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    Clinical Trial Results:
    Research into Antipsychotic Discontinuation and Reduction (RADAR): A Randomised Controlled Trial

    Summary
    EudraCT number
    		 2016-000709-36
    Trial protocol
    		 GB  
    Global end of trial date
    10 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2024
    First version publication date
    29 Mar 2024
    Other versions
    Summary report(s)
    		 Final Paper Published in the Lancet Psychiatry 2023

    Trial information

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    Trial identification
    Sponsor protocol code
    15/0947
    Additional study identifiers
    ISRCTN number
    		 ISRCTN90298520
    US NCT number
    		 NCT03559426
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Priment Clinical Trials Unit staff, Priment Clinical Trials Unit University College London, 44 020 7679 2000, priment@ucl.ac.uk
    Scientific contact
    Priment Clinical Trials Unit staff, Priment Clinical Trials Unit University College London, 44 020 7679 2000, priment@ucl.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
    18 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the benefits and risks of a supported programme of antipsychotic dose reduction, and where feasible discontinuation, in adults with multiple episode schizophrenia and psychotic disorders. These benefits and risks will be established in comparison to a control group from the same clinical population who will maintain their current antipsychotic regimen. The hypothesised principal outcome of the trial is that the programme of reduction will improve the social functioning of participants without increasing the risk of having a severe relapse. The principal secondary outcome will be severe relapse. Other secondary outcomes include quality of life, neuropsychological function, side effects and employment rates.
    Protection of trial subjects
    The eligibility criteria were designed to exclude people with known high risks of causing harm to themselves or other people. In addition, the gradual nature of the antipsychotic reduction enabled detection and treatment of early signs of relapse. All participants received usual care and monitoring of their mental state and behaviour by their clinical team. Those randomised to antipsychotic reduction had increased contact with a psychiatrist for the duration of the reduction, mirroring usual clinical practice of someone undergoing a significant reduction of medication. A Data Safety and Monitoring Board (DSMB) and Programme Steering Committee provided independent oversight of the trial. The DSMB safeguarded the interests of trial participants by assessing the safety and efficacy of the interventions during the trial, and monitoring its conduct and it made recommendations to the steering committee. There was no formal interim analysis, but the DSMB continually reviewed all adverse events data, with the agreement that the trial would be stopped if it was judged that there was a substantial increase in serious adverse events that are likely to be related to the intervention.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jan 2017
    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: 253
    Worldwide total number of subjects
    253
    EEA total number of subjects
    0
    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)
    238
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants meeting the eligibility criteria were recruited from a variety of clinical teams in mental health services in the UK. Potential participants were identified initially by clinical staff or recruited by advertisements placed in clinical settings. If agreed, participants were sent details of the study and a baseline assessment arranged.

    Pre-assignment
    Screening details
    		 4157 people were screened by the clinical teams to ensure they met the strict eligibility criteria, including capacity. After receiving informed consent to participate, participants were randomised to maintenance treatment or the antipsychotic reduction arm. This was an open, parallel group randomised trial with concealed, individual randomisation.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind [1]
    Roles blinded
    		 Assessor, Data analyst [2]
    Blinding implementation details
    Each participant and their clinicians were aware of the treatment allocation, but the researchers who conducted assessments were masked to allocation as far as possible and analysis was also conducted masked to group identity. Researchers were instructed to record incidences when they suspected they might have been unmasked.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Reduction
    Arm description
    		 An antipsychotic reduction strategy supported by the participant’s treating clinician, with an individualised reduction schedule provided as a guide.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    Not applicable for this trial.

    Arm title
    		 Maintenance
    Arm description
    		 Participants received maintenance antipsychotic treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    N/A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    Not applicable for this trial.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: Participants and treating clinicians were not blinded because participants started on different antipsychotic regimes, and those within the intervention group followed an individualised reduction protocol. Members of the research team conducting outcome assessments were blinded to treatment allocation.
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Participants and treating clinicians were not blinded because participants started on different antipsychotic regimes, and those within the intervention group followed an individualised reduction protocol. Members of the research team conducting outcome assessments were blinded to treatment allocation.
    Number of subjects in period 1
    		Reduction Maintenance
    Started
    126
    127
    6 month assessment
    106
    116
    12 month assessment
    95
    98
    24 month assessment
    91
    99
    Completed
    91
    99
    Not completed
    35
    28
         Consent/contact withdrawn, death, hospitalisation
    35
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Reduction
    Reporting group description
    		 An antipsychotic reduction strategy supported by the participant’s treating clinician, with an individualised reduction schedule provided as a guide.

    Reporting group title
    Maintenance
    Reporting group description
    		 Participants received maintenance antipsychotic treatment.

    Reporting group values
    		 Reduction Maintenance Total
    Number of subjects
    		 126 127 253
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 117 121 238
        From 65-84 years
    		 9 6 15
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.6 ± 12.2 46.0 ± 11.5 -
    Gender categorical
    Units: Subjects
        Female
    		 40 42 82
        Male
    		 85 83 168
        Transgender
    		 1 2 3
    Ethnicity
    Units: Subjects
        White
    		 89 82 171
        Black
    		 25 27 52
        Asian
    		 8 8 16
        Other
    		 4 8 12
        Not recorded
    		 0 2 2
    Diagnosis
    Units: Subjects
        Schizophrenia
    		 87 87 174
        Other Psychotic Disorder
    		 39 40 79
    Marital Status
    Units: Subjects
        Single, separated, divorced or widowed
    		 106 110 216
        Married, cohabiting or in a partnership
    		 20 17 37
    First Language
    Units: Subjects
        English
    		 106 114 220
        Other
    		 20 13 33
    Highest educational achievement
    Units: Subjects
        Primary and secondary education to age 16 years
    		 49 36 85
        Primary and secondary education to age 18 years
    		 22 27 49
        Tertiary or further education
    		 40 56 96
        Other general education
    		 14 7 21
        Not recorded
    		 1 1 2
    Employment
    Units: Subjects
        Employed, voluntary work or in education
    		 38 36 74
        Not working or in education
    		 88 89 177
        Not recorded
    		 0 2 2
    Length of time in contact with mental health services
    Units: Subjects
        0-3 years
    		 11 6 17
        4-10 years
    		 34 28 62
        11-15 years
    		 20 23 43
        16-20 years
    		 20 22 42
        >20 years
    		 41 48 89
    Age when first referred to mental health services
    Units: Subjects
        <20 years
    		 26 27 53
        20-30 years
    		 57 67 124
        31-40 years
    		 25 22 47
        ≥41 years
    		 18 11 29
    Alcohol use in the past month
    Units: Subjects
        Once a month or less
    		 80 82 162
        Two to four times a month
    		 24 20 44
        Two or more times a week
    		 22 19 41
        Not recorded
    		 0 6 6
    Recreational drugs used in the past month
    Units: Subjects
        Recreational drugs used
    		 11 14 25
        None
    		 115 113 228
    Years of completed education
    Units: Years
        arithmetic mean (standard deviation)
    		 14 ± 3.3 14 ± 3.9 -
    Antipsychotic medication dose in chlorpromazine equivalents, mg
    Units: Milligrams
        median (full range (min-max))
    		 300 (200 to 450) 300 (200 to 400) -
    Number of previous mental health admissions
    Units: Number of admissions
        median (full range (min-max))
    		 3 (1 to 5) 3 (1 to 5) -

    End points

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    End points reporting groups
    Reporting group title
    Reduction
    Reporting group description
    		 An antipsychotic reduction strategy supported by the participant’s treating clinician, with an individualised reduction schedule provided as a guide.

    Reporting group title
    Maintenance
    Reporting group description
    		 Participants received maintenance antipsychotic treatment.

    Primary: Social Functioning Scale (SFS) score

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    End point title
    		 Social Functioning Scale (SFS) score
    End point description
    Scale used to assess social engagement/withdrawal, interpersonal communication, independence performance, recreational activities, prosocial, independence - competence and occupation and employment. The scale uses the mean of the standardised scores from each domain.
    End point type
    Primary
    End point timeframe
    Social Functioning Score was measured at 24 months post baseline.
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    90
    94
    Units: Overall score
    arithmetic mean (standard deviation)
        SFS score
    105.7 ± 10.5
    106.7 ± 9.7
    Statistical analysis title
    		 Social Functioning Scale score
    Statistical analysis description
    With robust standard errors.
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.859
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 2.33

    Secondary: Severe relapse

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    End point title
    		 Severe relapse
    End point description
    Rates of severe relapse defined as hospitalisation in a mental health inpatient unit. Less severe cases of relapse, not requiring admission to hospital, were also assessed by a blinded 'endpoint committee' based on summary information prepared from clinical records according to predefined criteria.
    End point type
    Secondary
    End point timeframe
    Till the end of the follow-up.
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    126
    127
    Units: Hospitalisations
        Hospitalisations
    34
    17
    Attachments
    		 Kaplan Meier plot for severe relapse
    Statistical analysis title
    		 Time to severe relapse
    Statistical analysis description
    Time to severe relapse was analysed with survival analysis using a Cox proportional hazards model with robust SEs. The extent to which there was a departure from constant proportional hazards was assessed statistically using Schoenfeld residuals. Logistic models with robust SEs on the occurrence of severe relapse within 24 months and the combination of severe and less severe relapse were conducted as supportive analyses.
    Comparison groups
    Maintenance v Reduction
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.007 [1]
    Method
    		 Cox Proportional Hazard regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 3.99
    Notes
    [1] - No evidence that the assumption of proportional hazards was violated using Schoenfeld residuals (p=0.59).
    Statistical analysis title
    		 Severe relapse at any time to the end of the trial
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 4.56

    Secondary: Severe relapse at any time during 24 months

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    End point title
    		 Severe relapse at any time during 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    126
    127
    Units: Admissions
    32
    17
    Statistical analysis title
    		 Severe relapse at any time during 24 months
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 4.22

    Secondary: Non-severe relapse at any time during 24 months

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    End point title
    		 Non-severe relapse at any time during 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    126
    127
    Units: Relapse
        24 months
    20
    11
    Statistical analysis title
    		 Non-severe relapse at any time during 24 months
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 4.35

    Secondary: Any relapse at any time during 24 months

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    End point title
    		 Any relapse at any time during 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    126
    127
    Units: Relapse
        Any relapse
    52
    28
    Statistical analysis title
    		 Any relapse at any time during 24 months
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 4.3

    Secondary: Psychiatric bed days during 24 months

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    End point title
    		 Psychiatric bed days during 24 months
    End point description
    There was no difference in the median psychiatric bed days between groups. Mean bed days were higher for those in the reduction group, but the data were highly skewed.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    117
    121
    Units: Number of bed days
    0
    0
    Statistical analysis title
    		 Number of psychiatric bed days during 24 months
    Statistical analysis description
    Incidence rate ratio The interquartile range (IQR) for the reduction group was 0, 31, and IQR for the maintenance group was 0, 0
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 Zero inflated neg- binomial regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.7
    Notes
    [2] - Number of inpatient days was analysed using Poisson mixed models, with number by 24 months as the response variable, and the log(e) of the number of days of follow up as an offset. A random effect for Trust was included. Method used was zero inflated negative binomial regression with robust SEs.

    Secondary: PANSS positive symptoms subscale

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    End point title
    		 PANSS positive symptoms subscale
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    82
    91
    Units: Scale
        median (full range (min-max))
    10 (8 to 14)
    10 (8 to 14)
    Statistical analysis title
    		 PANSS positive symptoms sub scale score
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 1.56

    Secondary: PANSS negative symptoms sub scale

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    End point title
    		 PANSS negative symptoms sub scale
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    77
    88
    Units: Scale
        median (full range (min-max))
    9 (8 to 13)
    10 (8 to 14)
    Statistical analysis title
    		 PANSS negative symptoms sub scale
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 0.32

    Secondary: Positive and Negative Syndrome Scale (PANSS) total score

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    End point title
    		 Positive and Negative Syndrome Scale (PANSS) total score
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    52
    59
    Units: Scale score
        median (full range (min-max))
    43 (36 to 54)
    48 (38 to 63)
    Statistical analysis title
    		 PANSS total score
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.18
         upper limit
    		 1.97

    Secondary: Manchester Short Assessment of Quality of Life (MANSA)

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    End point title
    		 Manchester Short Assessment of Quality of Life (MANSA)
    End point description
    A measure of subjective quality of life. 12 questions on participants' satisfaction with various aspects of their life. The scale is a mean of each item assessing participants' satisfaction with various aspects of their life.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    86
    89
    Units: Scale score
        arithmetic mean (standard deviation)
    4.6 ± 1.0
    4.7 ± 0.7
    Statistical analysis title
    		 MANSA
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.14

    Secondary: Objective Social Outcomes Index (SIX)

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    End point title
    		 Objective Social Outcomes Index (SIX)
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    86
    90
    Units: Scale score
        arithmetic mean (standard deviation)
    3.3 ± 1.2
    3.3 ± 1.1
    Statistical analysis title
    		 SIX
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.26

    Secondary: Glasgow Antipsychotic Side-effect Scale (GASS)

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    End point title
    		 Glasgow Antipsychotic Side-effect Scale (GASS)
    End point description
    A 22 item scale with 20 questions using a Likert type response from 0=never to 3=every day. Eleven questions have been added to the scale from other side effect questionnaires, making it a modified version, with a total score of 99.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    70
    68
    Units: Scale score
        arithmetic mean (standard deviation)
    21.9 ± 15.5
    25.3 ± 16.0
    Statistical analysis title
    		 GASS
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.77
         upper limit
    		 0.81

    Secondary: Client Satisfaction Questionnaire (CSQ)

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    End point title
    		 Client Satisfaction Questionnaire (CSQ)
    End point description
    An 8 item measure which each item is scored on a four point Likert scale from 1 (lowest degree of satisfaction) to 4 (highest degree of satisfaction), giving an overall score between 8 and 32.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    83
    84
    Units: Scale score
        median (full range (min-max))
    25 (19 to 28)
    25 (22 to 29)
    Statistical analysis title
    		 CSQ-8
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.46
         upper limit
    		 0.85

    Secondary: Medication Adherence Report Scale (MARS-5)

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    End point title
    		 Medication Adherence Report Scale (MARS-5)
    End point description
    Antipsychotic medication adherence. A five item measure which is scored on a five point Likert scale with 1=always and 5=never. Item scores are summed to give an overall score between 5 and 25.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    81
    85
    Units: Scale score
        median (full range (min-max))
    25 (23 to 25)
    25 (23 to 25)
    Statistical analysis title
    		 MARS-5
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 1.21

    Secondary: Questionnaire of the Process of Recovery (QPR)

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    End point title
    		 Questionnaire of the Process of Recovery (QPR)
    End point description
    22 item scaled with Likert scale responses. Total measure ranged between 0-88, with higher scores indicating a more positive outlook and being further along the recovery process.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    78
    83
    Units: Scale score
        arithmetic mean (standard deviation)
    41.5 ± 9.5
    41.1 ± 9.5
    Statistical analysis title
    		 QPR-15
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.39
         upper limit
    		 2.32

    Secondary: Arizona Sexual Experience Scale (ASEX)

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    End point title
    		 Arizona Sexual Experience Scale (ASEX)
    End point description
    Consists of five items, scored on a six point Likert scale. Includes a sex specific question; people were encouraged to complete the question most suited to their gender identity.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    10
    18
    Units: Scale score
        arithmetic mean (standard deviation)
    14.6 ± 4.2
    17.4 ± 6.7
    Statistical analysis title
    		 ASEX
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 3.02

    Secondary: Bodyweight

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    End point title
    		 Bodyweight
    End point description
    Measured in kilograms
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    63
    71
    Units: Kilograms
        arithmetic mean (standard deviation)
    89.6 ± 25
    85.5 ± 18.4
    Statistical analysis title
    		 Bodyweight
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.29
         upper limit
    		 7.83

    Secondary: Cognitive tests – Digit span

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    End point title
    		 Cognitive tests – Digit span
    End point description
    The overall score is the sum of the forward and backward trials.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    83
    88
    Units: Score
        arithmetic mean (standard deviation)
    14.7 ± 4.9
    15.4 ± 4.7
    Statistical analysis title
    		 Digit span
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.12
         upper limit
    		 0.34

    Secondary: Cognitive tests - Digit symbol substitution

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    End point title
    		 Cognitive tests - Digit symbol substitution
    End point description
    Scored one point for each correctly drawn symbol in the time limit
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    62
    66
    Units: Score
        arithmetic mean (standard deviation)
    47.2 ± 20.8
    47.7 ± 20.9
    Statistical analysis title
    		 Digit symbol substitution
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 2.33

    Secondary: Cognitive tests - Auditory Verbal Learning Task

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    End point title
    		 Cognitive tests - Auditory Verbal Learning Task
    End point description
    Scored by the number of words correctly remembered in each trial. The scores from the trials are added to give an overall score.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    76
    85
    Units: Number of words correctly recalled
        arithmetic mean (standard deviation)
    37.0 ± 16.1
    38.2 ± 12.6
    Statistical analysis title
    		 Auditory verbal learning task
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.37
         upper limit
    		 2.55

    Secondary: Cognitive tests - Trail making

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    End point title
    		 Cognitive tests - Trail making
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    63
    69
    Units: Minutes
        median (full range (min-max))
    48 (35 to 61)
    44 (34 to 67)
    Statistical analysis title
    		 Trail making
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.71
         upper limit
    		 10.49

    Secondary: Cognitive tests - Verbal Fluency

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    End point title
    		 Cognitive tests - Verbal Fluency
    End point description
    Scored by the total number of each correct animal, minus number of errors.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    82
    83
    Units: Total number of words (minus errors)
        arithmetic mean (standard deviation)
    17.4 ± 6.8
    17.3 ± 5.5
    Statistical analysis title
    		 Verbal fluency
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 1.6

    Secondary: Employment status

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    End point title
    		 Employment status
    End point description
    Employment status was assessed using the employment sub scale of the SFS
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Reduction Maintenance
    Number of subjects analysed
    91
    99
    Units: Employment status
        Employed, voluntary work or in education
    18
    20
        Not working or in education
    73
    79
    Statistical analysis title
    		 Employment status
    Statistical analysis description
    Employment status was analysed using logistic regression with robust SEs.
    Comparison groups
    Reduction v Maintenance
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 2.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reviews were held at: - Baseline - Pilot trial 3m data collection - 6 month follow up - 12 month follow up - 24 month follow up
    Adverse event reporting additional description
    Serious adverse events were more common in the reduction group, largely due to a higher number of hospital admissions for relapse. Non-serious adverse events were more common in the reduction group, but the number of people experiencing one was lower in the reduction than the maintenance group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 n/a
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Reduction group
    Reporting group description
    		 Antipsychotic reduction arm

    Reporting group title
    Maintenance group
    Reporting group description
    		 Antipsychotic maintenance treatment group

    Serious adverse events
    		 Reduction group Maintenance group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 126 (38.89%)
    29 / 127 (22.83%)
         number of deaths (all causes)
    8
    4
         number of deaths resulting from adverse events
    Investigations
    Psychiatric care
    Additional description: Serious adverse events included death, hospital admissions, life threatening events and others. Please note that causality was assessed according to the antipsychotic participants were taking, not the randomised intervention.
         subjects affected / exposed
    49 / 126 (38.89%)
    29 / 127 (22.83%)
         occurrences causally related to treatment / all
    12 / 93
    11 / 64
         deaths causally related to treatment / all
    0 / 8
    1 / 4
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Reduction group Maintenance group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 126 (69.84%)
    97 / 127 (76.38%)
    Investigations
    Psychiatric care
         subjects affected / exposed
    88 / 126 (69.84%)
    97 / 127 (76.38%)
         occurrences all number
    691
    476

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2017
    Change of primary outcome measure, from the Groningen Social Disabilities Scale to the Social Functioning scale. Protocol: Update to one inclusion/exclusion criteria that was listed incorrectly. Recruitment and patient identification amended in order to recruit through service user groups and networks. Reporting of SAEs and pregnancies made clearer. Reference safety information amended to make it clearer how to determine expectedness. The 'questionnaire about the process of recovery (QPR)' added as it was omitted in error. Primary outcome measure amended and power calculation subsequently amended. Guidance for psychiatrists regarding how to manage increased symptoms and relapse updated.
    30 Oct 2017
    (REC only) Protocol: Social Cognition Questionnaire added to Secondary Outcomes. Exclusion criteria updated to clarify that patients subject to section 37/41 of the Mental Health Act are not eligible. Clarification added that data will be collected from medical records throughout the course of the study.
    30 Apr 2018
    Protocol: Safety reporting procedures amended to restrict the types of events that need to be reported. New list of Investigational Medicinal Products listed in appendix. RSI for assessment of expectedness amended.
    08 Mar 2019
    (REC only) Protocol: Addition of information relating to conducting qualitative interviews.
    20 May 2019
    (REC only) Protocol: Recruitment extended to 31 January 2020. Updated to include all established antipsychotic drugs that are used in Europe/USA; Melperone added. Social Outcomes Index added to secondary outcomes.
    28 Jun 2019
    Protocol: Updated to remove that antipsychotic drugs used in the USA can be used (added in error).
    20 Apr 2020
    Protocol and PIS: Updated to allow for follow up assessments to be conducted remotely, in response to the COVID-19 pandemic.
    14 Jul 2020
    Protocol: Updated to include interviews with participants from the maintenance group in the qualitative sub-study.
    20 May 2021
    Protocol: Update to qualitative interviews. Updates to IMP SmPC appendix.

    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.
    Recruitment was challenging and some participants did not adhere to their randomised treatment programme. The Covid pandemic affected the social functioning measure.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37778356
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