Clinical Trial Results:
A pilot randomised controlled trial of community led anti-psychotic drug reduction for adults with learning disabilities
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Summary
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EudraCT number |
2013-000389-12 |
Trial protocol |
GB |
Global end of trial date |
30 Jun 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jul 2017
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First version publication date |
09 Jul 2017
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Other versions |
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Summary report(s) |
Clean version of final report to funder |
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 |
SPON1173-12
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Additional study identifiers
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ISRCTN number |
ISRCTN38126962 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Sponsor Ref: SPON 1173-12, REC Ref: 13/WA/0034, ISRCTN: 38126962 | ||
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Sponsors
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Sponsor organisation name |
Cardiff University
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Sponsor organisation address |
30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE
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Public contact |
Randell, Cardiff University, 44 02920687608, randelle@cardiff.ac.uk
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Scientific contact |
Randell, Cardiff University, 44 02920687608, randelle@cardiff.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 |
05 Sep 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To assess the feasibility of recruitment and retention, and explore non-efficacy based barriers to a blinded anti-psychotic medication withdrawal programme for adults with LD without psychosis compared to treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes.
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Protection of trial subjects |
Participants in both the intervention arm and the control arm had five appointments with the PI, four to review appropriateness of progression through the trial and finally for unblinding. Appointments were on a monthly basis at which any concerns were addressed. Contact was also made with pharmacy/nursing staff who handed out trial medication. These contacts were also monthly and offset against meetings with the PI. Along with regular reviews, participants and their carers were encouraged to contact the clinical and study team with any concerns throughout the trial.
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Background therapy |
n/a | ||
Evidence for comparator |
The rate of prescription of antipsychotic medication in this population far exceeds the estimated prevalence of psychosis (3-4%). The discrepancy may be accounted for by the use of antipsychotic medications for the treatment of behavioural problems, the commonest reason for their prescription. Rates of prescription among samples of people with learning disabilities with challenging behaviour cluster around 50% and may be as high as 80-95% among those in specially designated services. The effectiveness of antipsychotic medications in treating or controlling challenging behaviour has not been demonstrated. Their use may therefore, in some cases, be considered mistreatment. A Cochrane Collaboration review failed to find evidence to support such treatment and a more recent review of 56 treatment trials found that the great majority lacked scientific rigour and the remainder found conflicting results. A double-blind RCT exploring the impact on aggression of haloperidol (a typical antipsychotic), risperidone (an atypical antipsychotic) and placebo found that patients given placebo showed no evidence of worse response than patients assigned to either of the antipsychotic drugs at any time point. Accompanying economic evaluation concluded that the treatment of challenging behaviour among people with learning disabilities by antipsychotic medication is not a cost-effective option. Apart from a lack of therapeutic and cost effectiveness for the treatment of challenging behaviour, concern about the high use of antipsychotic medication for this purpose is related to the common occurrence of a range of possible adverse medication side-effects in learning disability populations. | ||
Actual start date of recruitment |
01 Apr 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Scientific research | ||
Long term follow-up duration |
9 Months | ||
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: 22
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Worldwide total number of subjects |
22
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EEA total number of subjects |
22
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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) |
22
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment opened in primary care in April 2014. Primary care sites were in four health boards in South Wales and in Bristol, North Somerset, South Gloucestershire, Derby and Wiltshire. Recruitment then extended to Community Learning Disability Teams in April 2015 in south Wales and south west England. Recruitment at all sites closed November 2015 | |||||||||||||||
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Pre-assignment
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Screening details |
Information collected: age, gender, current medication and psychiatric history. In addition, adaptive behaviour was assessed as well as current mental health status. The data gathered was used to confirm inclusion and exclusion criteria. If required, clinical review was undertaken for those exceeding thresholds for the ABS. | |||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
36 [1] | |||||||||||||||
Number of subjects completed |
22 | |||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 14 | |||||||||||||||
| 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: 36 participants were screened in total. However, only 22 were eventually randomised into the trial. |
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Period 1
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Period 1 title |
Baseline
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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, Data analyst, Carer, Assessor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intervention | |||||||||||||||
Arm description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Arm title
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Control | |||||||||||||||
Arm description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Period 2
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Period 2 title |
6 month assessment
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer, Assessor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intervention | |||||||||||||||
Arm description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Arm title
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Control | |||||||||||||||
Arm description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Period 3
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Period 3 title |
9 month assessment
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer, Assessor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intervention | |||||||||||||||
Arm description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Arm title
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Control | |||||||||||||||
Arm description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Risperidone
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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 |
For blinding, medication was encapsulated. Encapsulated placebo medication identical in appearance to active medications was also produced. All participants experienced a change in the supply of their medication at the outset of the study but started on their usual dose. A run-in period was built-into the programme for all participants regardless of allocation and prior to any reduction. IMP was dispensed into Nomad Clear 2 disposable weekly trays with separate compartments for days of the week as well as times of day. Participant specific prescriptions were dispensed and dispatched directly to site. IMP was dispensed monthly for nine months.
When any new prescriptions of study drug were collected from site, unused IMP from previous stages had to be returned by the participant or their carer. Sites were then responsible for the destruction of any unused study medication according to local procedure.
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Baseline characteristics reporting groups
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Reporting group title |
Intervention
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Reporting group description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
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Reporting group description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intervention
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Reporting group description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | ||
Reporting group title |
Control
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Reporting group description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | ||
Reporting group title |
Intervention
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Reporting group description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | ||
Reporting group title |
Control
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Reporting group description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | ||
Reporting group title |
Intervention
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Reporting group description |
Participants in the intervention arm progressed through up to four approximately equal reduction stages to full withdrawal within a six month period, while the control group maintained baseline treatment. All trial medication was encapsulated to maintain the blind. Sites were supported by a detailed treatment and safety package. Treatment achieved at six months was maintained for a further three months under blind conditions. At nine months and following collection of follow-up data, the blind was broken and participants and PIs informed of treatment allocation and current dosage. | ||
Reporting group title |
Control
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Reporting group description |
Those in this arm received over encapsulated risperidone but there was no change in their dose throughout the trial. | ||
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End point title |
Number of participants who progressed through all stages of the intervention [1] | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Eight four-week stages post-randomisation (28-weeks in total)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: We reported the proportion of participants who progressed through the different stages of the intervention. This was a pilot study and therefore no formal statistical analysis was performed on this outcome. |
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From screening to 1 month after the intervention period.
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Assessment type |
Non-systematic | ||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||
Dictionary version |
17
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Reporting groups
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Reporting group title |
Randomised participants
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Reporting group description |
- | ||||||||||||||||||||||
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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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28 Aug 2013 |
1. Section 7 – confirmation from MHRA that site has been added is not required so reference was deleted.
2. Sections 10.4 and 12.1 – details of unblinding have been updated to remove reference to 24 hour unblinding.
3. Section 13.3 – Pharmacovigilance reporting procedures updated to reflect MHRA approved practice.
4. Section 14 – added detail of contents of Emergency Card.
5. Section 17 – End of trial definition refined.
6. Where reference has been made to time frames, calendar or working days have been defined throughout.
7. TSC member details updated.
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21 Jan 2014 |
1. Addition of study team member and updated contact details.
2. Clarification of reduction stages has been made clearer throughout (specifically section 6).
3. Section 7 – area for pilot recruitment redefined.
4. Section 8 – eligibility criteria has been slightly refined.
5. Section 9.1 – the use of the ABS as a screening measure has been clarified.
6. Section 9.3 – ABS should not have been listed as a secondary outcome measure.
7. Section 10.3 – Consent and capacity updated.
8. Section 13 - Updated to reflect MHRA and Sponsor approved wording.
9. Section 14. – Minor changes to GP contact and qualitative follow up.
10. Section 14.3 – Refined interview content and addition of participant interviews.
11. Section 16.1 – Definition of Per Protocol population.
12. Section 16.1.1 – No interim analysis.
13. Section 16.3 – Minor changes to cost effectiveness analysis wording.
14. Section 20.1 – TSC Carer member named.
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08 May 2014 |
1. Section 12.1 – Use of the NOMAD system for supplying IMP to participants safely. |
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01 Dec 2014 |
1. Throughout, reference has been made to PIs as recruitment will now change to include community LD psychiatrists as PIs.
2. GP practices will act as PICs.
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01 Sep 2015 |
1. Throughout, reference to the haloperidol arm has been removed.
2. The 12 month assessment time point has been removed. This includes removal of the details:
Medication changes and reasons for medication change will then be monitored for the final 3 months.
3. Reference to online randomisation has been removed and described as off-line.
4. The wording of the secondary objective has been altered to read as follows:
A secondary objective is to explore the potential non-efficacy-based barriers to drug reduction in clinical practice. We will conduct qualitative telephone interviews with PIs, carers and participants to gain their perceptions about involvement in the trial and medication usage as well as a final assessment of medication level at 12 months.
5. Under the ‘piloting’ section, the following has been added to allow for the various ‘options’ as submitted to the HTA in the recovery plan.
The study will then continue until full recruitment or until the point at which recruitment and/or retention rates dictate that the trial will be redefined as a feasibility trial (as confirmed by the study funder).
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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 | |||
