scholarly journals A pilot randomised controlled trial of community-led ANtipsychotic Drug REduction for Adults with Learning Disabilities

2017 ◽  
Vol 21 (47) ◽  
pp. 1-92 ◽  
Author(s):  
Rachel McNamara ◽  
Elizabeth Randell ◽  
David Gillespie ◽  
Fiona Wood ◽  
David Felce ◽  
...  

Background Data suggest that approximately 50,000 adults with learning disabilities (LDs) in England and Wales are currently prescribed antipsychotic medication. Illness in this population is common, including significant rates of challenging behaviour and mental illness, but there is particular concern over the use of antipsychotics prescribed for reasons other than the treatment of psychosis. Control of challenging behaviour is the primary reason why such medications are prescribed despite the absence of good evidence for any therapeutic effect for this purpose. Objectives To assess the feasibility of recruitment and retention and to explore non-efficacy-based barriers to a blinded antipsychotic medication withdrawal programme for adults with LDs without psychosis compared with treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes. Design A two-arm individually randomised double-blind placebo-controlled drug reduction trial. Setting Recruitment was through community learning disability teams (CLDTs) in south Wales and south-west England. Participants Adults with LDs who are prescribed risperidone for treatment of challenging behaviour with no known current psychosis or previous recurrence of psychosis following prior drug reduction. Intervention A double-blind drug reduction programme leading to full withdrawal within 6 months. Treatment in the intervention group was gradually reduced over a 6-month period and then maintained at the same level for a further 3 months, still under blind conditions. In the control group, the baseline level of medication was maintained throughout the 9-month period. The blind was broken at 9 months, following final data collection. Main outcome measures Feasibility outcomes were (1) the number and proportion of general practices/CLDTs that progressed from initial approach to recruitment of participants and (2) the number and proportion of recruited participants who progressed through the various stages of the study. Trial arms were also compared regarding clinical outcomes, the Modified Overt Aggression Scale, the Aberrant Behaviour Checklist, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist, the Antipsychotic Side-effect Checklist, the Dyskinesia Identification System Condensed User Scale, the Client Service Receipt Inventory, use of other interventions to manage challenging behaviour, use of as-required (pro re nata) medication and level of psychotropic medication use. Results Of the 22 participants randomised (intervention, n = 11; control, n = 11), 13 (59%) achieved progression through all four stages of reduction. Follow-up data at 6 and 9 months were obtained for 17 participants (intervention, n = 10; and control, n = 7; 77% of those randomised). There were no clinically important changes in participants’ levels of aggression or challenging behaviour at the end of the study. There were no expedited safety reports. Four adverse events and one serious adverse event were reported during the trial. Limitations Recruitment was challenging, which was largely a result of difficulty in identifying appropriate persons to consent and carer concerns regarding re-emergence of challenging behaviour. Reduced recruitment meant that the full trial became an exploratory pilot study. Conclusions The results indicate that drug reduction is possible and safe. However, concerns about taking part were probably exacerbated by limited availability of alternative (behavioural) interventions to manage behaviour; therefore, focused support and alternative interventions are required. The results of the qualitative study provide important insights into the experiences of people taking part in drug reduction studies that should influence future trial development. Future work We recommend that further work focuses on support for practitioners, carers and patients in reducing antipsychotic medication. Trial registration Current Controlled Trials ISRCTN38126962. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 47. See the NIHR Journals Library website for further project information.

2018 ◽  
Vol 22 (53) ◽  
pp. 1-130 ◽  
Author(s):  
Andrew Jahoda ◽  
Richard Hastings ◽  
Chris Hatton ◽  
Sally-Ann Cooper ◽  
Nicola McMeekin ◽  
...  

Background Depression is the most prevalent mental health problem among people with learning disabilities. Objective The trial investigated the clinical effectiveness and cost-effectiveness of behavioural activation for depression experienced by people with mild to moderate learning disabilities. The intervention was compared with a guided self-help intervention. Design A multicentre, single-blind, randomised controlled trial, with follow-up at 4, 8 and 12 months post randomisation. There was a nested qualitative study. Setting Participants were recruited from community learning disability teams and services and from Improving Access to Psychological Therapies services in Scotland, England and Wales. Participants Participants were aged ≥ 18 years, with clinically significant depression, assessed using the Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities. Participants had to be able to give informed consent and a supporter could accompany them to therapy. Interventions BeatIt was a manualised behavioural activation intervention, adapted for people with learning disabilities and depression. StepUp was an adapted guided self-help intervention. Main outcome measures The primary outcome measure was the Glasgow Depression Scale for people with a Learning Disability (GDS-LD). Secondary outcomes included carer ratings of depressive symptoms and aggressiveness, self-reporting of anxiety symptoms, social support, activity and adaptive behaviour, relationships, quality of life (QoL) and life events, and resource and medication use. Results There were 161 participants randomised (BeatIt, n = 84; StepUp, n = 77). Participant retention was strong, with 141 completing the trial. Most completed therapy (BeatIt: 86%; StepUp: 82%). At baseline, 63% of BeatIt participants and 66% of StepUp participants were prescribed antidepressants. There was no statistically significant difference in GDS-LD scores between the StepUp (12.94 points) and BeatIt (11.91 points) groups at the 12-month primary outcome point. However, both groups improved during the trial. Other psychological and QoL outcomes followed a similar pattern. There were no treatment group differences, but there was improvement in both groups. There was no economic evidence suggesting that BeatIt may be more cost-effective than StepUp. However, treatment costs for both groups were approximately only 4–6.5% of the total support costs. Results of the qualitative research with participants, supporters and therapists were in concert with the quantitative findings. Both treatments were perceived as active interventions and were valued in terms of their structure, content and perceived impact. Limitations A significant limitation was the absence of a treatment-as-usual (TAU) comparison. Conclusions Primary and secondary outcomes, economic data and qualitative results all clearly demonstrate that there was no evidence for BeatIt being more effective than StepUp. Future work Comparisons against TAU are required to determine whether or not these interventions had any effect. Trial registration Current Controlled Trials ISRCTN09753005. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 53. See the NIHR Journals Library website for further project information.


2019 ◽  
Vol 23 (62) ◽  
pp. 1-94 ◽  
Author(s):  
Mark T Drayson ◽  
Stella Bowcock ◽  
Tim Planche ◽  
Gulnaz Iqbal ◽  
Guy Pratt ◽  
...  

Background Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile. There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial. Objectives To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients. Design Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio. Setting A total of 93 NHS hospitals throughout England, Northern Ireland and Wales. Participants A total of 977 patients with newly diagnosed symptomatic myeloma. Intervention Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year. Main outcome measures The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond. Results In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival (p = 0.94). Limitations Short duration of prophylactic antibiotics and cost-effectiveness. Conclusions During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04). Trial registration Current Controlled Trials ISRCTN51731976. Funding details This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.


2014 ◽  
Vol 18 (71) ◽  
pp. 1-212 ◽  
Author(s):  
Andrew Wolf ◽  
Andrew McKay ◽  
Catherine Spowart ◽  
Heather Granville ◽  
Angela Boland ◽  
...  

BackgroundChildren in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful.ObjectiveEvaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam.DesignMulticentre, double-blind, randomised equivalence trial.SettingTen UK PICUs.ParticipantsChildren (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours.InterventionsClonidine (3 µg/kg loading then 0–3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0–200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine.Main outcome measuresPrimary end point Adequate sedation defined by COMFORT score of 17–26 for ≥ 80% of the time with a ± 0.15 margin of equivalence.Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data.ResultsThe study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) – clonidine, and 18 of 59 (30.5%) – midazolam. The difference in proportions for clonidine–midazolam was 0.04 [95% confidence interval (CI) –0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (–0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI –5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61).ConclusionsClonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment.Trial registrationCurrent Controlled Trials ISRCTN02639863.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information.


2013 ◽  
Vol 17 (7) ◽  
pp. 1-166 ◽  
Author(s):  
S Banerjee ◽  
J Hellier ◽  
R Romeo ◽  
M Dewey ◽  
M Knapp ◽  
...  

ObjectiveDepression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo.DesignMulticentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up.SettingNine English old-age psychiatry services.ParticipantsA pragmatic trial.Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+.Exclusions: clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer.Interventions(1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily.Main outcome measuresOutcome: CSDD score.Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation.Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed.ResultsNumbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine).Outcome: Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo–sertraline 1.17 (−0.23 to 2.78;p = 0.102); placebo–mirtazapine 0.01 (−1.37 to 1.38;p = 0.991); and mirtazapine–sertraline 1.16 (−0.27 to 2.60;p = 0.112).Harms: Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%;p = 0.017); 39-week mortality equal, five deaths in each group.ConclusionsThis is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.Trial registrationEudraCT Number – 2006–000105–38.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 7. See the HTA programme website for further project information.


2019 ◽  
Vol 23 (15) ◽  
pp. 1-140 ◽  
Author(s):  
Athimalaipet V Ramanan ◽  
Andrew D Dick ◽  
Ashley P Jones ◽  
Dyfrig A Hughes ◽  
Andrew McKay ◽  
...  

Background Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. Objective To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. Design This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost–utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. Setting The setting was tertiary care centres throughout the UK. Participants Patients aged 2–18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). Interventions All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. Main outcome measures Primary outcome – time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome – incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. Results A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. Conclusions Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. Future work A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. Trial registration Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.


BMJ ◽  
2019 ◽  
pp. l1029
Author(s):  
Rob Cook ◽  
Vaughan Thomas ◽  
Rosie Martin

The study FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet 2019;393:256-74. The study was funded by the UK Stroke Association and the NIHR Health Technology Assessment Programme project number 13/04/30. To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000729/a-commonly-used-antidepressant-doesnt-improve-recovery-after-stroke


2008 ◽  
Vol 19 (4) ◽  
pp. 253-269 ◽  
Author(s):  
Sabine Heel ◽  
Sonja Fischer ◽  
Stefan Fischer ◽  
Tobias Grässer ◽  
Ellen Hämmerling ◽  
...  

Zunächst führt dieser Artikel in die wesentlichen Begrifflichkeiten und Zielstellungen der Versorgungsforschung ein. Er befasst sich dann mit der Frage, wie die einzelnen Teildisziplinen der Versorgungsforschung, (1) die Bedarfsforschung, (2) die Inanspruchnahmeforschung, (3) die Organisationsforschung, (4) das Health Technology Assessment, (5) die Versorgungsökonomie, (6) die Qualitätsforschung und zuletzt (7) die Versorgungsepidemiologie konzeptionell zu fassen sind, und wie sie für neuropsychologische Anliegen ausformuliert werden müssen. In diesem Zusammenhang werden die in den einzelnen Bereichen jeweils vorliegenden versorgungsrelevanten Studienergebnisse referiert. Soweit es zulässig ist, werden Bedarfe für die Versorgungsforschung und Versorgungspraxis in der Neurorehabilitation daraus abgeleitet und Anregungen für die weitere empirische Forschung formuliert. Der Artikel bezieht sich – entsprechend seines Anliegens – ausschließlich auf Studien, die sich mit der Situation der deutschen Neurorehabilitation befassen.


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