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Background: Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome., Methods: We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing., Results: We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery., Limitations: Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered., Conclusions: There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit., Study Registration: This study is registered as PROSPERO CRD42020171098., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment ; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Background: Liaison mental health services provide mental health care to patients in acute hospital settings. Evaluation of liaison services is challenging due to their heterogeneous organisation and delivery, high case throughput and varied patient case mix. We aimed to link routinely collected National Health Service data from secondary care settings, chosen for their service characteristics, to data from primary care to evaluate hospital-based liaison mental health services in England., Methods: We planned to compare patients referred to hospital-based liaison services with comparable patients in the same hospital not referred to liaison services and comparable patients in hospitals without any liaison services. We designed and enacted a methodology to link data from: (1) Hospital Episode Statistics, a database controlled by the National Health Service Digital and (2) ResearchOne, a primary care database controlled by The Phoenix Partnership., Results: Obtaining approvals for the steps prespecified in the methodological protocol took 907 days. Enactment following approvals took 385 days. Data supplied from Hospital Episode Statistics contained 181,063 patients from 6 hospitals (mean = 30,177, standard deviation = 28,875.86) who matched the inclusion and exclusion criteria. Data supplied from ResearchOne contained 33,666 (18.6%) of these patients from the 6 hospitals (mean = 5611, standard deviation = 5206.59)., Discussion: Time required for approvals and enactment was attributable to slowness of data handling processes within each data holder and to resolution of technical and organisational queries between them. Variation in number of patients for which data was supplied between databases and between hospitals was attributable to coding inconsistencies and to the limited intersection of patient populations between databases and variation in recording practices between hospitals., Conclusion: Although it is technically feasible to link primary and secondary care data, the current system is challenging, complicated, unnecessarily bureaucratic, time consuming and costly. This limits the number of studies that could be conducted with these rich data sources., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number 13/58/08.

Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority., Objectives: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival., Design: This was a Phase III randomised controlled non-inferiority trial., Setting: The setting was 152 NHS hospitals., Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part., Intervention: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment., Main Outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model., Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p  = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p  = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p  = 0.03 (disease-free-survival) and p  = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p  = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p  < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently., Limitations: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered., Conclusions: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events., Future Work: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned., Trial Registration: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140., 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. 24, No. 40. See the NIHR Journals Library website for further project information., Competing Interests: Helena Earl reports grants from Roche (Basel, Switzerland) and Sanofi-Aventis (Paris, France), personal fees and travel expenses from Daiichi Sankyo (Tokyo, Japan), AstraZeneca plc (Cambridge, UK) and Intas Pharmaceuticals (Ahmedabad, India), travel expenses from Pfizer Inc. (New York, NY, USA) and Amgen Inc. (Thousand Oaks, CA, USA) and personal fees from prIME Oncology (Atlanta, GA, USA), all outside the submitted work. Karen McAdam reports grants from Roche and personal fees from Roche, Novartis International AG (Basel, Switzerland), Pfizer and Eisai Co., Ltd (Tokyo, Japan), all outside the submitted work. Daniel Rea reports personal fees and grants from Roche during the conduct of the study, as well as personal fees from Novartis, Pfizer, Genomic Health (Redwood City, CA, USA) and Daiichi Sankyo, and grants from Celgene Corporation (Summit, NJ, USA), all outside the submitted work. Chris Plummer reports personal fees and non-financial support from Roche Products Limited, Novartis UK Limited, Pfizer UK Limited, Celgene and Incyte Corporation (Wilmington, DE, USA) for attending education meetings. He also reports personal fees and non-financial support from Amgen Limited for attending education meetings and advisory boards, all outside the submitted work. Jean Abraham reports fees to her institution, and accommodation and travel expenses from AstraZeneca for session boards and advisory chairs, as well as fees to her institution, and accommodation and travel expenses from Pfizer for a lecture, all outside the submitted work. Carlos Caldas reports grants from Genentech, Inc. (South San Francisco, CA, USA), Roche, Servier Laboratories (Suresnes, France) and AstraZeneca outside the submitted work, and that he is a member of the AstraZeneca iMED External Science Panel. Peter Hall reports grants from Roche, Pfizer, AstraZeneca, Novartis, Eisai and Daiichi Sankyo outside the submitted work. Christopher McCabe’s institution holds research contracts with Roche and reports grants from Roche, all outside the submitted work. David Miles reports personal fees from Roche/Genetech, outside the submitted work. Claire Hulme reports that she is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Commissioning Board. Andrew M Wardley reports personal fees from Roche, Napp Pharmaceuticals Ltd (Cambridge, UK), Amgen, Merck Sharp & Dohme (Hoddesdon, UK), Novartis, Pfizer, AstraZeneca, Laboratoires Pierre Fabre (Paris, France), Accord (Barnstaple, UK), Athenex (Buffalo, NY, USA), Gerson Lehrman Group (New York, NY, USA), Coleman Research Expert Network Group (New York, NY, USA) and Guidepoint Global (New York, NY, USA). He also reports personal fees and other from Eli Lilly and Company (Indianapolis, IN, USA) and Daiichi Sankyo, all outside the submitted work. He is leading the National Cancer Research Institute Breast Group Initiative to develop the next de-escalation trial for HER2-positive breast cancer. David A Cameron reports funds to his institution from Novartis, Astrazeneca, Pfizer, Roche, Eli Lilly and Company, Puma Biotechnology (Los Angeles, CA, USA), Daiichi Sankyo, Synthon (Nijmegen, the Netherlands), SeaGen International GmbH (Zug, Switzerland), Zymeworks (Vancouver, BC, Canada), Elsevier (Amsterdam, the Netherlands), European Cancer Organisation (Brussels, Belgium), Celgene Corporation, Succinct Medical Communications (Wilmington, DE, USA), Immutep (Sydney, NSW, Australia), Oncolytics Biotech (U.S) Inc. (San Diego, CA, USA), Celldex Therapeutics Inc. (Hampton, NJ, USA), San Antonio Breast Cancer Consortium (TX, USA), Highfield Communication (Oxford, UK), Samsung Bioepis Co. Ltd (Incheon, South Korea), prIME Oncology, Merck Sharp & Dohme Ltd, Prima Biomed Ltd, RTI Health Solutions (Research Triangle, NC, USA) and Eisai, all outside the submitted work. Janet A Dunn reports that she is a member of the NIHR Efficacy and Mechanism Evaluation funding board and an NIHR senior investigator.

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., Competing Interests: Mark T Drayson reports personal fees from Abingdon Health (Abingdon Health, York, UK) outside the submitted work. Stella Bowcock reports personal fees from Amgen (Amgen, CA, USA) and Celgene (Celgene, NJ, USA) outside the submitted work, non-financial support to attend educational meetings and has a patent issued for a device broadly related to the work. Tim Planche reports personal fees from Pfizer (Pfizer, CT, USA), Actellion (Actellion, Allschnil, Switzerland) and Astellas (Astellas Pharma, Tokyo, Japan) outside the submitted work. Kwee Yong reports grants from Janssen (Janssen Pharmaceutica, Beerse, Belgium), Celgene and Chugai (Chugai Pharmaceutical Co Tokyo, Japan) outside the submitted work. David Meads is a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) European Economic and Social Committee (EESC) Methods Group and the NIHR HTA EESC Panel. Claire T Hulme is a member of the NIHR HTA Commissioning Board. Janet A Dunn is a member of the NIHR Efficacy and Mechanism Evaluation board.

Background: Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients., Primary Objective: Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM)., Design: A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element)., Setting: The trial was set in 42 secondary and community inpatient facilities in the UK., Participants: Adult inpatients with evidence of acute illness and at a high risk of PU development., Interventions and Follow-Up: APM or HSFM - the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up., Main Outcome Measures: Time to event., Results: From August 2013 to November 2016, 2029 participants were randomised to receive either APM ( n  = 1016) or HSFM ( n  = 1013). Primary end point - 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p -value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p  = 0.0176 and 2.6% absolute difference). Secondary end points - 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p -value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p  = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed - there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p  = 0.6122 and absolute difference 2.9%). Health economics - the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy - the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was 'very good' (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy - the Pressure Ulcer Quality of Life - Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness., Limitations: A lower than anticipated event rate., Conclusions: In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU., Future Work: Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore 'what works for whom and in what circumstances'., Trial Registration: Current Controlled Trials ISRCTN01151335., 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. 23, No. 52. See the NIHR Journals Library website for further project information., Competing Interests: Christopher McCabe has received grant funding from the University of Alberta and Alberta Innovates Health Solutions (Edmonton, AB, Canada). Julia Brown is Deputy Director of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Evaluation and Trials Board and has received grant funding for the following studies: the NIHR eRAPID Programme Grants for Applied Research (PGfAR) trial, the NIHR Efficacy and Mechanism Evaluation (EME) GLiSten trial, the NIHR HTA LAVA trial (liver resection surgery versus thermal ablation for colorectal liver metastases), the NIHR EME IntAct (Intraoperative flourescence angiography to prevent Anastomotic leak in rectal cancer surgery), NIHR Research for Patient Benefit LACE (Life After Cancer Epidemiology) trial, the NIHR EME ROLARR (RObotic vs. LAparoscopic Resection for Rectal cancer) trial, the NIHR HTA SaFarI (Sacral nerve stimulation versus the FENIX TM magnetic sphincter augmentation for faecal incontinence: a Randomised Investigation and the NIHR StamINA Programme Development Grant trial. Claire Hulme and E Andrea Nelson have been members of the NIHR HTA Commissioning Board and E Andrea Nelson has received funding for the NIHR HTA CODIFI (Concordance in Diabetic Foot Ulcer Infection) study. Elizabeth McGinnis has received funding for NIHR Health Service and Delivery Research (HSDR) Information Systems, Monitoring and Managing from Ward to Board and the NIHR PGfAR SWHSI (Surgical Wounds Healing by Secondary Intention) trial. Isabelle L Smith and Susanne Coleman have received a NIHR personal fellowship. Benjamin Thorpe has received a NIHR research methods fellowship. Delia Muir has received a Wellcome Trust Engagement Fellowship. Rachael Gilberts has received funding for the NIHR HTA ALPHA (ALitretinoin versus PUVA in severe chronic HAnd eczema) and MIDFUT (Multiple Interventions for Diabetic Foot Ulcer Treatment) trials. Nikki Stubbs has received funding for NIHR PGfAR SWHSI and NIHR HTA AMBER (Abdominal Massage for Bowel Dysfunction Effectiveness Research) trial. Jane Nixon has received funding for NIHR HTA MIDFUT, CODIFI and ALPHA. Sarah Brown has received funding for NIHR HTA ALPHA, MIDFUT, FORVAD (Clinical and cost-effectiveness of posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia: a multicentre, Phase III, randomised controlled trial), the NIHR PGfAR PROMPT (early detection to improve outcome in patients with undiagnosed psoriatic arthritis), ARUK (Arthritis Research UK) SALRISE (SALivary electro-stimulation for the treatment of dry mouth in patients with Sjögren’s syndrome: a multicentRe randomISEd sham-controlled double-blind study).

Background: The aim of fistula surgery is to eradicate the disease while preserving anal sphincter function. The efficacy of the Surgisis ® anal fistula plug (Cook Medical, Bloomington, IN, USA) in the treatment of trans-sphincteric fistula-in-ano has been variably reported., Objectives: To undertake a randomised comparison of the safety and efficacy of the Surgisis anal fistula plug in comparison with surgeon's preference for the treatment of trans-sphincteric anal fistulas., Design: A randomised, unblinded, parallel-arm, prospective, multicentre clinical trial., Setting: Hospitals in the UK NHS involving colorectal surgeons accredited by the Association of Coloproctology of Great Britain and Ireland., Participants: Adult patients suffering from trans-sphincteric fistula-in-ano of cryptoglandular origin., Interventions: Patients were randomised on a 1 : 1 basis to either the fistula plug or the surgeon's preference [e.g. fistulotomy, cutting seton, advancement flap or ligation of intersphincteric fistula tract (LIFT) procedure]., Main Outcome Measures: The primary outcome measure was quality of life as measured by the Faecal Incontinence Quality of Life (FIQoL) questionnaire at 12-month follow-up. Secondary outcome measures included clinical and radiological fistula healing rates, faecal incontinence rates, complications rates, reintervention rates and cost-effectiveness., Results: Between May 2011 and March 2016, 304 participants were recruited (152 fistula plug vs. 152 surgeon's preference). No difference in FIQoL score between the two trial groups was seen at the 6-week, 6-month or 12-month follow-up. Clinical evidence of fistula healing was reported in 66 of 122 (54%) participants in the fistula plug group and in 66 of 119 (55%) participants in the surgeon's preference group at 12 months. Magnetic resonance imaging (MRI) showed fistula healing in 54 of 110 (49%) participants in the fistula plug group and in 63 of 112 (56%) participants in the surgeon's preference group. Variation in 12-month clinical healing rates was observed: 55%, 64%, 75%, 53% and 42% for fistula plug, cutting seton, fistulotomy, advancement flap and LIFT procedure, respectively. Faecal incontinence rates were low at baseline, with small improvement in both groups post treatment. Complications and reinterventions were frequent. The mean total costs were £2738 [standard deviation (SD) £1151] in the fistula plug group and £2308 (SD £1228) in the surgeon's preference group. The average total quality-adjusted life-years (QALYs) gain was much smaller in the fistula plug group (0.829, SD 0.174) than in the surgeon's preference group (0.790, SD 0.212). Using multiple imputation and probabilistic sensitivity analysis, and adjusting for differences in baseline EuroQol-5 Dimensions, three-level version utility, there was a 35-45% chance that the fistula plug was as cost-effective as surgeon's preference over a range of thresholds of willingness to pay for a single QALY of £20,000-30,000., Limitations: Limitations include a smaller sample size than originally calculated, a lack of blinding that perhaps biased patient-reported outcomes and a lower compliance rate with MRI at 12-month follow-up., Conclusions: The Surgisis anal fistula plug is associated with similar FIQoL score to surgeon's preference at 12-month follow-up. The higher costs and highly uncertain and small gains in QALYs associated with the fistula plug mean that this technology is unlikely to be considered a cost-effective use of resources in the UK NHS., Future Work: Further in-depth analysis should consider the clinical and MRI characteristics of fistula-in-ano in an attempt to identify predictors of fistula response to treatment., Trial Registration: Current Controlled Trials ISRCTN78352529., 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. 21. See the NIHR Journals Library website for further project information., Competing Interests: David G Jayne was a member of the Health Technology Assessment (HTA) Surgery Themed Call Board from 2012 to 2013 and a member of the Efficacy and Mechanism Evaluation Strategy Group from 2015 to 2018. John Scholefield was a member of the HTA Surgery Themed Call Board from 2012 to 2013. Claire T Hulme was a member of the HTA Commissioning Board from 2012 to 2017.

Background: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population., Objectives: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy., Design: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status., Setting: UK outpatient rheumatology departments., Participants: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi., Interventions: Alternative TNFi, abatacept or rituximab (and continued background MTX)., Main Outcome Measures: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity., Limitations: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early., Results: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n  = 41; abatacept, n  = 41; rituximab, n  = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity., Future Work: The results will add to the randomised evidence base and could be included in future meta-analyses., Conclusions: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative., Trial Registration: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151., 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. 22, No. 34. See the NIHR Journals Library website for further project information., Competing Interests: Maya H Buch reports grants from Pfizer and Chugai Pharmaceutical Co. Ltd (Roche), and personal fees from AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd (Roche), Sandoz and R-Pharm, during the conduct of the study. Claire Hulme reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, during the conduct of the study, and was a member of the NIHR HTA Commissioning Board during the conduct of the study. Paul Emery reports grants and personal fees from Pfizer, Merck Sharp & Dohme Corp., AbbVie, Bristol-Myers Squibb, UCB Pharma Ltd, Roche, Novartis, Samsung, Sandoz, and Eli Lilly and Company, during the conduct of the study. Sue Pavitt is a member of the Efficacy and Mechanism Evaluation Board and NIHR Clinical Trials Unit Board and has been a recipient of NIHR Clinical Trials Unit Support funding. Linda Sharples, Sarah Brown and Claire Davies report grants from NIHR HTA programme during the conduct of the study. Christopher McCabe reports that historically he worked as a paid consultant for a number of pharmaceutical companies. He has also done paid extensive work for the NHS.

Background: Obesity and type 2 diabetes are common in adults with a learning disability. It is not known if the principles of self-management can be applied in this population., Objectives: To develop and evaluate a case-finding method and undertake an observational study of adults with a learning disability and type 2 diabetes, to develop a standardised supported self-management (SSM) intervention and measure of adherence and to undertake a feasibility randomised controlled trial (RCT) of SSM versus treatment as usual (TAU)., Design: Observational study and an individually randomised feasibility RCT., Setting: Three cities in West Yorkshire, UK., Participants: In the observational study: adults aged > 18 years with a mild or moderate learning disability, who have type 2 diabetes that is not being treated with insulin and who are living in the community. Participants had mental capacity to consent to research and to the intervention. In the RCT participants had glycated haemoglobin (HbA 1c ) levels of > 6.5% (48 mmol/mol), a body mass index (BMI) of > 25 kg/m 2 or self-reported physical activity below national guideline levels., Interventions: Standardised SSM. TAU supported by an easy-read booklet., Main Outcome Measures: (1) The number of eligible participants identified and sources of referral; (2) current living and support arrangements; (3) current health state, including level of HbA 1c , BMI and waist circumference, blood pressure and lipids; (4) mood, preferences for change; (5) recruitment and retention in RCT; (6) implementation and adherence to the intervention; (7) completeness of data collection and values for candidate primary outcomes; and (8) qualitative data on participant experience of the research process and intervention., Results: In the observational study we identified 147 eligible consenting participants. The mean age was 54.4 years. In total, 130 out of 147 (88%) named a key supporter, with 113 supporters (77%) being involved in diabetes management. The mean HbA 1c level was 54.5 mmol/mol [standard deviation (SD) 14.8 mmol/mol; 7.1%, SD 1.4%]. The BMI of 65% of participants was > 30 kg/m 2 and of 21% was > 40 kg/m 2 . Many participants reported low mood, dissatisfaction with lifestyle and diabetes management and an interest in change. Non-response rates were high (45/147, 31%) for medical data requested from the primary care team. In the RCT, 82 participants were randomised. The mean baseline HbA 1c level was 56 mmol/mol (SD 16.5 mmol/mol; 7.3%, SD 1.5%) and the mean BMI was 34 kg/m 2 (SD 7.6 kg/m 2 ). All SSM sessions were completed by 35 out of 41 participants. The adherence measure was obtained in 37 out of 41 participants. The follow-up HbA 1c level and BMI was obtained for 75 out of 82 (91%) and 77 out of 82 (94%) participants, respectively. Most participants reported a positive experience of the intervention. A low response rate and difficulty understanding the EuroQol-5 Dimensions were challenges in obtaining data for an economic analysis., Limitations: We recruited from only 60% of eligible general practices, and 90% of participants were on a general practice learning disability register, which meant that we did not recruit many participants from the wider population with milder learning disability., Conclusions: A definitive RCT is feasible and would need to recruit 194 participants per arm. The main barrier is the resource-intensive nature of recruitment. Future research is needed into the effectiveness of obesity treatments in this population, particularly estimating the longer-term outcomes that are important for health benefit. Research is also needed into improving ways of assessing quality of life in adults with a learning disability., Trial Registration: Current Controlled Trials ISRCTN41897033., 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. 22, No. 26. See the NIHR Journals Library website for further project information., Competing Interests: Allan House is a member of the Health Technology Assessment (HTA) Efficient Study Design Board and of a Programme Grants for Applied Research subpanel. Amy Russell was an associate member of the Health Services and Delivery Research Commissioning Board (Commissioned and Researcher-Led). Claire Hulme is a member of the HTA Commissioning Board. Amanda Farrin is a member of the HTA Themed Call panel.

Background: Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial., Objectives: To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting., Design: A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Cox's proportional hazards model., Settings: Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK., Participants: Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited., Intervention: Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage., Results: In total, 564 patients were recruited (ND arm, n  = 282; and surveillance arm, n  = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate ( p  = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon., Limitations: Pragmatic randomised controlled trial with a 36-month median follow-up., Conclusions: PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice., Future Work: PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work., Trial Registration: Current Controlled Trials ISRCTN13735240., 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. 17. See the NIHR Journals Library website for further project information.

Background: Mechanical chest compression devices may help to maintain high-quality cardiopulmonary resuscitation (CPR), but little evidence exists for their effectiveness. We evaluated whether or not the introduction of Lund University Cardiopulmonary Assistance System-2 (LUCAS-2; Jolife AB, Lund, Sweden) mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest (OHCA)., Objective: Evaluation of the LUCAS-2 device as a routine ambulance service treatment for OHCA., Design: Pragmatic, cluster randomised trial including adults with non-traumatic OHCA. Ambulance dispatch staff and those collecting the primary outcome were blind to treatment allocation. Blinding of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. We also conducted a health economic evaluation and a systematic review of all trials of out-of-hospital mechanical chest compression., Setting: Four UK ambulance services (West Midlands, North East England, Wales and South Central), comprising 91 urban and semiurban ambulance stations. Clusters were ambulance service vehicles, which were randomly assigned (approximately 1 : 2) to the LUCAS-2 device or manual CPR., Participants: Patients were included if they were in cardiac arrest in the out-of-hospital environment. Exclusions were patients with cardiac arrest as a result of trauma, with known or clinically apparent pregnancy, or aged < 18 years., Interventions: Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene., Main Outcome Measures: Survival at 30 days following cardiac arrest; survival without significant neurological impairment [Cerebral Performance Category (CPC) score of 1 or 2]., Results: We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 device and 2819 assigned to control) between 15 April 2010 and 10 June 2013. A total of 985 (60%) patients in the LUCAS-2 group received mechanical chest compression and 11 (< 1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30-day survival was similar in the LUCAS-2 (104/1652, 6.3%) and manual CPR groups [193/2819, 6.8%; adjusted odds ratio (OR) 0.86, 95% confidence interval (CI) 0.64 to 1.15]. Survival with a CPC score of 1 or 2 may have been worse in the LUCAS-2 group (adjusted OR 0.72, 95% CI 0.52 to 0.99). No serious adverse events were noted. The systematic review found no evidence of a survival advantage if mechanical chest compression was used. The health economic analysis showed that LUCAS-2 was dominated by manual chest compression., Limitations: There was substantial non-compliance in the LUCAS-2 arm. For 272 out of 1652 patients (16.5%), mechanical chest compression was not used for reasons that would not occur in clinical practice. We addressed this issue by using complier average causal effect analyses. We attempted to measure CPR quality during the resuscitation attempts of trial participants, but were unable to do so., Conclusions: There was no evidence of improvement in 30-day survival with LUCAS-2 compared with manual compressions. Our systematic review of recent randomised trials did not suggest that survival or survival without significant disability may be improved by the use of mechanical chest compression., Future Work: The use of mechanical chest compression for in-hospital cardiac arrest, and in specific circumstances (e.g. transport), has not yet been evaluated., Triai Registration: Current Controlled Trials ISRCTN08233942., 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. 11. See the NIHR Journals Library website for further project information.

Background: Patients with the acute respiratory distress syndrome (ARDS) require artificial ventilation but this treatment may produce secondary lung damage. High-frequency oscillatory ventilation (HFOV) may reduce this damage., Objectives: To determine the clinical benefit and cost-effectiveness of HFOV in patients with ARDS compared with standard mechanical ventilation., Design: A parallel, randomised, unblinded clinical trial., Setting: UK intensive care units., Participants: Mechanically ventilated patients with a partial pressure of oxygen in arterial blood/fractional concentration of inspired oxygen (P : F) ratio of 26.7 kPa (200 mmHg) or less and an expected duration of ventilation of at least 2 days at recruitment., Interventions: Treatment arm HFOV using a Novalung R100(®) ventilator (Metran Co. Ltd, Saitama, Japan) ventilator until the start of weaning. Control arm Conventional mechanical ventilation using the devices available in the participating centres., Main Outcome Measures: The primary clinical outcome was all-cause mortality at 30 days after randomisation. The primary health economic outcome was the cost per quality-adjusted life-year (QALY) gained., Results: One hundred and sixty-six of 398 patients (41.7%) randomised to the HFOV group and 163 of 397 patients (41.1%) randomised to the conventional mechanical ventilation group died within 30 days of randomisation (p = 0.85), for an absolute difference of 0.6% [95% confidence interval (CI) -6.1% to 7.5%]. After adjustment for study centre, sex, Acute Physiology and Chronic Health Evaluation II score, and the initial P : F ratio, the odds ratio for survival in the conventional ventilation group was 1.03 (95% CI 0.75 to 1.40; p = 0.87 logistic regression). Survival analysis showed no difference in the probability of survival up to 12 months after randomisation. The average QALY at 1 year in the HFOV group was 0.302 compared to 0.246. This gives an incremental cost-effectiveness ratio (ICER) for the cost to society per QALY of £88,790 and an ICER for the cost to the NHS per QALY of £ 78,260., Conclusions: The use of HFOV had no effect on 30-day mortality in adult patients undergoing mechanical ventilation for ARDS and no economic advantage. We suggest that further research into avoiding ventilator-induced lung injury should concentrate on ventilatory strategies other than HFOV., Trial Registration: Current Controlled Trials ISRCTN10416500.