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    Clinical Trial Results:
    A pragmatic randomised double-blind trial of Antipsychotic Treatment of very LAte-onset Schizophrenia-like psychosis: The ATLAS Trial

    Summary
    EudraCT number
    		 2010-022184-35
    Trial protocol
    		 GB  
    Global end of trial date
    14 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2019
    First version publication date
    20 Mar 2019
    Other versions
    Summary report(s)
    		 FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    ATLAS
    Additional study identifiers
    ISRCTN number
    		 ISRCTN45593573
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
    Scientific contact
    Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
    Sponsor organisation name
    South London and Maudsley NHS Foundation Trust
    Sponsor organisation address
    Bethlem Royal Hospital, Monks Orchard Road, Beckenham, London, United Kingdom, BR3 3BX
    Public contact
    Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
    Scientific contact
    Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@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
    14 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    (1) Is amisulpride superior to placebo in the treatment of very late-onset schizophrenia-like psychosis over 12 weeks as measured by significant differences between amisulpride and placebo treated groups in improvements in score on the brief psychiatric rating scale (BPRS) largely driven by improvements in the hostility, suspiciousness, hallucinations, tension, uncooperativeness and motor hyperactivity sub-scores? (2) Is prolonged treatment after 12 weeks superior to treatment withdrawal to receive placebo over the next 12 weeks as measured by significant differences in BPRS scores between groups and significantly greater numbers of patients in the group randomised to receive placebo being withdrawn to open treatment with amisulpride by their physicians?
    Protection of trial subjects
    Consent: Although the presence of cognitive impairment was an exclusion criterion for ATLAS, individuals with very late onset schizophrenialike psychosis often have low levels of insight, i.e. they have specific reasoning difficulties around their self-assessment as patients with an illness that requires treatment. For this reason the clinicians were asked to assess whether the patient is cosidered to have the capacity to give consent prior to doing so.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Sep 2012
    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: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    0
    From 65 to 84 years
    71
    85 years and over
    30

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were patients with very late-onset schizophrenia-like psychosis recruited from the community and inpatient teams of UK Old Age Psychiatry services across the UK between 2012 and 2016.

    Pre-assignment
    Screening details
    		 i. Diagnosis of very late-onset schizophrenia-like psychosis, including onset of delusions and/or hallucinations after the age of 60 years; and ii. BPRS score ≥30, or active psychotic symptoms of a nature and severity that would be consistent with a BPRS score of 30 or greater: and iii. Capacity to give informed consent to inclusion in trial

    Pre-assignment period milestones
    Number of subjects started
    		 92 [1]
    Number of subjects completed
    		 92

    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: 101 patients were randomised, but only 92 patients went on to start trial treatment and hence were included in the ITT analyses
    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, Monitor, Carer, Assessor
    Blinding implementation details
    Trial treatment will be oral amisulpride or identically appearing placebo packed into treatment cartons of 12 weeks’ treatment in the form of 3 x 28 blister-packed capsules

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 100mg amisulpride in both stages
    Arm type
    		 100mg amisulpride in both stages

    Investigational medicinal product name
    Amisulpride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Group A took one capsule containing 100mg amisulpride per day for 24 weeks

    Arm title
    		 Arm B
    Arm description
    		 Amisulpride in Stage 1, Placebo in Stage 2
    Arm type
    		 Amisulpride then placebo

    Investigational medicinal product name
    Amisulpride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Group B took one capsule containing 100mg amisulpride per day for 12 weeks, followed by one matched capsule containing placebo per day for a further 12 weeks

    Arm title
    		 Arm C
    Arm description
    		 Placebo in Stage 1, Amisulpride in Stage 2
    Arm type
    		 Placebo then amisulpride

    Investigational medicinal product name
    Amisulpride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Group C took one placebo capsule per day for 12 weeks, followed by one capsule containing 100mg amisulpride per day for a further 12 weeks

    Number of subjects in period 1 [2]
    		Arm A Arm B Arm C
    Started
    29
    32
    31
    Completed
    29
    32
    31
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 101 patients were randomised, but only 92 patients went on to start trial treatment and hence were included in the ITT analyses

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 100mg amisulpride in both stages

    Reporting group title
    Arm B
    Reporting group description
    		 Amisulpride in Stage 1, Placebo in Stage 2

    Reporting group title
    Arm C
    Reporting group description
    		 Placebo in Stage 1, Amisulpride in Stage 2

    Reporting group values
    		 Arm A Arm B Arm C Total
    Number of subjects
    		 29 32 31 92
    Age categorical
    Units: Subjects
        60-69
    		 0 5 0 5
        70-79
    		 13 14 12 39
        > or = 80
    		 16 13 19 48
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 81.2 ( 6.8 ) 78.8 ( 8.3 ) 80.6 ( 5.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 7 6 21
        Male
    		 21 25 25 71
    Ethnic Group
    Units: Subjects
        White
    		 22 22 22 66
        Black
    		 7 7 6 20
        Mixed
    		 0 1 0 1
        Other
    		 0 1 2 3
        Unknown
    		 0 1 1 2
    Home circumstances
    Units: Subjects
        Living alone
    		 23 20 20 63
        Living with spouse/partner
    		 4 6 6 16
        Other
    		 2 6 5 13
    BPRS score
    Brief Psychiatric Rating Scale
    Units: Subjects
        30-39
    		 11 13 18 42
        40-49
    		 15 12 11 38
        50+
    		 3 7 2 12
    Time with symptoms
    Units: Subjects
        <6 months
    		 10 3 8 21
        >/= 6 months
    		 17 28 23 68
        Unknown
    		 2 1 0 3
    Antipsychotics
    Taking amisulpride or other antipsychotic drug (now or previously)?
    Units: Subjects
        None previously
    		 13 17 15 45
        Yes, >1 month previously
    		 2 1 6 9
        Yes, in last month
    		 14 14 10 38
    SMMSE score
    Standardised Mini-Mental State Examination
    Units: Subjects
        25-27
    		 15 15 15 45
        28-30
    		 14 17 16 47
    BPRS score
    Brief Psychiatric Rating Scale
    Units: Point
        arithmetic mean (standard deviation)
    		 41.4 ( 7.2 ) 43.5 ( 9.4 ) 38.9 ( 6.2 ) -
    SMMSE score
    Standardised Mini-Mental State Examination
    Units: Point
        arithmetic mean (standard deviation)
    		 27.2 ( 1.5 ) 27.6 ( 1.6 ) 27.8 ( 1.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 100mg amisulpride in both stages

    Reporting group title
    Arm B
    Reporting group description
    		 Amisulpride in Stage 1, Placebo in Stage 2

    Reporting group title
    Arm C
    Reporting group description
    		 Placebo in Stage 1, Amisulpride in Stage 2

    Subject analysis set title
    Amisulpride in Stage 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving Amisulpride in Stage 1 (i.e. Arms A+B)

    Subject analysis set title
    Placebo in Stage 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving Placebo in Stage 1 (i.e. Arm C)

    Subject analysis set title
    Amisulpride in Stage 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving Amisulpride in Stage 2 (i.e. Arm A)

    Subject analysis set title
    Placebo in Stage 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving Placebo in Stage 2 (i.e. Arm B)

    Primary: Change in BPRS score

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    End point title
    		 Change in BPRS score
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Amisulpride in Stage 1 Placebo in Stage 1 Amisulpride in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    58
    31
    19
    22
    Units: Points
        number (not applicable)
    -11.9
    -4.2
    -1.1
    5.2
    Statistical analysis title
    		 Change in BPRS from Baseline to Week 12
    Comparison groups
    Amisulpride in Stage 1 v Placebo in Stage 1
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0002
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.8
         upper limit
    		 11.5
    Statistical analysis title
    		 Change in BPRS from Week 12 to final assessment
    Comparison groups
    Amisulpride in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.024
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 11.7

    Primary: Compliance with trial treatment

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    End point title
    		 Compliance with trial treatment
    End point description
    No. patients stopping trial treatment
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Amisulpride in Stage 1 Placebo in Stage 1 Amisulpride in Stage 2 Placebo in Stage 2
    Number of subjects analysed
    61
    31
    19
    22
    Units: Subjects
    20
    13
    7
    11
    Statistical analysis title
    		 Compliance with trial treatment
    Comparison groups
    Amisulpride in Stage 1 v Placebo in Stage 1
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.39
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Compliance with trial treatment
    Comparison groups
    Amisulpride in Stage 2 v Placebo in Stage 2
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to final assessment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Trial-specific
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 100mg amisulpride in both stages

    Reporting group title
    Arm B
    Reporting group description
    		 Amisulpride in Stage 1, Placebo in Stage 2

    Reporting group title
    Arm C
    Reporting group description
    		 Placebo in Stage 1, Amisulpride in Stage 2

    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: Data was not collected on all non-serious adverse events - only those deemed related to trial treatment; number of non-serious adverse events has therefore been reported as zero
    Serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 29 (31.03%)
    12 / 32 (37.50%)
    7 / 31 (22.58%)
         number of deaths (all causes)
    0
    2
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Cardiovascular
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Falls
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 32 (15.63%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genitourinary
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
    0 / 31 (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
    Other
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 32 (9.38%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Extrapyramidal symptoms
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric symptoms
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B Arm C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2012
    To clarify/amend 2 eligibility criteria -To amend the IMP labels;
    21 Mar 2013
    To change CTA to remove Solian brand of amisulpride and define the IMP by active substance only to allow any brand/generic to be used in the future manufacture of the IMP. Non-substantial changes notified to MHRA with substantial change above: Administrative changes to CTA (add ISRCTN number, update contact details). Correction of error on CTA regarding number of trial arms (changed from 2 to 3). Change in name of manufacturer. . . Removal of 2 sites: Suffolk Mental Health Partnership NHS Trust and Norfolk & Waveney Mental Health NHS Foundation Trust (merged to be become Norfolk & Suffolk NHS Foundation Trust) Change of 2 Pis: Dr. Tabet replacing Dr. Ferrera at Sussex Partnership NHS Foundation Trust; Dr. Fox replacing Dr. Khalifa at Norfolk & Suffolk NHS Foundation Trust.
    18 Jun 2015
    Submission of revised IMPD at the next Substantial Amendment, along with the updated MIA(IMP) to reflect the change of name from Bilcare to Sharp. The simplified IMPD submitted with this amendment reflects the fact that bioequivalent generic amisulpride can now be used in the manufacturing process. Documents in the CRF have not been altered, but have been removed from the protocol and appropriately version controlled. The purpose of this amendment is as follows: • To adjust the sample size (N= at least 100) • To add a safety monitoring assessment at Week 16 • To shorten Stg 2 treatment from 24 weeks to 12 weeks • To amend the IMP labels • To clarify the Informed Consent process • To stipulate that the original CRFs should be retained at site and copies returned to the Trial Office • To add visit windows (+/- 1 week) at Week 4 and Week 16 visit • To clarify the SAE reporting process • To revise the Statistics section • To amend the treatment allocation as there will now be a second treatment allocation at the 10-12wk visit
    09 Nov 2015
    The protocol has been amended to include an optional blood test at two time points during the trial; once during Stage 1 (ie Week 4 or week 10-12); and once during Stage 2 (Week 16 or Week 22-24). The exclusion criteria have been modified to highlight the optional nature of the blood tests, and the effects of amisulpride on blood levels of amisulpride and the hormone prolactin have been included as secondary efficacy parameters. The results from 20 ATLAS participants will be combined with the dataset obtained from the existing ethically approved trial “Optimisation of Amisulpride prescribing in older people” and the combined dataset will be analysed together. However, this analysis is outside the scope of the ATLAS protocol and the primary and secondary outcomes of the trial remain unchanged.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29880238
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