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Background: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse., Objective: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse?, Design: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up., Settings: Glasgow, UK, and Melbourne, Australia., Participants: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user., Interventions: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted., Main Outcome Measures: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse., Results: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference -4.29, 95% confidence interval -7.29 to -1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained., Limitations: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness., Conclusions: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible., Future Work: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3-0.4)., Trial Registration: This trial is registered as ISRCTN99559262., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Background: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes., Objective: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection., Design: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%., Setting: Twenty-six NHS hospitals., Participants: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively)., Interventions: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm., Main Outcome Measure: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data., Results: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial., Limitations: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded., Conclusions: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy., Future Work: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics., Trial Registration: Current Controlled Trials ISRCTN91566927., 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. 38. See the NIHR Journals Library website for further project information., Competing Interests: Adrian Taylor reports personal fees from Zimmer Inc., Corin Group and DePuy Synthes Companies outside the submitted work. Martin McNally reports personal fees from Bonesupport AB outside the submitted work. R Andrew Seaton reports personal fees from previous consultancy and funding for speaking at educational meetings (Novartis Pharma) and consultancy for Merck Sharp & Dohme Corp. (MSD) outside the submitted work. Harriet Hughes reports other competing interests from Gilead Sciences Inc., MSD, Biocomposites, and personal fees from Biocomposites and Cubist Pharmaceuticals outside the submitted work. Jennifer Bostock was a member of the Health Services and Delivery Research Commissioned Panel Members during this project.

Background: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD., Objective: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation., Design: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial., Setting: The trial was conducted in 121 UK primary and secondary care sites., Participants: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year., Interventions: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status., Primary Outcome: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs., Results: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV 1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV 1 ), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms., Limitations: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment ( n  = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study., Conclusion: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses., Future Work: To promote consideration of the findings of this trial in national and international COPD guidelines., Trial Registration: Current Controlled Trials ISRCTN27066620., 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. 37. See the NIHR Journals Library website for further project information., Competing Interests: Graham Burns reports personal fees from Boehringer Ingelheim GmbH (Ingelheim am Rhein, Germany), Teva Pharmaceutical Industries Ltd (Petah Tikva, Israel), Chiesi Farmaceutici SpA (Parma, Italy), Pfizer Inc. (New York City, NY, USA) and AstraZeneca plc (Cambridge, UK), and non-financial support from Chiesi and Boehringer Ingelheim, outside the submitted work. Rekha Chaudhuri reports personal fees from AstraZeneca, GlaxoSmithKline (GSK) plc (London, UK), Teva and Novartis International AG (Basel, Switzerland) for advisory board meetings, outside the submitted work. Anthony De Soyza reports grants and non-financial support from AstraZeneca and Chiesi, non-financial support from Boehringer Ingelheim, grants and personal fees from GSK, Bayer AG (Leverkusen, Germany) and Pfizer, and grants from Forest Laboratories (New York City, NY, USA)/Teva, outside the submitted work. He is also a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Elective and Emergency Specialist Care (EESC) Panel. Simon Gompertz reports personal fees from Pfizer and GSK, outside the submitted work. John Norrie reports grants from the NIHR HTA programme during the conduct of the study, was a member of the NIHR HTA Commissioning Board (2010–16) and is currently Deputy Chairperson of the NIHR HTA General Board (2016–present) and a NIHR Journals Library Editor (2014–present). Andrew Wilson reports grants from F. Hoffmann-La Roche (Basel, Switzerland), outside the submitted work. David Price reports grants and personal fees from Aerocrine AB (Stockholm, Sweden), AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan NV (Canonsburg, PA, USA), Mundipharma International Ltd (Cambridge, UK), Napp Pharmaceuticals Ltd (Cambridge, UK), Novartis, Pfizer, Teva, Theravance Biopharma (San Francisco, CA, USA) and Zentiva Group a.s. (Prague, Czech Republic); personal fees from Almirall SA (Barcelona, Spain), Amgen Inc. (Newbury Park, CA, USA), Cipla Ltd (Mumbai, India), GSK, Kyorin Pharmaceutical Co. Ltd (Tokyo, Japan), Merck Sharp & Dohme (Kenilworth, NJ, USA), Skyepharma Production SAS (Saint-Quentin-Fallavier, France); grants from AKL Research and Development Ltd (Stevenage, UK), the British Lung Foundation, the Respiratory Effectiveness Group and the UK NHS; and non-financial support from the NIHR Efficacy and Mechanism Evaluation and HTA programmes, outside the submitted work. He also reports stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals and owns 74% of the social enterprise Optimum Patient Care Ltd (Cambridge, UK, and Australia and Singapore) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore).

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., Competing Interests: Christopher Williams reports personal fees from Taylor and Francis (Abingdon, UK) and from Five Areas Ltd (Clydebank, UK) outside the submitted work and is president of the British Association for Behavioural and Cognitive Psychotherapies (BABCP). Sally-Ann Cooper reports grants from the National Institute for Health Research Health Technology Assessment programme during the conduct of the study.

Background: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use., Objective: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity., Design: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs., Setting: Multicentre study involving all five UK officially designated NHS adult lung transplant centres., Participants: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list., Intervention: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation., Main Outcome Measures: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs., Results: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study., Conclusions: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation., Trial Registration: Current Controlled Trials ISRCTN44922411., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.