Clinical Trial Results:
A pragmatic randomised double-blind trial of Antipsychotic Treatment of very LAte-onset Schizophrenia-like psychosis: The ATLAS Trial
Summary
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EudraCT number |
2010-022184-35 |
Trial protocol |
GB |
Global end of trial date |
14 Dec 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Mar 2019
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First version publication date |
20 Mar 2019
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Other versions |
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Summary report(s) |
FINAL STUDY REPORT |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ATLAS
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Additional study identifiers
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ISRCTN number |
ISRCTN45593573 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
King's College London
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Sponsor organisation address |
The Strand, London, United Kingdom, WC2R 2LS
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Public contact |
Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
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Scientific contact |
Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
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Sponsor organisation name |
South London and Maudsley NHS Foundation Trust
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Sponsor organisation address |
Bethlem Royal Hospital, Monks Orchard Road, Beckenham, London, United Kingdom, BR3 3BX
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Public contact |
Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
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Scientific contact |
Professor Rob Howard, University College London, 0044 20 3549 5114, robert.howard@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Dec 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Dec 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Dec 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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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?
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Sep 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 101
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Worldwide total number of subjects |
101
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EEA total number of subjects |
101
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
71
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85 years and over |
30
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Recruitment
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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
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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
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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 |
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Randomised - controlled
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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
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A | ||||||||||||
Arm description |
100mg amisulpride in both stages | ||||||||||||
Arm type |
100mg amisulpride in both stages | ||||||||||||
Investigational medicinal product name |
Amisulpride
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Group A took one capsule containing 100mg amisulpride per day for 24 weeks
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Arm title
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Arm B | ||||||||||||
Arm description |
Amisulpride in Stage 1, Placebo in Stage 2 | ||||||||||||
Arm type |
Amisulpride then placebo | ||||||||||||
Investigational medicinal product name |
Amisulpride
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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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
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Arm title
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Arm C | ||||||||||||
Arm description |
Placebo in Stage 1, Amisulpride in Stage 2 | ||||||||||||
Arm type |
Placebo then amisulpride | ||||||||||||
Investigational medicinal product name |
Amisulpride
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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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
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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 |
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Baseline characteristics reporting groups
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Reporting group title |
Arm A
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Reporting group description |
100mg amisulpride in both stages | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B
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Reporting group description |
Amisulpride in Stage 1, Placebo in Stage 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm C
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Reporting group description |
Placebo in Stage 1, Amisulpride in Stage 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A
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Reporting group description |
100mg amisulpride in both stages | ||
Reporting group title |
Arm B
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Reporting group description |
Amisulpride in Stage 1, Placebo in Stage 2 | ||
Reporting group title |
Arm C
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Reporting group description |
Placebo in Stage 1, Amisulpride in Stage 2 | ||
Subject analysis set title |
Amisulpride in Stage 1
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients receiving Amisulpride in Stage 1 (i.e. Arms A+B)
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Subject analysis set title |
Placebo in Stage 1
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients receiving Placebo in Stage 1 (i.e. Arm C)
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Subject analysis set title |
Amisulpride in Stage 2
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients receiving Amisulpride in Stage 2 (i.e. Arm A)
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Subject analysis set title |
Placebo in Stage 2
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients receiving Placebo in Stage 2 (i.e. Arm B)
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End point title |
Change in BPRS score | ||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
12 weeks
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Statistical analysis title |
Change in BPRS from Baseline to Week 12 | ||||||||||||||||||||
Comparison groups |
Amisulpride in Stage 1 v Placebo in Stage 1
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Number of subjects included in analysis |
89
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.0002 | ||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
7.7
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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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
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Number of subjects included in analysis |
41
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.024 | ||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
6.3
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.9 | ||||||||||||||||||||
upper limit |
11.7 |
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End point title |
Compliance with trial treatment | |||||||||||||||
End point description |
No. patients stopping trial treatment
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End point type |
Primary
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End point timeframe |
12 weeks
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Statistical analysis title |
Compliance with trial treatment | |||||||||||||||
Comparison groups |
Amisulpride in Stage 1 v Placebo in Stage 1
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.39 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Confidence interval |
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Statistical analysis title |
Compliance with trial treatment | |||||||||||||||
Comparison groups |
Amisulpride in Stage 2 v Placebo in Stage 2
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Number of subjects included in analysis |
41
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.4 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Confidence interval |
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Adverse events information [1]
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Timeframe for reporting adverse events |
From randomisation to final assessment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
Trial-specific | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
n/a
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Reporting groups
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Reporting group title |
Arm A
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Reporting group description |
100mg amisulpride in both stages | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B
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Reporting group description |
Amisulpride in Stage 1, Placebo in Stage 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm C
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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 |
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Jun 2012 |
To clarify/amend 2 eligibility criteria
-To amend the IMP labels; |
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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.
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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. |
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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
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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.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/29880238 |