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    Clinical Trial Results:
    A multi-centre, double-blind, individually randomised, placebo-controlled, parallel arm RCT with 12-week follow-up to establish the clinical and cost effectiveness of amisulpride augmentation of clozapine in treatment-resistant schizophrenia unresponsive to clozapine

    Summary
    EudraCT number
    		 2010-018963-40
    Trial protocol
    		 GB  
    Global end of trial date
    25 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    08 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO1498
    Additional study identifiers
    ISRCTN number
    		 ISRCTN68824876
    US NCT number
    		 NCT01246232
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Exhibition Road, London, United Kingdom, SW7 2AZ
    Public contact
    Clinical Trials Office, Centre for Mental Health, Imperial College London, v.leeson@imperial.ac.uk
    Scientific contact
    Clinical Trials Office, Centre for Mental Health, Imperial College London, v.leeson@imperial.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
    06 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test carefuly the possible benefits and problems when the antipsychotic amisulpride or a dummy tablet ('placebo') is added to clozapine for 12 weeks in people whose schizophrenia illness has not been helped much by any antipsychotic medication on its own, and who are now taking clozapine, but again with not much improvement.
    Protection of trial subjects
    Thorough monitoring of adverse events and participant wellbeing occurred as part of the assessment process. During assessment and testing, breaks were provided to minimise possible fatigue or stress, and if indicated,the assessments were spread over several days.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 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
    United Kingdom: 68
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    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)
    68
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 •Treatment for at least 12 weeks at a stable dose of 400mg or more of clozapine a day, unless the size of the dose was limited by side effects •A total score of 80+ on the Positive and Negative Syndrome Scale (PANSS) •A Clinical Global Impressions (CGI) score of 4+ •A Social and Occupational Functioning Assessment Scale (SOFAS) score of <41

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clozapine + Amisulpride
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    amisulpride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 400mg amisulpride or one matching placebo capsule for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800mg or two matching placebo capsules for the remaining 8 weeks.

    Arm title
    		 Clozapine + placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 400mg amisulpride or one matching placebo capsule for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800mg or two matching placebo capsules for the remaining 8 weeks.

    Number of subjects in period 1
    		Clozapine + Amisulpride Clozapine + placebo
    Started
    35
    33
    Six Weeks
    32
    26
    Completed
    32
    21
    Not completed
    3
    12
         Consent withdrawn by subject
    2
    3
         IMP discontinued
    -
    5
         Protocol deviation
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clozapine + Amisulpride
    Reporting group description
    		 -

    Reporting group title
    Clozapine + placebo
    Reporting group description
    		 -

    Reporting group values
    		 Clozapine + Amisulpride Clozapine + placebo Total
    Number of subjects
    		 35 33 68
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 35 33 68
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39 ± 11 40 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    		 11 10 21
        Male
    		 24 23 47
    Subject analysis sets

    Subject analysis set title
    Baseline data analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data present are analysed.

    Subject analysis set title
    Endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all people who have data at this time point

    Subject analysis sets values
    		 Baseline data analysis Endpoint
    Number of subjects
    68
    57
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    68
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39 ± 10
    ±
    Gender categorical
    Units: Subjects
        Female
    21
        Male
    47

    End points

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    End points reporting groups
    Reporting group title
    Clozapine + Amisulpride
    Reporting group description
    		 -

    Reporting group title
    Clozapine + placebo
    Reporting group description
    		 -

    Subject analysis set title
    Baseline data analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All data present are analysed.

    Subject analysis set title
    Endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all people who have data at this time point

    Primary: 20% reduction in total PANSS score from baseline

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    End point title
    		 20% reduction in total PANSS score from baseline
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks after baseline
    End point values
    		 Clozapine + Amisulpride Clozapine + placebo Endpoint
    Number of subjects analysed
    32
    25
    57 [1]
    Units: percentage
        Less than 20% reduction in PANSS from baseline
    18
    15
    33
        20% or more reduction in PANSS from baseline
    14
    10
    24
    Notes
    [1] - All those with data were analysed.
    Statistical analysis title
    		 Primary outcome statistical analysis
    Statistical analysis description
    The primary outcome was analysed using logistic regression, adjusting for baseline PANSS score. Results are presented in terms of the intervention (Clozapine + Amisulpride) arm.
    Comparison groups
    Clozapine + Amisulpride v Clozapine + placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.42

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 Nov 2011 - 24 Jun 2015
    Adverse event reporting additional description
    The Antipsychotic Non-Neurological Side-Effects Rating Scale was carried out at each timepoint.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    amisulpride
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 amisulpride placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 29 (6.90%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Psychotic behaviour
    Additional description: worsening of psychotic symptoms requiring hospitalisation
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 amisulpride placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 34 (61.76%)
    10 / 29 (34.48%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 29 (0.00%)
         occurrences all number
    4
    0
    Heart rate irregular
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 34 (17.65%)
    2 / 29 (6.90%)
         occurrences all number
    12
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 34 (17.65%)
    1 / 29 (3.45%)
         occurrences all number
    12
    1
    Endocrine disorders
    Hyperprolactinaemia
         subjects affected / exposed
    11 / 34 (32.35%)
    0 / 29 (0.00%)
         occurrences all number
    11
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2013
    - A change to the way in which participants are un-blinded at the end. Rather than the participant being able to request the information at the end of their participation, they will be advised in the Patient information Sheet that they will be send this information at the end of their participation, and a copy of this notification also sent directly to the referring psychiatrist. - The addition of an option for the prescriber to provide a further 28-day supply of study medication after the final 12-week follow-up assessment. In combination with the direct un-blinding of the referring psychiatrist, this will allow time for participants allocated to the active (amisulpride) arm of the trial to be provided with a standard prescription of amisulpride, and therefore allow an uninterrupted supply of medication where the participant and prescribing clinician agree that this is desirable. - The introduction of a small remuneration to participants in recognition of any expenses incurred (e.g. travel) and inconvenience. This will be £20 for the screening and baseline assessment, £20 for the 6-week assessment, and £20 for the 12-week assessment. Where a participant chooses to discontinue study medication but not to withdraw from the study, this payment will still be made for the completion of assessments.

    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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