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    Clinical Trial Results:
    A double-blind, placebo-controlled, randomized dose- ranging trial to investigate efficacy and safety of intravenous MIJ821 infusion in addition to comprehensive standard of care on the rapid reduction of symptoms of Major Depressive Disorder in subjects who have suicidal ideation with intent

    Summary
    EudraCT number
    		 2020-003720-16
    Trial protocol
    		 DE   SK   NL   PL  
    Global end of trial date
    26 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Oct 2024
    First version publication date
    09 Oct 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CMIJ821A12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04722666
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    26 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to investigate the dose response relationship for 4 doses (0.0048, 0.016, 0.048 and 0.16 mg/kg) of MIJ821 vs. placebo arm. The primary clinical question of interest was: what is the effect of MIJ821 versus placebo in conjunction with pharmacological standard of care (SoC) on change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 24 hours post first dose administration, in participants with Major Depressive Disorder (MDD) who have suicidal ideation with intent, accounting for intercurrent events (IEs) with potential confounding effects and IEs leading to study discontinuation prior to the 24 hours assessment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jul 2021
    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
    Argentina: 5
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    Malaysia: 15
    Country: Number of subjects enrolled
    Mexico: 31
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Türkiye: 11
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    199
    EEA total number of subjects
    88
    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)
    195
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in 39 investigative sites in 14 countries.

    Pre-assignment
    Screening details
    		 The Screening period started when the participant signed the informed consent form. The eligibility of the participant was determined based on assessments performed at the Screening visit (up to 48 h) and also on Day 1 before randomization.

    Period 1
    Period 1 title
    Core Period: 6 weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MIJ821 0.16 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.16 mg/kg i.v. dose for 40 minutes on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.16 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.048 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.048 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.016 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.016 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.016 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.0048 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.0048 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.16 mg/kg single dose
    Arm description
    		 MIJ821 0.16 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.16 mg/kg single dose

    Arm title
    		 MIJ821 0.048 mg/kg single dose
    Arm description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.048 mg/kg single dose

    Arm title
    		 Placebo
    Arm description
    		 40 minutes IV infusion of 0.9% sodium chloride on Day 1, Day 15 and Day 29
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Started
    30
    32
    25
    18
    32
    28
    34
    Full Analysis and Safety Set
    29
    32
    25
    18
    32
    28
    33
    Completed
    25
    29
    23
    15
    28
    26
    30
    Not completed
    5
    3
    2
    3
    4
    2
    4
         Adverse event, serious fatal
    -
    -
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    3
    2
    1
    2
    4
    1
    1
         Physician decision
    2
    -
    -
    1
    -
    -
    2
         progressive disease
    -
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    1
    -
    -
    -
    1
    -
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MIJ821 0.16 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.16 mg/kg i.v. dose for 40 minutes on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.16 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.048 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.16 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.016 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.016 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.016 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.0048 mg/kg bi-weekly
    Arm description
    		 MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.0048 mg/kg bi-weekly

    Arm title
    		 MIJ821 0.16 mg/kg single dose
    Arm description
    		 MIJ821 0.16 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.16 mg/kg single dose

    Arm title
    		 MIJ821 0.048 mg/kg single dose
    Arm description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIJ821
    Investigational medicinal product code
    MIJ821
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MIJ821 0.048 mg/kg single dose

    Arm title
    		 Placebo
    Arm description
    		 40 minutes IV infusion of 0.9% sodium chloride on Day 1, Day 15 and Day 29
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo

    Number of subjects in period 2 [1]
    		MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Started
    23
    26
    22
    14
    25
    25
    28
    Completed
    11
    10
    11
    8
    12
    14
    11
    Not completed
    12
    16
    11
    6
    13
    11
    17
         Consent withdrawn by subject
    3
    5
    1
    1
    2
    2
    4
         Physician decision
    -
    -
    1
    -
    1
    -
    1
         progressive disease
    1
    1
    3
    -
    -
    1
    1
         Unsatisfactory therapeutic effect
    -
    1
    -
    -
    -
    -
    -
         Pregnancy
    -
    -
    -
    -
    -
    1
    -
         Study terminated by sponsor
    7
    8
    4
    5
    9
    7
    8
         Lost to follow-up
    -
    1
    2
    -
    1
    -
    1
         New therapy for study indication
    -
    -
    -
    -
    -
    -
    1
         Guardian decision
    1
    -
    -
    -
    -
    -
    -
         Protocol deviation
    -
    -
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants who completed the cure study entered the extension phase

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MIJ821 0.16 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.16 mg/kg i.v. dose for 40 minutes on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.016 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.016 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.0048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.16 mg/kg single dose
    Reporting group description
    		 MIJ821 0.16 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg single dose
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    Placebo
    Reporting group description
    		 40 minutes IV infusion of 0.9% sodium chloride on Day 1, Day 15 and Day 29

    Reporting group values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo Total
    Number of subjects
    		 30 32 25 18 32 28 34 199
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 29 31 25 18 32 27 33 195
        From 65-84 years
    		 1 1 0 0 0 1 1 4
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.3 ( 14.24 ) 39.2 ( 12.11 ) 37.7 ( 9.63 ) 30.6 ( 9.21 ) 43.2 ( 13.11 ) 41.6 ( 15.30 ) 37.5 ( 15.42 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 16 16 12 13 18 19 15 109
        Male
    		 14 16 13 5 14 9 19 90
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 0 0 0 0 1
        Asian
    		 5 4 3 6 2 5 2 27
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0
        Black or African American
    		 1 1 0 0 0 2 5 9
        White
    		 24 26 22 12 30 21 27 162
        More than one race
    		 0 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    MIJ821 0.16 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.16 mg/kg i.v. dose for 40 minutes on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.016 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.016 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.0048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.16 mg/kg single dose
    Reporting group description
    		 MIJ821 0.16 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg single dose
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    Placebo
    Reporting group description
    		 40 minutes IV infusion of 0.9% sodium chloride on Day 1, Day 15 and Day 29
    Reporting group title
    MIJ821 0.16 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.16 mg/kg i.v. dose for 40 minutes on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.016 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.016 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.0048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion on Day 1, Day 15 and Day 29

    Reporting group title
    MIJ821 0.16 mg/kg single dose
    Reporting group description
    		 MIJ821 0.16 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    MIJ821 0.048 mg/kg single dose
    Reporting group description
    		 MIJ821 0.048 mg/kg dose for 40 minutes IV infusion on Day 1 and 0.9% sodium chloride for 40 minutes IV infusion on Day 15 and Day 29

    Reporting group title
    Placebo
    Reporting group description
    		 40 minutes IV infusion of 0.9% sodium chloride on Day 1, Day 15 and Day 29

    Subject analysis set title
    MIJ821 0.16 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.16 mg/kg i.v. dose for 40 minutes

    Subject analysis set title
    MIJ821 0.048 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.048 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.016 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.016 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.0048 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.16 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.16 mg/kg i.v. dose for 40 minutes

    Subject analysis set title
    MIJ821 0.048 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.048 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.016 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.016 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.0048 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.0048 mg/kg dose for 40 minutes IV infusion

    Subject analysis set title
    MIJ821 0.16 mg/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    MIJ821 0.16 mg/kg i.v. dose for 40 minutes

    Primary: Change from baseline in the total score of the Montgomery Åsberg Depression Rating Scale (MADRS)

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    End point title
    		 Change from baseline in the total score of the Montgomery Åsberg Depression Rating Scale (MADRS) [1] [2]
    End point description
    The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 0 - 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts and suicidal thoughts. The MADRS was collected electronically by qualified personnel. Since the MADRS total score at 24 hours was evaluated post the single first infusion (prior to the second infusion), the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg.
    End point type
    Primary
    End point timeframe
    Baseline, 24 hours
    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: Statistical analysis not performed for terminated trial.
    [2] - 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: arms were pooled
    End point values
    		 Placebo MIJ821 0.16 mg/kg MIJ821 0.048 mg/kg MIJ821 0.016 mg/kg MIJ821 0.0048 mg/kg
    Number of subjects analysed
    33
    61
    60
    25
    18
    Units: unit on a scale
        least squares mean (standard error)
    -17.5 ( 1.60 )
    -16.4 ( 1.18 )
    -17.2 ( 1.19 )
    -17.7 ( 1.84 )
    -12.7 ( 2.19 )
    No statistical analyses for this end point

    Secondary: Number of participants with treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) during the core period

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    End point title
    		 Number of participants with treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) during the core period
    End point description
    Treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESIs) in Core period
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    29
    32
    25
    18
    32
    28
    33
    Units: participants
        Number of participants with at least one TEAE
    19
    24
    15
    14
    16
    23
    16
        TEAEs leading to study treatment discontinuation
    0
    0
    0
    0
    0
    0
    0
        Treatment-emergent serious adverse events
    1
    0
    2
    3
    0
    1
    3
        any adverse event of special interest (AESIs)
    15
    8
    9
    7
    7
    8
    8
        Blood Pressure Increased (AESIs)
    2
    3
    1
    0
    1
    2
    0
        Cystitis (AESIs)
    0
    0
    1
    2
    0
    0
    0
        Dissociative reaction (AESIs)
    11
    3
    4
    1
    4
    4
    4
        Memory gaps Amnesia (AESIs)
    5
    0
    1
    0
    1
    0
    0
        QTc prolongation (AESIs)
    0
    0
    0
    0
    0
    0
    2
        Sedation (AESIs)
    4
    3
    1
    2
    2
    3
    0
        Suicidality (AESIs)
    2
    0
    3
    3
    0
    1
    2
    No statistical analyses for this end point

    Secondary: AUClast - Pharmacokinetics (PK) of MIJ821 in plasma

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    End point title
    		 AUClast - Pharmacokinetics (PK) of MIJ821 in plasma
    End point description
    AUClast of MIJ821 in plasma after 1st infusion. AUClast is the Area Under the Curve (AUC) from time zero to the last measurable concentration sampling time (tlast). Since PK was evaluated post the single first infusion, the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 20min, 40min, 4hours and 24hours post 1st infusion
    End point values
    		 MIJ821 0.16 mg/kg MIJ821 0.048 mg/kg MIJ821 0.016 mg/kg MIJ821 0.0048 mg/kg
    Number of subjects analysed
    47
    47
    18
    16
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    347 ( 354 )
    112 ( 123 )
    28.4 ( 22.2 )
    14.0 ( 23.9 )
    No statistical analyses for this end point

    Secondary: Cmax - Pharmacokinetics (PK) of MIJ821 in plasma

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    End point title
    		 Cmax - Pharmacokinetics (PK) of MIJ821 in plasma
    End point description
    Cmax of MIJ821 in plasma after 1st infusion. AUClast is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration. Since PK was evaluated post the single first infusion, the bi-weekly and single dosing regimens of the same dose level are pooled as one arm for 0.048 mg/kg and 0.16 mg/kg.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 20min, 40min, 4hours and 24hours post 1st infusion
    End point values
    		 MIJ821 0.048 mg/kg MIJ821 0.016 mg/kg MIJ821 0.0048 mg/kg MIJ821 0.16 mg/kg
    Number of subjects analysed
    47
    18
    16
    49
    Units: ng/mL
        arithmetic mean (standard deviation)
    25.4 ( 16.9 )
    8.35 ( 6.67 )
    6.02 ( 8.15 )
    118 ( 177 )
    No statistical analyses for this end point

    Secondary: Number of participants meeting response criteria of ≥50% reduction in MADRS total score.

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    End point title
    		 Number of participants meeting response criteria of ≥50% reduction in MADRS total score.
    End point description
    Response criteria of ≥50% reduction from baseline in MADRS total score over time in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    29
    32
    25
    18
    32
    28
    33
    Units: participants
        Day 1, 4 Hours
    10
    14
    7
    1
    8
    6
    16
        Day 2 (24 Hours)
    8
    15
    12
    4
    13
    10
    14
        Day 8
    10
    10
    11
    3
    9
    9
    13
        Day 15, Predose
    12
    10
    9
    3
    10
    7
    10
        Day 15, 4 Hours
    21
    23
    17
    7
    20
    17
    23
        Day 22
    15
    17
    10
    5
    10
    8
    13
        Day 29, Predose
    17
    16
    8
    7
    12
    10
    18
        Day 29, 4 Hours
    21
    23
    19
    11
    21
    19
    23
        Day 36
    15
    19
    14
    10
    18
    15
    21
        Day 43
    19
    19
    17
    9
    17
    16
    22
    No statistical analyses for this end point

    Secondary: Number of participants meeting criteria for sustained response of ≥50% reduction in MADRS total score

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    End point title
    		 Number of participants meeting criteria for sustained response of ≥50% reduction in MADRS total score
    End point description
    Sustained response (≥50% reduction from baseline) from baseline in MADRS total score for a period of at least four weeks in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    29
    32
    25
    18
    32
    28
    33
    Units: participants
    11
    11
    4
    3
    5
    4
    6
    No statistical analyses for this end point

    Secondary: Number of participants meeting remission criteria of MADRS total score of ≤12

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    End point title
    		 Number of participants meeting remission criteria of MADRS total score of ≤12
    End point description
    Remission criteria of MADRS total score of ≤12 over time in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    29
    32
    25
    18
    32
    28
    33
    Units: participants
        Day 1, 4 Hours
    4
    5
    2
    0
    2
    4
    6
        Day 2 (24 Hours)
    4
    8
    6
    1
    5
    7
    7
        Day 8
    5
    5
    4
    1
    5
    2
    8
        Day 15, Predose
    6
    4
    4
    1
    5
    2
    5
        Day 15, 4 Hours
    13
    15
    10
    4
    10
    10
    16
        Day 22
    9
    7
    3
    2
    8
    3
    10
        Day 29, Predose
    8
    5
    4
    3
    6
    2
    12
        Day 29, 4 Hours
    13
    18
    11
    6
    9
    11
    18
        Day 36
    8
    12
    6
    3
    8
    4
    15
        Day 43
    11
    10
    7
    6
    7
    5
    13
    No statistical analyses for this end point

    Secondary: Number of participants meeting sustained remission criteria of MADRS total score of ≤12

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    End point title
    		 Number of participants meeting sustained remission criteria of MADRS total score of ≤12
    End point description
    Remission criteria of MADRS total score of ≤12 sustained for a period of at least four weeks in the Core Period. The Montgomery Åsberg Depression Rating Scale (MADRS, SIGMA version), is a clinician rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test has a total possible score of 0 - 60. Higher scores represent a more severe condition.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    29
    32
    25
    18
    32
    28
    33
    Units: participants
    5
    3
    2
    2
    4
    1
    5
    No statistical analyses for this end point

    Secondary: Number of participants meeting criteria for relapse in the Extension Period

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    End point title
    		 Number of participants meeting criteria for relapse in the Extension Period
    End point description
    For participants classified as responders in the core period who entered the extension period. Response is defined as a ≥ 50% reduction from the baseline MADRS score at any visit during the study. All participants meeting criteria for relapse over fixed period in the Extension Period. A relapse manifests as the appearance of new depressive symptoms or worsening of previously stable or improving MDD symptoms. During the Extension Period, participants experiencing deterioration must be assessed by the treating physician and the relapse must be confirmed by assessment with MADRS during scheduled or unscheduled visit.
    End point type
    Secondary
    End point timeframe
    From 6 weeks up to 58 weeks
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose Placebo
    Number of subjects analysed
    16
    18
    17
    9
    16
    16
    22
    Units: participants
    7
    7
    10
    3
    5
    8
    10
    No statistical analyses for this end point

    Secondary: Number of relapsing participants meeting response criteria after the first retreatment infusion in the extension period

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    End point title
    		 Number of relapsing participants meeting response criteria after the first retreatment infusion in the extension period [3]
    End point description
    Relapsing participants meeting response criteria or remission criteria after the first infusion of MIJ821 retreatment in the Extension Period. Response criteria (>=50% reduction from baseline in MADRS total score). Reinfusions are given at Day 1, 15 and 29 after relapse.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks after first retreatment infusion. Timepoints are relative to first retreatment (R) infusion for each patient, including Follow Up (F/U).
    Notes
    [3] - 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: arms were pooled
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose
    Number of subjects analysed
    9
    8
    9
    2
    7
    10
    Units: participants
        Day 1 R, 4 Hours
    3
    5
    4
    0
    1
    3
        Day 2 R (24 Hours)
    5
    6
    6
    0
    2
    5
        Day 8 R
    5
    2
    2
    1
    2
    1
        Day 15 R, Predose
    3
    4
    3
    0
    2
    2
        Day 15 R, 4 Hours
    4
    5
    7
    1
    2
    7
        Day 22 R
    8
    6
    5
    1
    2
    2
        Day 29 R, Predose
    6
    5
    4
    0
    2
    2
        Day 29 R, 4 Hours
    8
    6
    5
    2
    4
    6
        Day 36 R
    8
    6
    5
    0
    2
    5
        Day 43 R
    7
    5
    6
    1
    4
    5
        Week 8 F/U R
    1
    0
    0
    0
    0
    0
        Week 12 F/U R
    1
    0
    0
    0
    0
    1
        Week 16 F/U R
    1
    3
    0
    0
    0
    1
        Week 20 F/U R
    2
    4
    2
    0
    1
    4
        Week 24 F/U R
    4
    4
    2
    0
    2
    0
        Week 28 F/U R
    6
    2
    2
    1
    5
    2
        Week 32 F/U R
    5
    1
    4
    1
    3
    0
        Week 36 F/U R
    4
    2
    5
    1
    3
    0
        Week 40 F/U R
    4
    2
    1
    1
    3
    0
        Week 44 F/U R
    5
    2
    2
    0
    1
    2
        Week 48 F/U R
    4
    1
    2
    0
    2
    3
        Week 52 F/U R
    3
    1
    1
    1
    3
    2
    No statistical analyses for this end point

    Secondary: Number of relapsing participants meeting remission criteria after the first retreatment infusion in the extension period

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    End point title
    		 Number of relapsing participants meeting remission criteria after the first retreatment infusion in the extension period [4]
    End point description
    Relapsing participants meeting response criteria or remission criteria after the first infusion of MIJ821 retreatment in the Extension Period. Remission criteria (MADRS total score <=12). Reinfusions are given at Day 1, 15 and 29 after relapse.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks after first retreatment infusion. Timepoints are relative to first retreatment (R) infusion for each patient, including Follow Up (F/U).
    Notes
    [4] - 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: arms were pooled
    End point values
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly MIJ821 0.0048 mg/kg bi-weekly MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose
    Number of subjects analysed
    9
    8
    9
    2
    7
    10
    Units: participants
        Day 1 R, 4 Hours
    2
    3
    2
    0
    1
    1
        Day 2 R (24 Hours)
    5
    6
    4
    0
    2
    3
        Day 8 R
    3
    2
    1
    0
    2
    0
        Day 15 R, Predose
    2
    3
    2
    0
    0
    0
        Day 15 R, 4 Hours
    3
    4
    6
    1
    3
    6
        Day 22 R
    5
    4
    3
    1
    1
    0
        Day 29 R, Predose
    4
    4
    2
    0
    2
    0
        Day 29 R, 4 Hours
    7
    5
    5
    1
    4
    7
        Day 36 R
    3
    3
    4
    1
    2
    2
        Day 43 R
    6
    4
    5
    1
    3
    4
        Week 8 F/U R
    1
    0
    0
    0
    0
    0
        Week 12 F/U R
    1
    0
    0
    0
    0
    1
        Week 16 F/U R
    1
    3
    0
    0
    0
    0
        Week 20 F/U R
    2
    3
    0
    0
    1
    2
        Week 24 F/U R
    4
    4
    1
    0
    2
    1
        Week 28 F/U R
    3
    2
    1
    1
    5
    1
        Week 32 F/U R
    4
    1
    2
    1
    3
    0
        Week 36 F/U R
    4
    2
    3
    1
    3
    0
        Week 40 F/U R
    4
    2
    1
    1
    3
    0
        Week 44 F/U R
    4
    2
    2
    0
    1
    1
        Week 48 F/U R
    4
    1
    2
    0
    2
    1
        Week 52 F/U R
    3
    1
    1
    1
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of 58 weeks.
    Adverse event reporting additional description
    Placebo responders in the Core period who were followed up in the 52-week Extension period but required to be retreated due to a relapse were randomly switched to a MIJ821 regimen. For these participants AEs that occurred after start of treatment with MIJ821 are counted under the respective MIJ821 regimen.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    MIJ821 0.16 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.16 mg/kg bi-weekly

    Reporting group title
    MIJ821 0.048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.048 mg/kg bi-weekly

    Reporting group title
    MIJ821 0.016 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.016 mg/kg bi-weekly

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    MIJ821 0.16 mg/kg single dose
    Reporting group description
    		 MIJ821 0.16 mg/kg single dose

    Reporting group title
    MIJ821 0.048 mg/kg single dose
    Reporting group description
    		 MIJ821 0.048 mg/kg single dose

    Reporting group title
    MIJ821 0.0048 mg/kg bi-weekly
    Reporting group description
    		 MIJ821 0.0048 mg/kg bi-weekly

    Serious adverse events
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly Placebo MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose MIJ821 0.0048 mg/kg bi-weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 31 (16.13%)
    7 / 34 (20.59%)
    6 / 25 (24.00%)
    8 / 33 (24.24%)
    4 / 34 (11.76%)
    5 / 30 (16.67%)
    4 / 18 (22.22%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    2 / 25 (8.00%)
    1 / 33 (3.03%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 34 (8.82%)
    2 / 25 (8.00%)
    2 / 33 (6.06%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 34 (8.82%)
    3 / 25 (12.00%)
    5 / 33 (15.15%)
    1 / 34 (2.94%)
    4 / 30 (13.33%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 4
    0 / 5
    0 / 1
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 MIJ821 0.16 mg/kg bi-weekly MIJ821 0.048 mg/kg bi-weekly MIJ821 0.016 mg/kg bi-weekly Placebo MIJ821 0.16 mg/kg single dose MIJ821 0.048 mg/kg single dose MIJ821 0.0048 mg/kg bi-weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 31 (80.65%)
    27 / 34 (79.41%)
    18 / 25 (72.00%)
    19 / 33 (57.58%)
    20 / 34 (58.82%)
    29 / 30 (96.67%)
    13 / 18 (72.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal hamartoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    2 / 33 (6.06%)
    1 / 34 (2.94%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    3
    0
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 34 (5.88%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Illness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    0
    0
    3
    1
    Asthenia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Medical device site rash
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Intermenstrual bleeding
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Breast cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endometrial disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Galactorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Polymenorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hyperventilation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory symptom
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    2
    Anxiety
         subjects affected / exposed
    5 / 31 (16.13%)
    1 / 34 (2.94%)
    5 / 25 (20.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    2 / 30 (6.67%)
    2 / 18 (11.11%)
         occurrences all number
    8
    1
    5
    0
    1
    3
    2
    Bradyphrenia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Daydreaming
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Depersonalisation/derealisation disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    Hypnagogic hallucination
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Derealisation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Dissociation
         subjects affected / exposed
    9 / 31 (29.03%)
    3 / 34 (8.82%)
    4 / 25 (16.00%)
    3 / 33 (9.09%)
    1 / 34 (2.94%)
    4 / 30 (13.33%)
    0 / 18 (0.00%)
         occurrences all number
    15
    5
    6
    4
    1
    5
    0
    Dissociative amnesia
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    2 / 34 (5.88%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    1
    2
    2
    0
    Generalised anxiety disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 34 (8.82%)
    2 / 25 (8.00%)
    3 / 33 (9.09%)
    1 / 34 (2.94%)
    3 / 30 (10.00%)
    3 / 18 (16.67%)
         occurrences all number
    3
    3
    3
    3
    1
    3
    3
    Illusion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Impulsive behaviour
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    6 / 31 (19.35%)
    5 / 34 (14.71%)
    3 / 25 (12.00%)
    3 / 33 (9.09%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    6
    7
    3
    3
    1
    0
    0
    Intentional self-injury
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    2
    2
    0
    1
    0
    1
    1
    Suicidal ideation
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 34 (2.94%)
    3 / 25 (12.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    4 / 30 (13.33%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    4
    0
    1
    4
    2
    Logorrhoea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Major depression
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    2 / 25 (8.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    1
    Panic attack
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Terminal insomnia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Amylase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Heart rate decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    1
    0
    1
    4
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    Liver function test increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 34 (5.88%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    0
    0
    2
    0
    3
    Weight increased
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 34 (11.76%)
    5 / 25 (20.00%)
    5 / 33 (15.15%)
    2 / 34 (5.88%)
    3 / 30 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    4
    5
    5
    2
    5
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Post procedural erythema
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Overdose
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 34 (5.88%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Coordination abnormal
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    5
    1
    0
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dystonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
    10 / 34 (29.41%)
    5 / 25 (20.00%)
    4 / 33 (12.12%)
    4 / 34 (11.76%)
    7 / 30 (23.33%)
    3 / 18 (16.67%)
         occurrences all number
    8
    16
    7
    4
    10
    14
    3
    Hypoaesthesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 31 (12.90%)
    4 / 34 (11.76%)
    1 / 25 (4.00%)
    2 / 33 (6.06%)
    4 / 34 (11.76%)
    4 / 30 (13.33%)
    2 / 18 (11.11%)
         occurrences all number
    8
    6
    1
    2
    4
    4
    2
    Memory impairment
         subjects affected / exposed
    5 / 31 (16.13%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    7
    0
    1
    0
    0
    0
    1
    Nerve compression
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Sedation
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    0
    0
    2
    1
    Somnolence
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 34 (5.88%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    4 / 30 (13.33%)
    1 / 18 (5.56%)
         occurrences all number
    3
    2
    0
    0
    3
    5
    1
    Syncope
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Tunnel vision
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Sensory disturbance
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    3 / 30 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    0
    Hypoacusis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Acid peptic disease
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    Colitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    2
    2
    1
    0
    0
    3
    1
    Dental caries
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    5 / 34 (14.71%)
    2 / 25 (8.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    2
    6
    2
    0
    1
    1
    1
    Lip swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    2 / 25 (8.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Pancreatic steatosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 34 (5.88%)
    1 / 25 (4.00%)
    1 / 33 (3.03%)
    2 / 34 (5.88%)
    2 / 30 (6.67%)
    3 / 18 (16.67%)
         occurrences all number
    3
    2
    1
    1
    2
    3
    5
    Paraesthesia oral
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    1
    Toothache
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Urinary hesitation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    1
    Back pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Pain in jaw
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    2 / 34 (5.88%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    0
    3
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Joint stiffness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    COVID-19
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    1
    0
    0
    2
    1
    Bronchitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    1 / 34 (2.94%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    2 / 25 (8.00%)
    2 / 33 (6.06%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 34 (2.94%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hyperphagia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    1 / 25 (4.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    2 / 25 (8.00%)
    0 / 33 (0.00%)
    0 / 34 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Overweight
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    1 / 34 (2.94%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 34 (0.00%)
    0 / 25 (0.00%)
    1 / 33 (3.03%)
    0 / 34 (0.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2021
    • Inclusion and exclusion criteria were updated to align with the current product labelling medications. • The infusion device compatibility studies performed to date do not cover the patients with body weight below 50 kg and above 120 kg. Hence, the relapsing patients were not allowed to be retreated if their body weight is no longer within the allowed range of 50-120 kg. • List of prohibited medications was updated to include the medications with additive effect on cardiac safety. Rescue medications were added not only for agitation, anxiety but also for aggressive behavior and the clarification for benzodiazepines was provided. • The requirement of prohibiting changes to psychotherapy treatment was removed to align with clinical practice and facilitate recruitment of patients who received psychotherapy at the time of study initiation. • Audio-recording and independent analysis of S-STS scale assessments were included.

    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
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    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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