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    Clinical Trial Results:
    Phase II, multicenter, randomized, double-blind, two-part, placebo-controlled, parallel-group, study to assess the effects of ralmitaront in participants with schizophrenia or schizoaffective disorder and negative symptoms

    Summary
    EudraCT number
    		 2020-004752-16
    Trial protocol
    		 ES   PL   BG   HR  
    Global end of trial date
    12 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2024
    First version publication date
    24 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP40283
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche, +41 616878333, global.trial_information@roche.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
    13 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to compare the effectiveness of placebo to ralmitaront as monotherapy or as add-on therapy on negative symptoms in participants with schizophrenia or schizoaffective disorder.
    Protection of trial subjects
    All participants were required to sign an Informed Consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Oct 2018
    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
    United States: 86
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Spain: 5
    Worldwide total number of subjects
    131
    EEA total number of subjects
    5
    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)
    131
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male or female participants aged 18-55 years (inclusive) with a diagnosis of schizophrenia or schizoaffective disorder.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Monotherapy (placebo)
    Arm description
    		 Participants received placebo each day (QD) for 12 weeks after a 1-week washout from their usual antipsychotic therapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken orally each day (QD)

    Arm title
    		 Part A: Monotherapy (150 mg)
    Arm description
    		 Participants received 150 mg of ralmitaront QD for 12 weeks after a 1-week washout from their usual antipsychotic therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralmitaront
    Investigational medicinal product code
    Other name
    RO6889450
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken orally QD

    Arm title
    		 Part B: Add-on Therapy (placebo)
    Arm description
    		 Participants received placebo QD for 12 weeks in addition to their usual antipsychotic therapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (prior to protocol v5); 6 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (after protocol v5)

    Arm title
    		 Part B: Add-on Therapy (45 mg)
    Arm description
    		 Participants received 45 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (prior to protocol v5; arm was removed thereafter).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralmitaront
    Investigational medicinal product code
    Other name
    RO6889450
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (prior to protocol v5; removed thereafter)

    Arm title
    		 Part B: Add-on Therapy (150 mg)
    Arm description
    		 Participants received 150 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralmitaront
    Investigational medicinal product code
    Other name
    RO6889450
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (prior to protocol v5); 6 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (after protocol v5)

    Arm title
    		 Part B: Add-on Therapy (300 mg)
    Arm description
    		 Participants received 300 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (after protocol v5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralmitaront
    Investigational medicinal product code
    Other name
    RO6889450
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    6 capsules taken orally each day (QD) in addition to usual prescribed antipsychotic therapy (after protocol v5)

    Number of subjects in period 1
    		Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Started
    15
    12
    37
    5
    30
    32
    Completed
    10
    7
    33
    5
    27
    29
    Not completed
    5
    5
    4
    0
    3
    3
         Consent withdrawn by subject
    1
    2
    1
    -
    1
    3
         Physician decision
    -
    2
    -
    -
    -
    -
         Adverse event, non-fatal
    2
    1
    -
    -
    1
    -
         Death
    -
    -
    1
    -
    -
    -
         Disease relapse
    1
    -
    -
    -
    -
    -
         Study terminated by sponsor
    -
    -
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    2
    -
    -
    -
         Protocol deviation
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Monotherapy (placebo)
    Reporting group description
    		 Participants received placebo each day (QD) for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part A: Monotherapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (placebo)
    Reporting group description
    		 Participants received placebo QD for 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (45 mg)
    Reporting group description
    		 Participants received 45 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (prior to protocol v5; arm was removed thereafter).

    Reporting group title
    Part B: Add-on Therapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (300 mg)
    Reporting group description
    		 Participants received 300 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (after protocol v5).

    Reporting group values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg) Total
    Number of subjects
    		 15 12 37 5 30 32 131
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 15 12 37 5 30 32 131
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 42.7 ( 9.9 ) 43.3 ( 6.6 ) 41.3 ( 9.7 ) 41.6 ( 11.3 ) 40.0 ( 9.6 ) 40.9 ( 9.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 3 10 0 11 12 39
        Male
    		 12 9 27 5 19 20 92
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 2 0 6 5 14
        Not Hispanic or Latino
    		 14 11 35 5 24 27 116
        Unknown or Not Reported
    		 0 1 0 0 0 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 1 0 8 0 6 4 19
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 0 0 0 1
        Black or African American
    		 12 9 11 5 7 10 54
        White
    		 2 3 16 0 16 18 55
        More than one race
    		 0 0 0 0 1 0 1
        Unknown or Not Reported
    		 0 0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part A: Monotherapy (placebo)
    Reporting group description
    		 Participants received placebo each day (QD) for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part A: Monotherapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (placebo)
    Reporting group description
    		 Participants received placebo QD for 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (45 mg)
    Reporting group description
    		 Participants received 45 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (prior to protocol v5; arm was removed thereafter).

    Reporting group title
    Part B: Add-on Therapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (300 mg)
    Reporting group description
    		 Participants received 300 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (after protocol v5).

    Primary: Brief Negative Symptoms Scale (BNSS) Avolition/Apathy Subscore and Total Score at Baseline and Week 12

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    End point title
    		 Brief Negative Symptoms Scale (BNSS) Avolition/Apathy Subscore and Total Score at Baseline and Week 12 [1]
    End point description
    The BNSS is a 13-item instrument designed for clinical trials that measures the severity of negative symptoms in five domains (subscales): blunted affect, alogia, asociality, anhedonia, and avolition/apathy. Items are rated on a 7-point scale where higher scores indicate worse outcomes, with 0 = absent symptoms and 6 = severe symptoms.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analysis was planned for this endpoint.
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    14 [2]
    12 [3]
    36 [4]
    5 [5]
    29 [6]
    32 [7]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline Avolition/Apathy Subscore
    5.71 ( 2.81 )
    5.50 ( 2.71 )
    6.0 ( 2.3 )
    6.2 ( 1.3 )
    5.8 ( 1.9 )
    5.9 ( 2.4 )
        Week 12 (Day 84) Avolition/Apathy Subscore
    5.50 ( 2.55 )
    4.67 ( 3.27 )
    5.0 ( 1.9 )
    5.3 ( 1.0 )
    4.1 ( 2.1 )
    4.7 ( 2.1 )
    Notes
    [2] - Week 12 n = 10
    [3] - Week 12 n = 6
    [4] - Week 12 n = 31
    [5] - Week 12 n = 4
    [6] - Week 12 n = 20
    [7] - Week 12 n = 21
    No statistical analyses for this end point

    Secondary: Clinical Global Impression Severity (CGI-S) Overall Scores

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    End point title
    		 Clinical Global Impression Severity (CGI-S) Overall Scores [8]
    End point description
    The CGI-S measures the severity of illness on a 7-point scale ranging from no symptoms to very severe symptoms, with higher scores indicating greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to study part B.
    End point values
    		 Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    37 [9]
    5 [10]
    30 [11]
    32 [12]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    4.1 ( 0.7 )
    3.8 ( 0.4 )
    3.9 ( 0.7 )
    4.0 ( 0.7 )
        Day 14
    4.0 ( 0.6 )
    3.8 ( 0.5 )
    3.8 ( 0.6 )
    4.0 ( 0.8 )
        Day 28
    3.9 ( 0.8 )
    3.8 ( 0.5 )
    3.8 ( 0.6 )
    3.7 ( 0.7 )
        Day 42
    3.8 ( 0.8 )
    3.8 ( 0.5 )
    3.6 ( 0.6 )
    3.6 ( 0.7 )
        Day 56
    3.8 ( 0.8 )
    3.8 ( 0.5 )
    3.5 ( 0.7 )
    3.5 ( 0.8 )
        Day 84
    3.7 ( 0.8 )
    3.8 ( 0.5 )
    3.4 ( 0.6 )
    3.5 ( 0.7 )
    Notes
    [9] - Day 14 n = 35 Day 28 n =34 Day 42 n = 32 Day 56 n = 33 Day 84 n = 31
    [10] - Day 14-84 n = 4
    [11] - Day 14 n = 27 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [12] - Day 14 n = 31 Day 28 n = 29 Day 42 n = 26 Day 56 n = 25 Day 84 n = 22
    No statistical analyses for this end point

    Secondary: CGI-S Negative Symptoms Scores

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    End point title
    		 CGI-S Negative Symptoms Scores [13]
    End point description
    The CGI-S measures the severity of illness on a 7-point scale ranging from no symptoms to very severe symptoms, with higher scores indicating greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to study part B.
    End point values
    		 Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    37 [14]
    5 [15]
    30 [16]
    32 [17]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    4.4 ( 0.6 )
    4.2 ( 0.4 )
    4.3 ( 0.7 )
    4.3 ( 0.7 )
        Day 14
    4.3 ( 0.7 )
    4.3 ( 0.5 )
    3.9 ( 0.7 )
    4.1 ( 0.7 )
        Day 28
    4.1 ( 0.8 )
    4.3 ( 0.5 )
    3.8 ( 0.7 )
    3.9 ( 0.7 )
        Day 42
    3.9 ( 0.9 )
    4.0 ( 0.0 )
    3.8 ( 0.7 )
    3.7 ( 0.7 )
        Day 56
    3.9 ( 0.8 )
    4.0 ( 0.0 )
    3.6 ( 0.7 )
    3.5 ( 0.7 )
        Day 84
    3.9 ( 0.8 )
    3.8 ( 0.5 )
    3.4 ( 0.6 )
    3.5 ( 0.9 )
    Notes
    [14] - Day 14 n = 35 Day 28 n = 34 Day 42 n = 32 Day 56 n = 33 Day 84 n = 31
    [15] - Day 14-84 n = 4
    [16] - Day 14 n = 27 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [17] - Day 14 n = 31 Day 28 n = 29 Day 42 n = 26 Day 56 n = 25 Day 84 n = 22
    No statistical analyses for this end point

    Secondary: Clinical Global Impression - Improvement (CGI-I) Overall Scores

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    End point title
    		 Clinical Global Impression - Improvement (CGI-I) Overall Scores
    End point description
    The CGI-I assesses clinical change in symptoms as compared to baseline using a 7-point scale ranging from very much improved to very much worse, with higher scores indicating increasing worsening of symptoms. 999 = Value could not be calculated from a single data point. 9999 = Data was not collected for Part B at this timepoint.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 (Day 84)
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    15 [18]
    12 [19]
    37 [20]
    5 [21]
    30 [22]
    32 [23]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Day 14
    3.71 ( 0.91 )
    3.56 ( 0.53 )
    3.7 ( 0.4 )
    4.0 ( 0.0 )
    3.6 ( 0.5 )
    3.6 ( 0.6 )
        Day 21
    4.00 ( 999 )
    2.00 ( 999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 28
    3.56 ( 0.73 )
    3.50 ( 0.76 )
    3.5 ( 0.7 )
    4.0 ( 0.0 )
    3.5 ( 0.8 )
    3.4 ( 0.8 )
        Day 35
    3.50 ( 0.71 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 42
    3.73 ( 0.65 )
    3.29 ( 0.76 )
    3.4 ( 0.7 )
    3.8 ( 0.5 )
    3.3 ( 0.8 )
    3.3 ( 0.9 )
        Day 56
    3.70 ( 0.48 )
    3.14 ( 0.69 )
    3.4 ( 0.7 )
    3.8 ( 0.5 )
    3.4 ( 0.9 )
    3.1 ( 1.0 )
        Day 70
    3.50 ( 0.71 )
    2.86 ( 0.90 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84
    3.80 ( 0.42 )
    3.00 ( 0.63 )
    3.2 ( 0.7 )
    3.8 ( 0.5 )
    3.0 ( 0.9 )
    3.0 ( 1.0 )
    Notes
    [18] - Day 14 n = 14 Day 21 n = 1 Day 28 n = 9 Day 35 n = 2 Day 42 n = 11 Day 56-84 n = 10
    [19] - Day 14 n = 9 Day 21 n = 1 Day 28 n = 8 Day 42 - 70 n = 7 Day 84 n = 6
    [20] - Day 14 n = 35 Day 28 n = 34 Day 42 n = 32 Day 56 n = 33 Day 84 n = 31
    [21] - Day 14-84 n = 4
    [22] - Day 14 n = 27 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [23] - Day 14 n = 31 Day 28 n = 29 Day 42 n = 26 Day 56 n = 25 Day 84 n = 22
    No statistical analyses for this end point

    Secondary: CGI-I Negative Symptoms Scores

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    End point title
    		 CGI-I Negative Symptoms Scores
    End point description
    The CGI-I assesses clinical change in symptoms as compared to baseline using a 7-point scale ranging from very much improved to very much worse, with higher scores indicating increasing worsening of symptoms. Data for this endpoint was not collected for Part B Days 21, 35, and 70. 999 = Value could not be calculated from a single data point. 9999 = Data was not collected at this timepoint.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 (Day 84)
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    15 [24]
    12 [25]
    37 [26]
    5 [27]
    30 [28]
    32 [29]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Day 14
    3.71 ( 0.61 )
    3.44 ( 0.73 )
    3.7 ( 0.5 )
    4.0 ( 0.0 )
    3.5 ( 0.6 )
    3.5 ( 0.6 )
        Day 21
    5.00 ( 999 )
    4.00 ( 999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 28
    3.44 ( 0.73 )
    3.38 ( 0.74 )
    3.5 ( 0.7 )
    4.0 ( 0.0 )
    3.3 ( 0.7 )
    3.2 ( 0.8 )
        Day 35
    4.50 ( 0.71 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 42
    3.45 ( 0.69 )
    3.43 ( 0.79 )
    3.3 ( 0.6 )
    3.5 ( 0.6 )
    3.3 ( 0.8 )
    3.2 ( 0.8 )
        Day 56
    3.50 ( 0.71 )
    3.43 ( 0.53 )
    3.2 ( 0.7 )
    3.5 ( 0.6 )
    3.2 ( 0.8 )
    2.9 ( 0.8 )
        Day 70
    3.40 ( 0.70 )
    3.00 ( 0.82 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84
    3.10 ( 0.74 )
    2.83 ( 0.41 )
    3.1 ( 0.7 )
    3.0 ( 0.8 )
    2.9 ( 0.9 )
    2.8 ( 0.9 )
    Notes
    [24] - Day 14 n = 14 Day 21 n = 1 Day 28 n = 9 Day 35 n = 2 Day 42 n = 11 Day 56-84 n = 10
    [25] - Day 14 n = 9 Day 21 n = 1 Day 28 n = 8 Day 42-70 n = 7 Day 84 n = 6
    [26] - Day 14 n = 35 Day 28 n = 34 Day 42 n = 32 Day 56 n = 33 Day 84 n = 31
    [27] - Day 14-84 n = 4
    [28] - Day 14 n = 27 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [29] - Day 14 n = Day 28 n = 29 Day 42 n = 26 Day 56 n = 25 Day 84 n = 22
    No statistical analyses for this end point

    Secondary: Positive and Negative Syndrome Scale (PANSS) Total Scores

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    End point title
    		 Positive and Negative Syndrome Scale (PANSS) Total Scores
    End point description
    The PANSS is a 30-item scale for assessing symptoms in participants with schizophrenia. Each item is rated on a 7-point scale where 1 = absent symptoms and 7 = extreme psychopathology. The PANSS Marder factor negative symptom score is calculated from 7 PANSS items while the PANSS Marder factor positive symptom score is calculated from 8 PANSS items, with higher score in both scales indicating greater symptom severity. 9999 = Data was not collected for Part B at this timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    14 [30]
    12 [31]
    37 [32]
    5 [33]
    30 [34]
    32 [35]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    67.43 ( 9.35 )
    67.92 ( 10.86 )
    71.4 ( 10.3 )
    62.8 ( 6.7 )
    69.6 ( 11.1 )
    67.8 ( 11.1 )
        Day 14
    68.38 ( 10.37 )
    69.00 ( 11.40 )
    67.3 ( 8.5 )
    69.5 ( 13.5 )
    67.4 ( 10.5 )
    67.9 ( 13.6 )
        Day 28
    66.10 ( 10.38 )
    65.44 ( 7.30 )
    67.0 ( 10.9 )
    81.3 ( 4.7 )
    66.8 ( 11.4 )
    66.5 ( 11.1 )
        Day 42
    70.09 ( 10.88 )
    65.88 ( 12.01 )
    68.3 ( 12.7 )
    73.3 ( 9.8 )
    61.8 ( 10.9 )
    64.1 ( 12.5 )
        Day 56
    66.60 ( 8.13 )
    61.14 ( 6.91 )
    64.3 ( 11.7 )
    70.0 ( 7.1 )
    63.2 ( 14.4 )
    61.4 ( 11.7 )
        Day 70
    68.50 ( 7.65 )
    59.57 ( 7.14 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84 (Week 12)
    64.70 ( 13.92 )
    59.17 ( 6.27 )
    64.4 ( 12.2 )
    74.8 ( 7.2 )
    59.0 ( 11.1 )
    60.9 ( 11.3 )
    Notes
    [30] - Day 14 n = 13 Day 28 n = 10 Day 42 n = 11 Day 56 n = 10 Day 70 n = 10 Day 84 n = 10
    [31] - Day 14 n = 10 Day 28 n = 9 Day 42 n = 8 Day 56 n = 7 Day 70 n = 7 Day 84 n = 6
    [32] - Day 14 n = 36 Day 28 n = 33 Day 42 n = 32 Day 56 n = 32 Day 84 n = 31
    [33] - Day 14 n = 4 Day 28 n = 3 Day 42 n = 4 Day 56 n = 4 Day 84 n = 4
    [34] - Day 14 n = 26 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [35] - Day 14 n = 30 Day 28 n = 28 Day 42 n = 24 Day 56 n = 23 Day 84 n = 21
    No statistical analyses for this end point

    Secondary: PANSS Symptom Factor Scores

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    End point title
    		 PANSS Symptom Factor Scores
    End point description
    The PANSS is a 30-item scale for assessing symptoms in participants with schizophrenia. Each item is rated on a 7-point scale where 1 = absent symptoms and 7 = extreme psychopathology. The PANSS Marder factor negative symptom score is calculated from 7 PANSS items while the PANSS Marder factor positive symptom score is calculated from 8 PANSS items, with higher score in both scales indicating greater symptom severity. 9999 = Data was not collected for Part B at this timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    14 [36]
    12 [37]
    37 [38]
    5 [39]
    30 [40]
    32 [41]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline - Negative symptoms
    21.29 ( 4.45 )
    21.00 ( 5.20 )
    23.0 ( 4.7 )
    20.6 ( 3.3 )
    23.3 ( 4.7 )
    23.5 ( 4.1 )
        Day 14 - Negative symptoms
    22.46 ( 5.13 )
    20.40 ( 3.95 )
    22.9 ( 3.4 )
    20.8 ( 2.9 )
    21.8 ( 4.5 )
    22.2 ( 5.3 )
        Day 28 - Negative symptoms
    18.40 ( 6.67 )
    20.44 ( 3.68 )
    20.9 ( 4.8 )
    20.3 ( 3.1 )
    21.5 ( 4.0 )
    22.1 ( 4.9 )
        Day 42 - Negative symptoms
    21.09 ( 5.45 )
    19.00 ( 5.50 )
    21.3 ( 4.5 )
    22.3 ( 3.2 )
    21.5 ( 5.1 )
    20.7 ( 5.1 )
        Day 56 - Negative symptoms
    21.10 ( 5.93 )
    18.71 ( 4.72 )
    20.4 ( 4.7 )
    21.8 ( 4.2 )
    19.8 ( 4.9 )
    20.3 ( 5.7 )
        Day 70 - Negative symptoms
    21.20 ( 5.07 )
    17.71 ( 2.75 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84 (Week 12) - Negative symptoms
    18.90 ( 5.38 )
    15.33 ( 3.08 )
    20.5 ( 5.9 )
    22.5 ( 4.8 )
    18.6 ( 4.4 )
    19.4 ( 4.8 )
        Baseline - Positive symptoms
    17.93 ( 3.99 )
    19.75 ( 3.93 )
    18.9 ( 4.6 )
    18.0 ( 3.7 )
    17.6 ( 4.2 )
    17.2 ( 5.4 )
        Day 14 - Positive symptoms
    18.23 ( 4.75 )
    21.30 ( 4.35 )
    17.8 ( 3.8 )
    18.3 ( 5.3 )
    18.1 ( 3.9 )
    18.0 ( 5.7 )
        Day 28 - Positive symptoms
    17.60 ( 4.77 )
    19.22 ( 5.19 )
    17.9 ( 4.3 )
    24.3 ( 6.0 )
    18.0 ( 4.9 )
    17.4 ( 5.9 )
        Day 42 - Positive symptoms
    17.82 ( 4.31 )
    18.75 ( 4.13 )
    18.2 ( 4.8 )
    22.5 ( 6.0 )
    16.0 ( 4.4 )
    16.2 ( 4.7 )
        Day 56 - Positive symptoms
    17.90 ( 4.93 )
    20.71 ( 1.50 )
    17.7 ( 5.0 )
    20.5 ( 3.1 )
    17.2 ( 6.1 )
    15.8 ( 4.5 )
        Day 70 - Positive symptoms
    19.20 ( 2.86 )
    19.29 ( 2.69 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84 (Week 12) - Positive symptoms
    17.70 ( 5.25 )
    19.67 ( 3.61 )
    17.3 ( 4.5 )
    21.5 ( 2.6 )
    16.5 ( 4.7 )
    15.5 ( 4.3 )
    Notes
    [36] - Day 14 n = 13 Day 28 n = 10 Day 42 n = 11 Day 56 n = 10 Day 70 n = 10 Day 84 n = 10
    [37] - Day 14 n = 10 Day 28 n = 9 Day 42 n = 8 Day 56 n = 7 Day 70 n = 7 Day 84 n = 6
    [38] - Day 14 n = 36 Day 28 n = 33 Day 42 n = 32 Day 56 n = 32 Day 84 n = 31
    [39] - Day 14 n = 4 Day 28 n = 3 Day 42 n = 4 Day 56 n = 4 Day 84 n = 4
    [40] - Day 14 n = 26 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 20
    [41] - Day 14 n = 30 Day 28 n = 28 Day 42 n = 24 Day 56 n = 23 Day 84 n = 21
    No statistical analyses for this end point

    Secondary: Brief Negative Symptom Scale (BNSS) Total Scores

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    End point title
    		 Brief Negative Symptom Scale (BNSS) Total Scores
    End point description
    The BNSS is a 13-item instrument designed for clinical trials that measures the severity of negative symptoms in five domains (subscales): blunted affect, alogia, asociality, anhedonia, and avolition/apathy. Items are rated on a 7-point scale (total score range = 0-78) where higher scores indicate worse outcomes, with 0 = absent symptoms and 6 = severe symptoms. 9999 = Data was not collected for Part B at this timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    14 [42]
    12 [43]
    36 [44]
    5 [45]
    29 [46]
    32 [47]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    34.79 ( 14.98 )
    35.17 ( 13.68 )
    36.6 ( 14.9 )
    36.4 ( 6.7 )
    38.1 ( 13.7 )
    38.4 ( 13.8 )
        Day 14
    35.08 ( 12.48 )
    32.90 ( 13.47 )
    36.1 ( 11.4 )
    29.3 ( 11.1 )
    34.1 ( 12.8 )
    35.2 ( 12.8 )
        Day 28
    29.90 ( 14.49 )
    33.25 ( 8.94 )
    32.6 ( 12.9 )
    32.7 ( 7.4 )
    33.1 ( 13.4 )
    36.5 ( 10.3 )
        Day 42
    34.09 ( 11.95 )
    36.38 ( 14.79 )
    35.1 ( 11.3 )
    35.0 ( 11.8 )
    35.5 ( 12.6 )
    32.7 ( 13.4 )
        Day 56
    37.40 ( 18.60 )
    34.00 ( 12.12 )
    30.3 ( 12.1 )
    37.5 ( 16.3 )
    30.8 ( 11.8 )
    32.3 ( 13.6 )
        Day 70
    33.10 ( 7.23 )
    34.00 ( 15.15 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
        Day 84 (Week 12)
    30.40 ( 12.86 )
    28.17 ( 20.44 )
    32.7 ( 13.4 )
    33.3 ( 10.6 )
    29.6 ( 9.2 )
    29.2 ( 12.4 )
    Notes
    [42] - Day 14 n = 13 Day 28 n = 10 Day 42 n = 11 Day 56 n = 10 Day 70 n = 10 Day 84 n = 10
    [43] - Day 14 n = 10 Day 28 n = 8 Day 42 n = 8 Day 56 n = 7 Day 70 n = 7 Day 84 n = 6
    [44] - Day 14 n = 36 Day 28 n = 33 Day 42 n = 32 Day 56 n = 31 Day 84 n = 31
    [45] - Day 14 n = 4 Day 28 n = 3 Day 42 n = 4 Day 56 n = 4 Day 84 n = 4
    [46] - Day 14 n = 25 Day 28 n = 26 Day 42 n = 24 Day 56 n = 24 Day 84 n = 19
    [47] - Day 14 n = 30 Day 28 n = 28 Day 42 n = 24 Day 56 n = 23 Day 84 n = 21
    No statistical analyses for this end point

    Secondary: Defeatist Performance Attitude Scale (DPAS) Scores

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    End point title
    		 Defeatist Performance Attitude Scale (DPAS) Scores
    End point description
    The DPAS is a 15-item, patient-rated assessment that evaluates expectations of failures or self-defeating beliefs related to prior failed experiences as well as illness on a 7-point Likert scale (total range = 15-105) ranging from totally agree (1) to totally disagree (7).
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    15 [48]
    12 [49]
    37 [50]
    5 [51]
    30 [52]
    32 [53]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    34.73 ( 13.92 )
    30.25 ( 12.43 )
    40.2 ( 14.6 )
    40.0 ( 6.4 )
    38.2 ( 15.9 )
    35.9 ( 16.2 )
        Day 42
    40.54 ( 16.37 )
    27.50 ( 18.65 )
    37.5 ( 14.2 )
    39.3 ( 9.3 )
    38.8 ( 16.2 )
    36.0 ( 16.2 )
        Day 84 (Week 12)
    38.80 ( 13.42 )
    16.00 ( 4.98 )
    36.0 ( 15.2 )
    54.3 ( 16.3 )
    39.0 ( 19.9 )
    32.2 ( 13.6 )
    Notes
    [48] - Day 42 n = 13 Day 84 n = 10
    [49] - Day 42 n = 10 Day 84 n = 6
    [50] - Day 42 n = 32 Day 84 n = 31
    [51] - Day 42 n = 4 Day 84 n = 4
    [52] - Day 42 n = 24 Day 84 n = 20
    [53] - Day 42 n = 26 Day 84 n = 22
    No statistical analyses for this end point

    Secondary: Number of Participants with Suicidal Ideation or Behavior, and Self-injurious Behavior without Suicidal Intent on the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Participants with Suicidal Ideation or Behavior, and Self-injurious Behavior without Suicidal Intent on the Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS is a suicide risk assessment tool used to help identify the risk of suicide.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 84
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    15
    12
    37
    5
    30
    32
    Units: Number of participants
        Suicidal ideation or behavior
    0
    0
    1
    0
    2
    1
        Self-injurious behavior without suicidal intent
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Extrapyramidal Symptom Rating Scale, Abbreviated (ESRS-A)

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    End point title
    		 Extrapyramidal Symptom Rating Scale, Abbreviated (ESRS-A)
    End point description
    The ESRS-A is used to evaluate the presence and severity of extrapyramidal symptoms. Items are rated on a scale of 0 (no symptoms) to 5 (extreme symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline through Day 84
    End point values
    		 Part A: Monotherapy (placebo) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    15 [54]
    12 [55]
    37 [56]
    5 [57]
    30 [58]
    32 [59]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Akathisia Baseline
    0.07 ( 0.26 )
    0.08 ( 0.29 )
    0.27 ( 0.87 )
    0.00 ( 0.00 )
    0.27 ( 0.83 )
    0.38 ( 0.98 )
        Akathisia Day 84
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.29 ( 0.94 )
    0.00 ( 0.00 )
    0.10 ( 0.45 )
    0.10 ( 0.44 )
        Dyskinesia Baseline
    0.00 ( 0.00 )
    0.33 ( 0.89 )
    0.46 ( 1.95 )
    0.75 ( 0.96 )
    0.17 ( 0.38 )
    0.63 ( 1.68 )
        Dyskinesia Day 84
    0.10 ( 0.32 )
    0.00 ( 0.00 )
    0.16 ( 0.90 )
    0.00 ( 0.00 )
    0.15 ( 0.49 )
    0.29 ( 0.72 )
        Dystonia Baseline
    0.07 ( 0.26 )
    0.00 ( 0.00 )
    0.24 ( 0.86 )
    0.00 ( 0.00 )
    0.03 ( 0.18 )
    0.16 ( 0.51 )
        Dystonia Day 84
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.26 ( 1.03 )
    0.00 ( 0.00 )
    0.05 ( 0.22 )
    0.00 ( 0.00 )
        Parkinsonism Baseline
    0.13 ( 0.52 )
    0.42 ( 1.00 )
    1.03 ( 2.36 )
    2.20 ( 1.92 )
    2.00 ( 3.24 )
    2.22 ( 4.15 )
        Parkinsonism Day 84
    0.20 ( 0.63 )
    0.33 ( 0.82 )
    1.03 ( 2.87 )
    0.33 ( 0.58 )
    1.15 ( 2.68 )
    1.00 ( 2.30 )
    Notes
    [54] - Day 84 n = 10
    [55] - Day 84 n = 6
    [56] - Day 84 n = 31
    [57] - Day 84 n = 3 Dystonia and Parkinsonism Baseline n = 5
    [58] - Day 84 n = 20
    [59] - Day 84 n = 21
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of RO6889450

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    End point title
    		 Maximum Serum Concentration (Cmax) of RO6889450 [60]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 42
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to study part B with the exclusion of the placebo arm as participants in that arm did not receive RO6889450.
    End point values
    		 Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    4
    27
    28
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    157 ( 58.7 )
    794 ( 40.3 )
    1550 ( 43.9 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve at Steady State (AUCss) of RO6889450

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    End point title
    		 Area Under the Curve at Steady State (AUCss) of RO6889450 [61]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 42
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was specific to study part B with the exclusion of the placebo arm as participants in that arm did not receive RO6889450.
    End point values
    		 Part B: Add-on Therapy (45 mg) Part B: Add-on Therapy (150 mg) Part B: Add-on Therapy (300 mg)
    Number of subjects analysed
    4
    27
    28
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    2980 ( 54.8 )
    15100 ( 43.8 )
    28600 ( 48.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 84 (Week 12)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Part B: Add-on Therapy (placebo)
    Reporting group description
    		 Participants received placebo QD for 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (45 mg)
    Reporting group description
    		 Participants received 45 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (prior to protocol v5; arm was removed thereafter).

    Reporting group title
    Part A: Monotherapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (150 mg)
    Reporting group description
    		 Participants received 150 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy.

    Reporting group title
    Part A: Monotherapy (placebo)
    Reporting group description
    		 Participants received placebo each day (QD) for 12 weeks after a 1-week washout from their usual antipsychotic therapy.

    Reporting group title
    Part B: Add-on Therapy (300 mg)
    Reporting group description
    		 Participants received 300 mg of ralmitaront QD 12 weeks in addition to their usual antipsychotic therapy (after protocol v5).

    Serious adverse events
    		 Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (150 mg) Part A: Monotherapy (placebo) Part B: Add-on Therapy (300 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    2 / 30 (6.67%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part B: Add-on Therapy (placebo) Part B: Add-on Therapy (45 mg) Part A: Monotherapy (150 mg) Part B: Add-on Therapy (150 mg) Part A: Monotherapy (placebo) Part B: Add-on Therapy (300 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 37 (24.32%)
    2 / 5 (40.00%)
    4 / 12 (33.33%)
    8 / 30 (26.67%)
    7 / 15 (46.67%)
    4 / 32 (12.50%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    2 / 30 (6.67%)
    0 / 15 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    2 / 30 (6.67%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Lip pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    0 / 15 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Libido decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
    0 / 30 (0.00%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    3 / 30 (10.00%)
    0 / 15 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    2
    0
    0
    3
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    2 / 15 (13.33%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    0 / 30 (0.00%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
    0 / 30 (0.00%)
    0 / 15 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
    1 / 30 (3.33%)
    1 / 15 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2019
    Replaced IQ-PANNS with IC-PANNS. Updated eligibility criteria.
    15 Sep 2020
    Increased dose of study drug for Part B.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Mar 2020
    Recruitment was paused at all sites from 18 March 2020 to 4 November 2020 due to the COVID-19 pandemic.
    04 Nov 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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