, Klinikum der Universität München - AöR vertreten durch den Vorstand des Bereichs Humanmedizin, 0049 821 4803 1001, alkomiet.hasan@med.uni-augsburg.de
    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
    15 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary endpoint: Improvement of working memory in n-back after 3 weeks. Primary Objective • To evaluate the improvement of working memory according to the n-Back performance (2-back level, relative hit rate) before and after the intervention period (V1 vs V10)
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles of Good Clinical Practice (GCP). Each participating subject signed informed consent form and they could withdraw from the study at any time without any disadvantages and without giving reasons for this decision. The study was regularly monitored by the Sponsor and all investigators connected to the study were GCP trained. The competent Ethics Committee and the German competent authorities approved the clinical trial.
    Background therapy
    		 Ongoing stable antipsychotic treatment (standard of care) for at least one week.
    Evidence for comparator
    		 n.a.
    Actual start date of recruitment
    08 Jul 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Scientific research
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    84
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The placebo-controlled, double blind and three-arm clinical trial was conducted in Germany at three sites. Between July 2015 and May 2020 all patients were randomised in one of the three arms. A randomization did not take place until a final check conforms that all inclusion or no exclusion criteria applied.

    Pre-assignment
    Screening details
    		 Pre-screening processes were in place, a total of 162 patients were scheduled for screening. The pre-screening and the screening phases took place in the two weeks prior to randomization. Suitable patients were approached by the investigators regarding participation in the study. No study-specific procedures took place in the pre-screening phase.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    In every group, participants receive two identical capsules per day to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Add-on 100
    Arm description
    		 Add-on 100 mg spironolactone (3 weeks of double-blind intervention phase)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spironolactone
    Investigational medicinal product code
    C03DA01
    Other name
    Spironolacton HEXAL, SPIRONOLACTONE, SUB10631MIG
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Group I: Spironolactone 100 mg At day (D) 1 capsule with 50 mg spironolactone and 1 capsule with placebo, from D2 to D21 two capsules with 50 mg spironolactone (100 mg in total) per day.

    Arm title
    		 Add-on 200
    Arm description
    		 Add-on 200 mg spironolactone (3 weeks of double-blind intervention phase)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spironolactone
    Investigational medicinal product code
    C03DA01
    Other name
    Spironolacton HEXAL, SPIRONOLACTONE, SUB10631MIG
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Group II: Spironolactone 200 mg At D1 one capsule with 50 mg spironolactone and one capsule with placebo, at D2 two capsules with 50 mg spironolactone (100 mg in total), at D3 one capsule with 50 mg spironolactone and one capsule with 100 mg spironolactone (150 mg in total) and from D4 to D21 two capsules with 100 mg spironolactone per day (200 mg in total).

    Arm title
    		 Add-on
    Arm description
    		 Add-on placebo (3 weeks of double-blind intervention phase)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Group III: Placebo In group III (placebo), two capsules with placebo from D 1 to D 21.

    Number of subjects in period 1
    		Add-on 100 Add-on 200 Add-on
    Started
    30
    28
    26
    Completed
    29
    25
    19
    Not completed
    1
    3
    7
         Not randomized, no study medication
    -
    -
    1
         Consent withdrawn by subject
    -
    2
    2
         Other reasons
    -
    1
    1
         Lost to follow-up
    -
    -
    1
         Protocol deviation
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Add-on 100
    Reporting group description
    		 Add-on 100 mg spironolactone (3 weeks of double-blind intervention phase)

    Reporting group title
    Add-on 200
    Reporting group description
    		 Add-on 200 mg spironolactone (3 weeks of double-blind intervention phase)

    Reporting group title
    Add-on
    Reporting group description
    		 Add-on placebo (3 weeks of double-blind intervention phase)

    Reporting group values
    		 Add-on 100 Add-on 200 Add-on Total
    Number of subjects
    		 30 28 26 84
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 30 28 26 84
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 36.5 (20 to 62) 35.5 (19 to 57) 35.5 (18 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9 5 23
        Male
    		 21 19 21 61
    Course of the disease
    Course of the disease (no. continuous / no. episodic)
    Units: Subjects
        No. continous
    		 14 7 9 30
        No. episodic
    		 16 21 17 54
    Age at first hospitilisation
    Age of first indication-related hospital stay
    Units: Years
        median (full range (min-max))
    		 25 (17 to 56) 24 (17 to 44) 26 (16 to 48) -
    Duration of illness
    Units: months
        median (full range (min-max))
    		 72 (7 to 432) 114 (8 to 324) 114 (11 to 456) -
    Number of hospitalizations
    Units: Number
        median (full range (min-max))
    		 3 (1 to 30) 2 (1 to 20) 3 (3 to 30) -
    Duration of school education
    Units: years
        median (full range (min-max))
    		 10 (8 to 15) 12 (9 to 17) 11 (8 to 17) -
    Duration school and Vocational Training
    Units: years
        median (full range (min-max))
    		 13 (8 to 23) 15 (9 to 26) 13 (9 to 23) -
    Blood pressure sys
    Blood pressure systolisch at baseline
    Units: mmHg
        median (full range (min-max))
    		 120.0 (101 to 164) 124.5 (103 to 160) 125.5 (96 to 145) -
    Blood pressure dia
    Blood pressure diastolisch at baseline
    Units: mmHg
        median (full range (min-max))
    		 79 (62 to 103) 83 (62 to 102) 82 (57 to 96) -
    Heart Frequence
    Units: bpm
        median (full range (min-max))
    		 80,5 (61 to 101) 83 (55 to 120) 85,5 (64 to 105) -
    Weight
    Units: kg
        median (full range (min-max))
    		 79.1 (54 to 114) 87.45 (50,3 to 116) 88 (59 to 157) -
    Height
    Units: cm
        median (full range (min-max))
    		 172 (153 to 193) 178.5 (162 to 191) 179 (158 to 193) -
    Body-Mass-Index
    BMI at baseline
    Units: BMI
        median (full range (min-max))
    		 26.5 (17.9 to 40.4) 26.4 (18.4 to 38.6) 28.1 (23.2 to 44.1) -
    PANSS pos
    PANSS positive score baseline
    Units: Score
        median (full range (min-max))
    		 11.5 (7 to 19) 12 (7 to 20) 12 (7 to 20) -
    PANSS neg
    PANSS negative score baseline
    Units: Score
        median (full range (min-max))
    		 14.5 (7 to 24) 13 (8 to 25) 15 (8 to 22) -
    PANSS general
    PANSS general score baseline
    Units: Score
        median (full range (min-max))
    		 26.5 (18 to 43) 24 (16 to 35) 27 (16 to 38) -
    PANSS total
    PANSS total score baseline
    Units: Score
        median (full range (min-max))
    		 50.5 (36 to 72) 51.5 (32 to 75) 53.5 (33 to 71) -
    Subject analysis sets

    Subject analysis set title
    IIT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of IMP

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients who received at least one dose of IMP

    Subject analysis sets values
    		 IIT PP
    Number of subjects
    84
    73
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    84
    73
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    36 (18 to 62)
    36 (18 to 62)
    Gender categorical
    Units: Subjects
        Female
    23
    19
        Male
    61
    54
    Course of the disease
    Course of the disease (no. continuous / no. episodic)
    Units: Subjects
        No. continous
    29
    23
        No. episodic
    54
    49
    Age at first hospitilisation
    Age of first indication-related hospital stay
    Units: Years
        median (full range (min-max))
    25 (17 to 56)
    27 (16 to 56)
    Duration of illness
    Units: months
        median (full range (min-max))
    100 (7 to 456)
    96 (7 to 456)
    Number of hospitalizations
    Units: Number
        median (full range (min-max))
    2,67 (1 to 30)
    2,8 (1 to 30)
    Duration of school education
    Units: years
        median (full range (min-max))
    11 (8 to 17)
    11 (8 to 17)
    Duration school and Vocational Training
    Units: years
        median (full range (min-max))
    13,66 (8 to 26)
    13,5 (8 to 26)
    Blood pressure sys
    Blood pressure systolisch at baseline
    Units: mmHg
        median (full range (min-max))
    124 (101 to 164)
    124 (103 to 164)
    Blood pressure dia
    Blood pressure diastolisch at baseline
    Units: mmHg
        median (full range (min-max))
    81,3 (57 to 103)
    81,2 (62 to 103)
    Heart Frequence
    Units: bpm
        median (full range (min-max))
    83 (55 to 120)
    82 (55 to 120)
    Weight
    Units: kg
        median (full range (min-max))
    84.9 (50.3 to 157)
    85 (50.3 to 157)
    Height
    Units: cm
        median (full range (min-max))
    176 (153 to 193)
    175.5 (157 to 193)
    Body-Mass-Index
    BMI at baseline
    Units: BMI
        median (full range (min-max))
    27.0 (17.9 to 40.4)
    27.5 (17.9 to 44.1)
    PANSS pos
    PANSS positive score baseline
    Units: Score
        median (full range (min-max))
    12 (7 to 20)
    12 (7 to 20)
    PANSS neg
    PANSS negative score baseline
    Units: Score
        median (full range (min-max))
    15 (7 to 25)
    15 (7 to 25)
    PANSS general
    PANSS general score baseline
    Units: Score
        median (full range (min-max))
    26 (16 to 43)
    26 (16 to 43)
    PANSS total
    PANSS total score baseline
    Units: Score
        median (full range (min-max))
    52 (32 to 75)
    52 (32 to 75)

    End points

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    End points reporting groups
    Reporting group title
    Add-on 100
    Reporting group description
    		 Add-on 100 mg spironolactone (3 weeks of double-blind intervention phase)

    Reporting group title
    Add-on 200
    Reporting group description
    		 Add-on 200 mg spironolactone (3 weeks of double-blind intervention phase)

    Reporting group title
    Add-on
    Reporting group description
    		 Add-on placebo (3 weeks of double-blind intervention phase)

    Subject analysis set title
    IIT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients who received at least one dose of IMP

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients who received at least one dose of IMP

    Primary: Change in 2-back relative hits of n-back test on ITT

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    End point title
    		 Change in 2-back relative hits of n-back test on ITT
    End point description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    End point type
    Primary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: Points
        arithmetic mean (standard deviation)
    -7.96 ( 13.23 )
    -10.39 ( 22.86 )
    -2.98 ( 15.47 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.548
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change in 2-back relative hits of n-back test on PP

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    End point title
    		 Change in 2-back relative hits of n-back test on PP
    End point description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    26 [1]
    26 [2]
    21 [3]
    Units: Points
        arithmetic mean (standard deviation)
    -6.84 ( 12.98 )
    -10.33 ( 23.7 )
    -3.4 ( 16.74 )
    Notes
    [1] - Per protocol set
    [2] - Per protocol set
    [3] - Per protocol set
    Statistical analysis title
    		 Interaction between time and group on PP
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor on the per protocol set. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.869
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change in 1-back relative hits of n-back test on ITT

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    End point title
    		 Change in 1-back relative hits of n-back test on ITT
    End point description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -6.41 ( 17.07 )
    -8.93 ( 24.87 )
    -5.68 ( 15.76 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.586
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change in 0-back relative hits of n-back test on ITT

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    End point title
    		 Change in 0-back relative hits of n-back test on ITT
    End point description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -4.64 ( 16.1 )
    1.23 ( 13.55 )
    -4.65 ( 16.33 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.967
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: VLMT 5th trial

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    End point title
    		 VLMT 5th trial
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -0.17 ( 1.46 )
    0.3 ( 1.92 )
    -0.38 ( 2.33 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.368
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: VLMT 7th trial

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    End point title
    		 VLMT 7th trial
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    0.1 ( 2.63 )
    0.27 ( 2.63 )
    -0.1 ( 2.7 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.687
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: VLMT recognition V1

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    End point title
    		 VLMT recognition V1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Visit 1
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    25
    Units: points
        arithmetic mean (standard deviation)
    37.93 ( 12.000 )
    12.39 ( 3.337 )
    10.68 ( 4.394 )
    Statistical analysis title
    		 VLMT recognition at V1
    Statistical analysis description
    Kruskal-Wallis Test
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.173
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: VLMT recognition V10

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    End point title
    		 VLMT recognition V10
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Visit 10.
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    29
    27
    21
    Units: points
        arithmetic mean (standard deviation)
    28.38 ( 10.304 )
    10.63 ( 5.443 )
    9.86 ( 5.053 )
    Statistical analysis title
    		 VLMT recognition at V10
    Statistical analysis description
    Kruskal-Wallis Test
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.627
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: TMT A

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    End point title
    		 TMT A
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: second
        arithmetic mean (standard deviation)
    6.6 ( 10.12 )
    6.04 ( 10.96 )
    2.77 ( 8.8 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.443
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: TMT B

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    End point title
    		 TMT B
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: second
        arithmetic mean (standard deviation)
    6.3 ( 42.56 )
    11.19 ( 30.01 )
    4.45 ( 32.57 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.378
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: TMT B-A

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    End point title
    		 TMT B-A
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: second
        arithmetic mean (standard deviation)
    -0.3 ( 45.62 )
    5.15 ( 28.33 )
    1.68 ( 30.96 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.191
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: d2 total signs

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    End point title
    		 d2 total signs
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -14.36 ( 43.57 )
    -29.22 ( 39.93 )
    -33.95 ( 50.83 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: d2 failures

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    End point title
    		 d2 failures
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    5.11 ( 10.92 )
    4.52 ( 15.55 )
    2.38 ( 18.47 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.969
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: d2 concentration score

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    End point title
    		 d2 concentration score
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -12.57 ( 15.94 )
    -18.52 ( 16.1 )
    -6.86 ( 64.17 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.649
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: GAF

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    End point title
    		 GAF
    End point description
    End point type
    Secondary
    End point timeframe
    Change between V1 and V10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    -6.7 ( 7.42 )
    -1.52 ( 5.6 )
    -2.23 ( 7.26 )
    Statistical analysis title
    		 Interaction between time and group
    Statistical analysis description
    Analyzed with a linear mixed model with group as a fixed factor and time as a within-subject factor. The statistic analyzed for significance was the interaction between time of measurement and group.
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: CDSS at V1

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    End point title
    		 CDSS at V1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Visit 1
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    28
    28
    26
    Units: points
        arithmetic mean (standard deviation)
    3.82 ( 3.300 )
    2.07 ( 3.066 )
    2.81 ( 2.191 )
    Statistical analysis title
    		 CDSS at V1
    Statistical analysis description
    Kruskal-Wallis test
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: SDSS at V10

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    End point title
    		 SDSS at V10
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Visit 10
    End point values
    		 Add-on 100 Add-on 200 Add-on
    Number of subjects analysed
    30
    27
    22
    Units: points
        arithmetic mean (standard deviation)
    3.10 ( 2.869 )
    2.15 ( 2.797 )
    3.68 ( 4.674 )
    Statistical analysis title
    		 CDSS at V10
    Statistical analysis description
    Kruskal-Wallis test
    Comparison groups
    Add-on 100 v Add-on 200 v Add-on
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.305
    Method
    		 Kruskal-wallis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the follow-up period (starts after V11), hospitalization to a psychiatric hospital due to schizophrenia was a priori defined not to be considered a SAE.
    Adverse event reporting additional description
    Adverse events (AE), severe adverse events (SAE) and Suspected Unexpected Serious Adverse Reactions (SUSAR) were to be documented following established definitions and legal requirements.The intensity of AEs was defined according to the Common Terminology Criteria for Adverse Events (CTCAE Version 4.03).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 The safety set consisted of all patients who entered the trial and was used for conducting all safety analyses.

    Serious adverse events
    		 Overall study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 84 (2.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Psychotic disorder
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 84 (46.43%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Tremor
         subjects affected / exposed
    4 / 84 (4.76%)
         occurrences all number
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 84 (11.90%)
         occurrences all number
    10
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    6 / 84 (7.14%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    10 / 84 (11.90%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2015
    The following major changes were included in AM 2: extension of inclusion criterion 3 (not only patients with monotherapy, but with two antipsychotics allowed) and clearer definition of inclusion criterion 5 and exclusion criterion 8.
    11 Oct 2016
    The following major changes were included in AM 3: additional inclusion of women allowed (not pregnant, contraception according to CTFG guideline), clearer definition of excluded antipsychotics.
    18 Apr 2017
    The following major changes were included in AM 4: Additional site Regensburg, clarification of the negative wording of an exclusion criterion, extension of study period.
    25 Jun 2018
    The following major changes were included in AM 6: change in IMP Manufacturer and add-on to patient information to reflect new regulation on data protection.
    31 Oct 2019
    The following major changes were included in AM 7: adapted description in power planning and statistical analysis and improved specification of secondary endpoints.

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32072071
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