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    Clinical Trial Results:
    OCTUMI-4: Evaluation of Mirtazapine and Folic Acid for Schizophrenia: A randomised, double-blind, 2x2 factorial trial

    Summary
    EudraCT number
    		 2009-014469-19
    Trial protocol
    		 GB   FI   IT  
    Global end of trial date
    18 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jul 2016
    First version publication date
    27 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RECOVERY[OCTUMI-4]
    Additional study identifiers
    ISRCTN number
    		 ISRCTN32434568
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Wellington Square, Oxford, United Kingdom, OX1 2JD
    Public contact
    Professor John Geddes, University of Oxford Department of Psychiatry, =44 Email address, john.geddes@psych.ox.ac.uk
    Scientific contact
    Professor John Geddes, University of Oxford Department of Psychiatry, +44 1865 226451, john.geddes@psych.ox.ac.uk
    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
    11 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Principal research question: Is mirtazapine as add-on therapy to antipsychotic treatment more effective than placebo for treatment of positive and negative symptoms of schizophrenia? Current treatments for schizophrenia, primarily antipsychotic drugs, are not fully effective. There is some evidence that treatment with mirtazapine plus an antipsychotic may be more effective than an antipsychotic alone ((Berk, Ichim & Brook 2001; Joffe et al. 2009; Zoccali et al. 2004)). OCTUMI-4 is designed to evaluate the effects of mirtazapine as add-on therapy to antipsychotic treatment in patients with schizophrenia who are currently experiencing active psychotic symptoms. OCTUMI-4 will be a double-blind placebo controlled randomised trial. References Berk, Ichim & Brook 2001. Int.Clin.Psychopharmacol, vol. 16, no. 2, pp. 87-92. Joffe et al. 2009. Schizophr.Res., vol. 108, no. 1-3, pp. 245-251. Zoccali et al. 2004. Int.Clin.Psychopharmacol, vol. 19, no. 2, pp. 71-76.
    Protection of trial subjects
    If participants had difficulty concentrating during trial visits or became distressed the visit could be stopped and continued on another day.
    Background therapy
    		 The eligibility criteria required participants to be on an effective dose of an antipsychotic medicine. (Effective was defined as the range given in the British National Formulary for maintenance treatment.)
    Evidence for comparator
    		 Both IMPs (mirtazapine and folic acid) were compared to matched placebos. Participants were already being prescribed standard therapy for psychotic symptoms and the IMPs were prescribed as adjunctive treatment. There were no standard adjunctive treatments to use as comparators.
    Actual start date of recruitment
    01 Jan 2011
    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
    Finland: 9
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    53
    EEA total number of subjects
    53
    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)
    52
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 First participant was randomised on 13/4/2011 and last participant was randomised on 23/7/2013 across seven UK sites (Berkshire, Humber, Leeds, Lothian, Coventry/Warwick, Oxford, SW York), one Italy site and one Finland site.

    Pre-assignment
    Screening details
    		 Participants were enrolled into a 7 to 14 day run-in phase prior to randomisation. During which, the antipsychotic treatment were prescribed for the duration of the randomised phase was established. No trial drugs or placebos were given during this phase. After the run-in phase, participants were assessed for eligibility for randomisation.

    Pre-assignment period milestones
    Number of subjects started
    		 64 [1]
    Number of subjects completed
    		 53

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 PANSS score < 60: 11
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 11 particpants were no longer eligible for randomisation after the run-un
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This is a placebo blind study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mirtazapine + Folic Acid
    Arm description
    		 Mirtazapine + Folic Acid
    Arm type
    		 Experimental + Experimental

    Investigational medicinal product name
    Mirtazapine
    Investigational medicinal product code
    N06AX11
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Mirtazapine: 30mg/day for 12 weeks followed by a 2-week tapering period of 30mg every other day.

    Investigational medicinal product name
    Folic acid
    Investigational medicinal product code
    A11E
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Folic acid: 500microg/day for 12 weeks.

    Arm title
    		 Mirtazapine + Folic Acid placebo
    Arm description
    		 Mirtazapine + Folic Acid Placebo
    Arm type
    		 Experimental + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + No Folic Acid
    Arm description
    		 Mirtazapine + No Folic Acid
    Arm type
    		 Experimental + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Placebo + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid placebo
    Arm description
    		 Mirtazapine Placebo + Folic Acid placebo
    Arm type
    		 Placebo + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + No Folic Acid
    Arm description
    		 Mirtazapine Placebo + No Folic Acid
    Arm type
    		 Placebo + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid placebo Mirtazapine Placebo + No Folic Acid
    Started
    14
    12
    1
    12
    13
    1
    Completed
    14
    12
    1
    12
    13
    1
    Period 2
    Period 2 title
    Week 4
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mirtazapine + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Experimental + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + Folic Acid placebo
    Arm description
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm type
    		 Experimental + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + No Folic Acid
    Arm description
    		 Mirtazapine + No Folic Acid
    Arm type
    		 Experimental + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Placebo + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm description
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm type
    		 Placebo + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + No Folic Acid
    Arm description
    		 Mirtazapine Placebo + No Folic Acid
    Arm type
    		 Placebo + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [2]
    		Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Started
    13
    12
    1
    12
    13
    1
    Completed
    13
    10
    1
    10
    12
    1
    Not completed
    0
    2
    0
    2
    1
    0
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    -
         Trial terminated
    -
    1
    -
    -
    1
    -
         Lost to follow-up
    -
    1
    -
    1
    -
    -
    Notes
    [2] - 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: Participants excluded due to attrition
    Period 3
    Period 3 title
    Week 8
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mirtazapine + Folic Acid
    Arm description
    		 Mirtazapine + Folic Acid
    Arm type
    		 Experimental + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + Folic Acid placebo
    Arm description
    		 Mirtazapine + Folic Acid placebo
    Arm type
    		 Experimental + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + No Folic Acid
    Arm description
    		 Mirtazapine + No Folic Acid
    Arm type
    		 Experimental + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Placebo + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Placebo + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + No Folic Acid
    Arm description
    		 Mirtazapine Placebo + No Folic Acid
    Arm type
    		 Placebo + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + No Folic Acid
    Started
    13
    10
    1
    10
    12
    1
    Completed
    13
    10
    1
    10
    12
    1
    Period 4
    Period 4 title
    Week 12
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mirtazapine + Folic Acid
    Arm description
    		 Mirtazapine + Folic Acid
    Arm type
    		 Experimental + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + Folic Acid Placebo
    Arm description
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm type
    		 Experimental + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine + No Folic Acid
    Arm description
    		 Mirtazapine Placebo + No Folic Acid
    Arm type
    		 Experimental + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid
    Arm description
    		 Mirtazapine Placebo + Folic Acid
    Arm type
    		 Placebo + Experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm description
    		 Mirtazapine Placebo + Folic Acid Placebo
    Arm type
    		 Placebo + Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Mirtazapine Placebo + No Folic Acid
    Arm description
    		 Mirtazapine Placebo + No Folic Acid
    Arm type
    		 Placebo + No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4 [3]
    		Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Started
    13
    9
    1
    10
    12
    1
    Completed
    13
    9
    1
    10
    11
    0
    Not completed
    0
    0
    0
    0
    1
    1
         Unknown
    -
    -
    -
    -
    -
    1
         Protocol deviation
    -
    -
    -
    -
    1
    -
    Notes
    [3] - 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: Particpants excluded due to attrition

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 Mirtazapine + Folic Acid

    Reporting group title
    Mirtazapine + Folic Acid placebo
    Reporting group description
    		 Mirtazapine + Folic Acid Placebo

    Reporting group title
    Mirtazapine + No Folic Acid
    Reporting group description
    		 Mirtazapine + No Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid placebo

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid

    Reporting group values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid placebo Mirtazapine Placebo + No Folic Acid Total
    Number of subjects
    		 14 12 1 12 13 1 53
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 13 12 1 12 13 1 52
        From 65-84 years
    		 1 0 0 0 0 0 1
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.9 ( 11.8 ) 42.5 ( 8.7 ) 20.7 ( 0 ) 42.4 ( 11.7 ) 44.4 ( 8.7 ) 42.2 ( 0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 2 0 4 2 1 13
        Male
    		 10 10 1 8 11 0 40
    PANSS negative score
    Units: Subjects
        0-2
    		 4 9 1 8 5 0 27
        3-7
    		 10 3 0 4 8 1 26
    PANSS Score
    Units: Subjects
        < 75
    		 5 5 1 5 6 0 22
        >=75
    		 9 7 0 7 7 1 31
    Duration of illness
    Units: Subjects
        < 1 year
    		 0 0 0 0 0 0 0
        1-5 years
    		 1 1 0 2 3 0 7
        >=5 years
    		 13 11 1 10 10 1 46
    Benzodiazepines
    Units: Subjects
        Not prescribed/not taken
    		 10 11 1 9 9 1 41
        Prescribed/taken
    		 4 1 0 3 4 0 12
    Mood stabilisers
    Units: Subjects
        Missing
    		 0 1 0 0 1 0 2
        No
    		 11 9 1 12 12 1 46
        Yes
    		 3 2 0 0 0 0 5
    Antipschotics
    Units: Subjects
        FGA only
    		 3 2 0 2 2 0 9
        SGA only
    		 10 9 1 6 8 1 35
        Both
    		 1 1 0 4 3 0 9
    Calgary Depression Scale
    Units: Subjects
        < 6
    		 10 8 0 8 11 0 37
        >=6
    		 4 4 1 4 2 1 16
    Global Clinical Assessment of Akathisia
    Units: Subjects
        Absent
    		 7 1 1 5 8 1 23
        Questionable
    		 3 9 0 3 1 0 16
        Mild Akathisia
    		 3 2 0 4 2 0 11
        Moderate Akathisia
    		 0 0 0 0 1 0 1
        Marked Akathisia
    		 1 0 0 0 1 0 2
        Severe Akathisia
    		 0 0 0 0 0 0 0
    PANSS Score
    Units: point
        arithmetic mean (standard deviation)
    		 83.5 ( 16.5 ) 76.9 ( 9.2 ) 69 ( 0 ) 76.5 ( 10.2 ) 84.2 ( 23 ) 85 ( 0 ) -
    Barnes Akathisia Scale
    Units: Point
        arithmetic mean (standard deviation)
    		 1.4 ( 1.9 ) 2.2 ( 1.3 ) 0 ( 0 ) 1.4 ( 1.7 ) 2.2 ( 1.3 ) 1 ( 0 ) -
    Simpson-Angus Extrapyramidal Scale
    Units: point
        arithmetic mean (standard deviation)
    		 4.6 ( 1.3 ) 3.2 ( 1.7 ) 0 ( 0 ) 4.2 ( 1.3 ) 1.7 ( 1.7 ) 1 ( 0 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 Mirtazapine + Folic Acid

    Reporting group title
    Mirtazapine + Folic Acid placebo
    Reporting group description
    		 Mirtazapine + Folic Acid Placebo

    Reporting group title
    Mirtazapine + No Folic Acid
    Reporting group description
    		 Mirtazapine + No Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid placebo

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine + Folic Acid placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid Placebo

    Reporting group title
    Mirtazapine + No Folic Acid
    Reporting group description
    		 Mirtazapine + No Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid Placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid Placebo

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 Mirtazapine + Folic Acid

    Reporting group title
    Mirtazapine + Folic Acid placebo
    Reporting group description
    		 Mirtazapine + Folic Acid placebo

    Reporting group title
    Mirtazapine + No Folic Acid
    Reporting group description
    		 Mirtazapine + No Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 Mirtazapine + Folic Acid

    Reporting group title
    Mirtazapine + Folic Acid Placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid Placebo

    Reporting group title
    Mirtazapine + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid

    Reporting group title
    Mirtazapine Placebo + Folic Acid Placebo
    Reporting group description
    		 Mirtazapine Placebo + Folic Acid Placebo

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 Mirtazapine Placebo + No Folic Acid

    Primary: PANSS score

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    End point title
    		 PANSS score [1]
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks
    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: Trial terminated early and sample size too small to make any interference. Descriptive statistics were presented as per SAP
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    13
    9
    1
    10
    11
    0 [2]
    Units: point
        arithmetic mean (standard deviation)
    75.2 ( 22.9 )
    61.9 ( 11.6 )
    47 ( 0 )
    69.8 ( 9 )
    73.6 ( 22.9 )
    ( )
    Notes
    [2] - Participant dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Negative PANSS score

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    End point title
    		 Negative PANSS score
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    13
    9
    1
    10
    11
    0 [3]
    Units: point
        arithmetic mean (standard deviation)
    22.9 ( 8.9 )
    17.6 ( 5.7 )
    9 ( 0 )
    19.6 ( 5.2 )
    21.4 ( 6.9 )
    ( )
    Notes
    [3] - Participant dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Calgary Depression Scale

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    End point title
    		 Calgary Depression Scale
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    13
    9
    1
    10
    11
    0 [4]
    Units: point
        arithmetic mean (standard deviation)
    1.8 ( 2.1 )
    2.1 ( 3.5 )
    5 ( 0 )
    5 ( 4.5 )
    2.2 ( 2.5 )
    ( )
    Notes
    [4] - Participant dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Clinical Global Severity Scale

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    End point title
    		 Clinical Global Severity Scale
    End point description
    End point type
    Secondary
    End point timeframe
    collected at 4, 8 and 12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    12
    10
    1
    10
    12
    1
    12
    10
    1
    10
    12
    1
    13
    9
    1
    10
    11
    0 [5]
    Units: point
        arithmetic mean (standard deviation)
    3.2 ( 1.3 )
    3.2 ( 0.8 )
    1 ( 0 )
    3.3 ( 0.8 )
    3.3 ( 1.4 )
    4 ( 0 )
    3.4 ( 1.2 )
    3.2 ( 0.8 )
    1 ( 0 )
    3.3 ( 0.8 )
    3.3 ( 1.4 )
    4 ( 0 )
    3.4 ( 1 )
    2.8 ( 0.8 )
    1 ( 0 )
    3.1 ( 1.1 )
    3.1 ( 1.3 )
    ( )
    Notes
    [5] - Participant dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Change in Barnes Akathisia Scale from baseline

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    End point title
    		 Change in Barnes Akathisia Scale from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 4, 8, 12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    12
    10
    1
    10
    12
    1
    12
    10
    1
    10
    12
    1
    13
    9
    1
    10
    11
    0 [6]
    Units: point
        arithmetic mean (standard deviation)
    -1 ( 1.9 )
    -1.3 ( 1.4 )
    0 ( 0 )
    -0.6 ( 0.8 )
    -0.5 ( 0.8 )
    -1 ( 0 )
    -1.3 ( 2.1 )
    -1.1 ( 1.4 )
    0 ( 0 )
    -0.6 ( 2 )
    -0.8 ( 1.1 )
    -1 ( 0 )
    -1 ( 1.8 )
    -1.2 ( 1.1 )
    0 ( 0 )
    -0.3 ( 1.7 )
    -0.9 ( 1.4 )
    ( )
    Notes
    [6] - Participants dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Change in Global clinical Assessment of Akathisia from baseline

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    End point title
    		 Change in Global clinical Assessment of Akathisia from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 4, 8 and 12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    12
    10
    1
    10
    12
    1
    12
    10
    1
    10
    12
    1
    13
    9
    1
    10
    11
    0 [7]
    Units: point
        arithmetic mean (standard deviation)
    -0.6 ( 1.3 )
    -0.5 ( 0.8 )
    0 ( 0 )
    -0.2 ( 0.4 )
    -0.3 ( 0.6 )
    0 ( 0 )
    -0.8 ( 1.3 )
    -0.5 ( 0.8 )
    0 ( 0 )
    -0.3 ( 0.8 )
    -0.6 ( 0.8 )
    0 ( 0 )
    -0.7 ( 1.3 )
    -0.4 ( 0.9 )
    0 ( 0 )
    -0.1 ( 0.7 )
    -0.5 ( 0.8 )
    ( )
    Notes
    [7] - Participant dropped out at 12 weeks
    No statistical analyses for this end point

    Secondary: Adherence to Mirtazapine

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    End point title
    		 Adherence to Mirtazapine
    End point description
    End point type
    Secondary
    End point timeframe
    at 4, 8, 12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine + No Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine Placebo + No Folic Acid
    Number of subjects analysed
    13
    10
    1
    10
    12
    1
    13
    10
    1
    10
    12
    1
    13
    9
    1
    10
    11
    0 [8]
    Units: subject
        Missing
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Discontinued
    1
    1
    0
    0
    1
    0
    2
    1
    0
    3
    3
    1
    4
    0
    0
    3
    2
        <= 50%
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        51-70%
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        70-90%
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    1
    0
    1
    1
        >=91%
    0
    9
    1
    10
    11
    1
    9
    9
    1
    7
    8
    0
    8
    8
    1
    6
    8
    Notes
    [8] - Participant dropped out
    No statistical analyses for this end point

    Secondary: Adherence to Folate Acid

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    End point title
    		 Adherence to Folate Acid
    End point description
    End point type
    Secondary
    End point timeframe
    at 4, 8, 12 weeks
    End point values
    		 Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo Mirtazapine + Folic Acid Mirtazapine + Folic Acid placebo Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Mirtazapine + Folic Acid Mirtazapine + Folic Acid Placebo Mirtazapine Placebo + Folic Acid Mirtazapine Placebo + Folic Acid Placebo
    Number of subjects analysed
    13
    10
    10
    12
    13
    10
    10
    12
    13
    9
    10
    11
    Units: Subject
        Missing
    1
    1
    0
    0
    1
    0
    0
    0
    0
    0
    1
    0
        Discontinued
    1
    0
    0
    0
    2
    1
    3
    2
    3
    1
    3
    1
        <=50%
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
        51-70%
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        71-90%
    1
    9
    0
    0
    1
    0
    0
    1
    1
    1
    0
    1
        >=91%
    9
    0
    10
    12
    9
    9
    7
    9
    8
    7
    6
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    +Investigators were required to report all suspected SAEs to the Chief Investigator within one working day of discovery. The event was assessed by the CI or delegate within one working day and SAE were immediately reporting to the DMC
    Adverse event reporting additional description
    Investigators recorded SAEs and reportable AEs (those outwith the SmPC and/or leading to withdrawal) on trial forms. AEs were classified in terms of severity, causality and expectedness by both the investigator and the (CI or delegate). SAEs were reported to the DMC. Procedures were in place for reporting of SARs and SUSARs but none occurred.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Mirtazapine + Folic Acid
    Reporting group description
    		 -

    Reporting group title
    Mirtazapine Placebo + No Folic Acid
    Reporting group description
    		 -

    Reporting group title
    Mirtazapine Placebo + Folic Acid
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events only SAE.
    Serious adverse events
    		 Mirtazapine + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine Placebo + Folic Acid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 1 (100.00%)
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Psychotic state
    Additional description: Admission to hospital
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 1 (100.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Self-inflicted laceration
    Additional description: Admission to hospital
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 1 (100.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic behaviour
    Additional description: Admission to hospital
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 1 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
    Additional description: Admission to hospital
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 1 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Mirtazapine + Folic Acid Mirtazapine Placebo + No Folic Acid Mirtazapine Placebo + Folic Acid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 1 (0.00%)
    0 / 12 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2011
    Rating scales added at screening - Mini-International Neuropsychiatric Interview and AUDIT Alcohol Scale. Exclusion of patients with current mood episode. Change to minimisation variables and algorithm.
    05 Dec 2011
    Increase in minimum age for inclusion from 16 to 18 and option for researchers to provide trial medication in small quantities if there are concerns that the participant might take an overdose.
    08 May 2012
    Extension of recruitment period for the trial to 31/07/2013 with last patient out around the end of November 2013 (exact date depending on length of run-in phase of last participant).
    13 Mar 2013
    Change of manufacturer of folic acid placebo and of packager for both placebo and active tablets

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Sep 2013
    Recruitment was stopped in July 2013 due to withdrawal of funding. Participants already in the trial were given the option to terminate early or to complete the trial as per protocol. The final participant to complete the trial did so on 5th September 2013.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the early termination of the trial only 53 participants entered the randomised phase and, of those, MMM did not complete the trial due to the forced termination.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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