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Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon’s decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing. Cite this article: Bone Jt Open 2024;5(6):464–478.

Objective To determine the feasibility of conducting a randomised controlled trial (RCT) to evaluate a prehabilitation programme for frail patients undergoing total hip replacement (THR) or total knee replacement (TKR).Design Randomised feasibility study with embedded qualitative work.Setting Three National Health Service hospitals.Participants Adults aged ≥65 years, frail and scheduled for primary THR or TKR.Intervention Appointment with a physiotherapist to individualise a home-based exercise programme. Participants were encouraged to do the home exercises daily for 12 weeks pre-operative and were provided with a daily protein supplement. Participants were supported by six telephone calls over the 12-week intervention period.Outcome measures Eligibility and recruitment rates, intervention adherence, data completion rates of patient-reported outcome measures, retention rates and acceptability of the trial and intervention. Qualitative interviews were conducted with participants and non-participants and analysed using thematic analysis.Results Between December 2022 and August 2023, 411 patients were sent a screening pack. Of the 168 patients who returned a screening questionnaire, 79 were eligible and consented to participate, and 64 were randomised. Of the 33 participants randomised to the intervention, 26 attended the intervention appointment. Eighteen participants (69%) received all six intervention follow-up telephone calls. Nineteen participants (73%) completed an intervention adherence log; 13 (68%) adhered to the exercise programme and 11 (58%) adhered to the protein supplementation. The overall retention rate was 86% (55/64 overall) at 12 weeks. The 12-week follow-up questionnaire was returned by 46 of the 55 participants (84%) who were sent a questionnaire. Interviews with 19 patients found that the trial processes and intervention were generally acceptable, but areas of potential improvements were identified.Conclusions This study demonstrated that a larger study is possible and has identified improvements to optimise the design of an RCT.Trial registration number ISRCTN11121506.

Background Barth syndrome is a rare, life-threatening X-linked recessive mitochondrial disorder of lipid metabolism primarily affecting males. Previous research suggests that bezafibrate may ameliorate cellular lipid abnormalities and reduce cardiac dysfunction in an animal model. Objectives Estimate the effect of bezafibrate on clinical, biochemical, and quality-of-life outcomes. Investigate whether within-participant clinical changes parallel in vitro changes in cardiolipin ratio/profile and mitochondrial morphology when each participant’s cells are cultured with bezafibrate. Investigate as for objective 2, culturing each participant’s cells with resveratrol. Describe the most feasible methods and standardised outcome measures to optimise the conduct of future trials and evaluations in Barth syndrome. Describe features of the research infrastructure which optimised recruitment, retention and communication with families and people with Barth syndrome. Describe the perceptions of participants and their families about the research and any important potential barriers to participation. Design Randomised, placebo-controlled, crossover trial of bezafibrate versus placebo. Setting NHS hospital providing UK-wide Barth Syndrome Service. Participants Males aged ≥ 6 years with a confirmed diagnosis of Barth syndrome with stable cardiac status, able to swallow tablets of bezafibrate/placebo. Exclusions were: hypersensitivity or allergy to bezafibrate or any component of bezafibrate; hepatic, liver or renal dysfunction; gallbladder disease; or recent deterioration in general health. Interventions Fifteen weeks of bezafibrate in one period and placebo in a second period, or vice versa (randomly allocated), with at least a 1-month washout between periods. Main outcome measures The primary outcome was peak VO2; secondary outcomes were cardiac function rest and exercise echocardiography and magnetic resonance imaging, cardiolipin ratio, quality of life, dynamic skeletal muscle P-magnetic resonance spectroscopy, mitochondrial studies and neutrophil counts, and adverse events. Outcomes were measured at baseline and the end of each period. Results Eleven males were studied; all attended all three assessments. There was no difference in peak VO2 between periods (0.66 ml/kg/min lower with bezafibrate than placebo, 95% confidence interval 2.34 to 1.03; p = 0.43). There was a trend towards a higher left ventricular ejection fraction with bezafibrate when measured by echocardiography but not magnetic resonance imaging, and better echocardiography-derived rest longitudinal and circumferential strain with bezafibrate. There was no difference in quality of life or cardiolipin ratio between periods. Skeletal muscle 31P magnetic resonance spectroscopy was performed cross-sectionally and showed a trend to higher Tau and lower Qmax indices in the bazafibrate group. Two participants had serious, expected adverse reactions when taking bezafibrate; otherwise, bezafibrate was well tolerated. Limitations The sample size was very small; the bezafibrate dose may have been too low or 15 weeks too short to observe an effect; measurements of mitochondrial content and membrane potential were highly variable; P-magnetic resonance spectroscopy was available only at the final assessment. Conclusions This study did not show significant improvement in the primary and secondary outcomes with bezafibrate treatment. Future work Elamipretide, studied in a small crossover trial in the USA, is another potential intervention which may be worth evaluating in an international study. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. Plain language summary Barth syndrome is a rare genetic syndrome with mutations in the tafazzin gene causing long-term effects in several organ systems, leading to significant lifelong comorbidities and a reduced quality of life. Barth syndrome shows an X-linked inheritance, hence it is almost exclusively present in males. Tafazzin gene mutations impair overall cell energy metabolism, and affected individuals show compromise of the immune system with a high risk for life-threatening infections, as well as cardiac dysfunction and cardiomyopathy, muscle and general fatigue, and generally reduced mobility also leading to psychological challenges and dysfunction. Currently, specific medical therapies are limited to symptomatic treatment, and drug therapies targeting the causative mitochondrial energy disturbance are urgently needed. This randomised controlled trial explored the use of oral bezafibrate, a licensed drug that can improve cell energy metabolism. Eleven male patients received either bezafibrate or a placebo for 4 months. Exercise capacity by cardiopulmonary exercise testing on a cycle ergometer, as the primary outcome measurement, as well as cardiac function by echocardiography and magnetic resonance imaging, and cellular anatomy and function by in vitro assays and microscopy, were measured before and after this 4-month period. Bezafibrate did not significantly improve exercise capacity, cardiac function or the cellular metabolism, although several cardiac function parameters showed slight improvements with bezafibrate treatment. No significant adverse effects were recorded. The limitations of the trial were its low participant number and the relatively short duration of the drug treatment phase. The trial did prove that complex randomised controlled drug trials are feasible in people with rare diseases. Adherence was good, with parents reporting few difficulties with pill swallowing. The qualitative interviews also found that the study was acceptable to participants and the burden of participating not too onerous. We hope the research can provide a template for future studies. Scientific summary Introduction Barth syndrome is a very rare, life-threatening, X-linked recessive genetic disease almost exclusively affecting young males, caused by abnormal lipids in mitochondria. The tafazzin gene (TAZ) encodes tafazzin, a phospholipid acyltransferase. Tafazzin transfers unsaturated fatty acids with acyl chains from phospholipids to monolysocardiolipin (MLCL) and regulates remodelling and maturation of cardiolipin, a phospholipid located exclusively in the inner mitochondrial membrane. Mature tetralinoleoyl-cardiolipin (L4-CL) is essential in the mitochondrial membrane for maintaining mitochondrial membrane potential, structural integrity of electron transport chain complexes and mitochondrial cristae architecture. Cardiolipin is a major constituent of inner mitochondrial membranes, and the major effects of the aberrant gene are on muscular tissues. Cardiac and skeletal manifestations of Barth syndrome are thought to result from impaired formation of respiratory chain super-complexes. TAZ mutations decrease L4-CL and increase intermediate species of MLCL, resulting in a marked increase in the MLCL : L4-CL ratio, which provides a highly sensitive and specific biochemical test for Barth syndrome. Barth syndrome is characterised by many gene mutations and profound phenotypic variability between affected patients within families and those in different families. The disease carries many risks and problems for its sufferers, as well as major healthcare costs. Almost one-third (30%) of living UK patients have undergone cardiac transplantation. Several patients who have died due to cardiac rejection or post-transplant lymphoproliferative disease had previously undergone cardiac transplantation. Other patients who have died deteriorated too fast to undergo transplantation or died of complications while awaiting transplantation. Neutropenia is another life-threatening issue. Two-thirds of UK patients are treated with granulocyte colony-stimulating factor by subcutaneous injection. Managing neutropenia in this disease is challenging, since patients have highly variable neutrophil counts, which prevents administration of a consistent daily dose and requires repeated blood counts and physician oversight. Exercise intolerance, lethargy and fatigue are universal, interfering with daily life, schoolwork and play and often necessitating use of a wheelchair. Patients cannot perform strenuous or demanding jobs. Many have major feeding problems from infancy through to adult life; for example, requiring feeding via gastrostomies. There can be rapid deterioration during periods of stable health despite expert medical care. Ventricular arrhythmia (tachycardia or fibrillation) affects 10% of adolescents and can cause sudden cardiac death at any time. There are no specific treatments for Barth syndrome. There is no evidence that standard medications for cardiomyopathy ameliorate long-term poor outcomes. Treatment is multidisciplinary and currently limited to treating intercurrent bacterial infections, bone marrow support, physiotherapy, nutritional support, management of heart failure and arrhythmia, and consideration for heart transplantation. Experiments using lymphoblasts from patients with Barth syndrome show that either bezafibrate or resveratrol can partially normalise the deranged cardiolipin ratio. This may be important, since some patients with Barth syndrome who lack neutropenia and tend to have good exercise tolerance have cardiolipin ratios intermediate between those of typical patients and normal individuals. Bezafibrate also improved left ventricular function and showed other benefits at supraphysiological doses in a TAZ knockdown mouse model. This trial was motivated by the need for disease-specific therapy to prevent morbidity, mortality, psychological distress, and disruption of quality of life (QoL) in affected patients and their families. An effective therapy also has the potential to generate savings for the NHS. Bezafibrate is a lipid-lowering drug used in adults and children, with a good safety record in long-term use. These characteristics made it a candidate for investigation. Bezafibrate has been reported to significantly ameliorate a mitochondrial myopathy in adults and shown promising results in several animal/human cellular models of mitochondrial disease. Several of the laboratory assays and clinical investigations proposed in this study were also considered potentially important beyond the scope of this specific study, to assess associations between genotype and phenotype and for future evaluations of therapies in Barth syndrome. Objectives Estimate the effect on clinical, biochemical and QoL outcome measures of bezafibrate compared to placebo. Investigate whether clinical improvements parallel in vitro changes in cardiolipin ratio and mitochondrial morphology in each participant’s cells when cultured with bezafibrate. Investigate whether clinical improvements and culture findings with bezafibrate parallel in vitro changes in each participant’s cells when exposed to resveratrol in laboratory culture. Describe the most feasible methods and standardised outcome measures for future trials. Describe features of the research infrastructure which optimised recruitment, retention and communication with participants and families. Describe participants’ and their families’ perceptions of research and important potential barriers to participation. Methods Study design and participants CARDIOlipin MANipulation trial (CARDIOMAN) was a double-blind, placebo-controlled crossover randomised trial. Treatment was given in two 15-week periods with a minimum of 1 month’s washout period between these when no treatment was given. Twenty-six males and one female with the disease were alive in the UK when the trial was designed. Males aged ≥ 6 years in the UK diagnosed with Barth syndrome were eligible. Exclusion criteria were: hypersensitivity to bezafibrate or component of the investigational medicinal product (IMP), photoallergic or phototoxic reaction to fibrate, unstable cardiac condition, cardiac chamber shortening fraction < 25% or significant decrease in shortening fraction in the preceding year, atrial or ventricular arrhythmia not stabilised by treatment, inability to swallow the IMP, hepatic dysfunction, renal impairment (creatinine clearance < 90 ml/min), gallbladder disease, recent unspecified significant deterioration in general health, prisoners and adults lacking capacity to provide informed consent. Randomisation and masking Participants were randomised to receive either bezafibrate then placebo, or the reverse order. Allocations were generated in advance by the Bristol Trials Centre and provided to the trial pharmacy which dispensed the IMP. All investigators, members of the research team (apart from pharmacy) and participants remained blind to treatment allocation. Intervention and procedures The intervention IMP was bezafibrate taken orally as 100-mg tablets. Children aged 6–9 years started on 100 mg once daily for the first 4 weeks and, if well tolerated, increased to 100 mg twice daily for the remaining 11 weeks. Children aged 10–17 years started on 200 mg once daily for the first 4 weeks and, if well tolerated, increased to 200 mg twice daily for the remaining 11 weeks. Adults (≥ 18 years) took 200 mg twice daily throughout. The comparator IMP was placebo taken orally as visually identical tablets and manufactured to be as similar as possible in taste and smell to the intervention. The IMP was prescribed at the start of the first period and again at the end of the first period for the second period. Outcomes All in vivo outcomes except magnetic resonance spectroscopy (MRS) were assessed three times: at baseline and in the final week of each treatment phase. The primary outcome measure was peak oxygen consumption on bicycle ergometry [peak volume of oxygen (VO2)]. Secondary outcomes were: MLCL/L4-CL ratio and cardiolipin profile in blood cells; phosphocreatine (PCr)/adenosine 5’ triphosphate (ATP) ratio in cardiac muscle on 31P MRS; skeletal muscle oxidative function/on 31P MRS; QoL [age-appropriate Pediatric Quality of Life Inventory (PedsQLTM) questionnaires]; absolute neutrophil count; amino acid expression (serum arginine and cysteine); cardiac function [left and right ventricular function: left ventricular ejection fraction (LVEF%), right ventricular ejection fraction (RVEF%); and 2-D longitudinal and circumferential strain at rest, peak exercise and after recovery]; mitochondrial size and number in lymphocytes; mitochondrial area in lymphocytes and as a proportion of cytoplasm area; mitochondrial function and cristae organisation in lymphocytes/neutrophils; arrhythmia profile from 12-lead electrocardiogram at rest and during exercise. Qualitative research methods explored participants’ and families’ experiences of the different interventions. Adverse events Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from participants from the time of consent until 1 month after the final period. Participants’ general practitioners were asked to inform the research team of suspected AEs. Participants were asked questions about SAEs/AEs at each research clinic visit and in monthly phone calls, including during the washout period. SAEs were reviewed by the Chief Investigator, who decided whether the SAE was related to bezafibrate. Statistical analysis A total of 20 males aged ≥ 6 years were potentially eligible. The sample size was dictated by the number of eligible boys willing to take part. The primary analysis estimated the difference in mean peak VO2 between placebo and bezafibrate periods (two-tailed 5% significance level). A sample size of 12 participants allowed the trial to detect a difference of 0.90 (within subject) standard deviations with 80% power. The statistical analysis plan (SAP) prespecified that all analyses should be conducted according to the intention-to-treat (ITT) principle. The ITT population comprised all participants and periods, according to the randomised allocations. The safety population comprised all randomised participants, according to the treatment received in each period, who received at least one dose of IMP. All statistical tests were two-sided and used a 5% significance level, except for interactions that used a 10% significance level. Treatment effects were estimated with 95% confidence intervals (CIs). No formal adjustment was made for multiple testing. The treatment effect for the primary outcome was analysed using mixed linear regression models, adjusting for period (fixed effect; exploring interactions where necessary) and participants (random effects). Model assumptions were tested using standard methods, and the carry-over effect was estimated by including treatment order. Treatment effects for continuously scaled secondary outcomes (prespecified in the SAP) were estimated and tested using the same methods. Results There was no statistically significant difference between bezafibrate and placebo in peak VO2, which was 0.66 ml/kg/min lower (95% CI −2.34 to 1.03; p = 0.43) with bezafibrate. There was a borderline statistically significant increase in LVEF% using echocardiography (3.72%, 95% CI −0.26% to 7.69%; p = 0.065) but no evidence of a difference when using magnetic resonance imaging (MRI) (0.15%, 95% CI −3.21% to 3.51%; p = 0.926). There was also no difference for RVEF% between bezafibrate and placebo (0.32, 95% CI −2.32 to 2.96; p = 0.801). Longitudinal and circumferential strain at rest were better (lower) with bezafibrate than with placebo; differences were –1.67 (95% CI −3.11 to −0.22; p = 0.026) and −2.72 (95% CI −5.03 to −0.40; p = 0.024) respectively. There was no difference in diastolic ratio at rest between bezafibrate and placebo, and no differences in strain or diastolic ratio at peak exercise or after 2 minutes’ recovery. All participants had sinus rhythm at rest and during exercise for all three time points. Magnetic resonance spectroscopy was only performed after the second period for 10 participants. PCr/ATP ratio in cardiac muscle was not collected. Cross-sectionally (five vs. five participants), MRS appeared to increase Tau and reduce Qmax parameters with bezafibrate compared to placebo. Monolysocardiolipin/L4-CL ratio did not differ between bezafibrate and placebo but deteriorated in the second period (20% higher, 95% CI 3% to 40%; p = 0.024). Neutrophil count also showed no difference between bezafibrate and placebo but increased in the second period (2.26, 95% CI 0.08 to 4.45; p = 0.043). Plasma cysteine increased with bezafibrate (32% higher, 95% CI 8% to 62%; p = 0.001) but plasma arginine did not (25% higher, 95% CI −10% to 72%; p = 0.180). Mitochondrial outcomes on blood samples did not show marked differences and were not formally compared. Quality-of-life scores were transformed to a 0–100 scale (higher being better). Bezafibrate had no effect on core (−3.41, 95% CI −8.67 to 1.86; p = 0.192) or fatigue (1.71, 95% CI −6.28 to 9.71; p = 0.659) QoL scores. Emerging themes identified in qualitative interviews were classified as overarching, related to lived experience with Barth syndrome, and trial participation and conduct. Participants and families were pleased to take part in the trial, viewing participation as ‘giving back’ to the medical community. No participant withdrew, and the trial was not perceived to be too onerous for families. Participating in the research gave both individuals and families a sense of responsibility for their condition, partly driven by appreciation for the Barth Syndrome Service and staff expertise. Monolysocardiolipin/L4-CL ratio in vitro was estimated from samples of cells incubated with control, bezafibrate or resveratrol. Each drug reduced the MLCL/L4-CL ratio, largely by increasing intermediate cardiolipin species, and more so with resveratrol than with bezafibrate. Ratios were nevertheless profoundly abnormal in comparison to patients with intermediate Barth phenotypes. Discussion Main findings: study results There was no clinically important or statistically significant improvement in peak VO2 with bezafibrate compared to placebo. There were inconsistent findings for LVEF% by method of measurement; echocardiography showed a borderline improvement that cardiac MRI did not demonstrate. Longitudinal and circumferential strain measurements were better at rest with bezafibrate, but not at peak exercise. There were no clinically important or statistically significant improvements in core or fatigue QoL domains. Plasma cysteine was significantly improved with bezafibrate treatment. Plasma arginine also increased but not significantly. Neutrophil count was unaffected and there was no significant change in cardiolipin ratio in participants’ blood with bezafibrate. There were no significant period effects except for MLCL/L4-CL ratio and neutrophil count, both increased in the second period. In vitro incubation of Epstein–Barr virus-transformed patient lymphoblasts with either bezafibrate or resveratrol resulted in improved MLCL/L4-CL ratios, an effect that was more profound with resveratrol. Treatment with this drug also resulted in a more obvious increase in intermediate MLCL species. Strengths and limitations Strengths of the trial are: randomisation and placebo blinding; crossover design; excellent retention; completeness of the data, good adherence and IMP tolerance. There were several limitations. The sample size (outside our control) was very small, and interpretation of effects for many secondary outcomes was challenging. Longer treatment duration or a higher bezafibrate dose might have produced better outcomes. Bezafibrate may have induced adverse reactions in some participants, inadvertently causing unblinding. The group of participants randomised to receive bezafibrate first was older than the group randomised to the opposite order, which may explain period effects. The electron microscopic and mitochondrial assessments proved problematic and were not completed in vitro. Measurements of mitochondrial content and membrane potential were highly variable. Amino acid levels were not assayed after fasting. Echocardiography images during exercise testing were often suboptimal. Lessons for the future Magnetic resonance spectroscopy in children is still exploratory, and protocols need to be better validated, but it is considered very promising as a potential objective functional outcome. Cardiolipin profile is not a good outcome for research, although it is appropriate for diagnosis because the Barth cardiolipin profile is so extremely different from a normal profile. Electron microscopy measurements of mitochondria should not be considered as outcomes in future trials. Peak VO2 should be the preferred current primary outcome because it is resistant to bias compared to other functional outcomes. Conclusion The trial did not show a significant treatment effect for the primary outcome, peak VO2. Some secondary outcomes such as systolic function measured by echocardiography and amino acid levels provided some evidence of benefit. The trial provided insights about trial methods and conduct in the context of a very rare paediatric disease that should inform future studies. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information.

Introduction Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking.Methods and analysis RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period.Ethics and dissemination Ethics approval was obtained from the London—Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries.Trial registration number ISRCTN16473239.

Abstract Background In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September–November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months. Methods ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared. Results Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 [at least] daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial. Conclusion The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods. Trial registration ISRCTN14391248, registered on 30 March 2021

Abstract Background In February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response. Methods ComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites. Results ComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published. Conclusion The rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in ‘non-pandemic’ situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings. Trial registration ISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021.

Abstract Background Approximately, 8% of community-based adults aged ≥ 50 years in England are frail. Frailty has been found to be associated with poorer outcomes after joint replacement. Targeting frailty preoperatively via exercise and protein supplementation has the potential to improve outcomes for people undergoing joint replacement. Prior to proceeding with a randomised controlled trial (RCT), a feasibility study is necessary to address key uncertainties and explore how to optimise trial design and delivery. Methods The Joint PRehabilitation with Exercise and Protein (Joint PREP) study is a feasibility study for a multicentre, two-arm, parallel group, pragmatic, RCT to evaluate the clinical and cost-effectiveness of prehabilitation for frail patients undergoing total hip or knee replacement. Sixty people who are ≥ 65 years of age, frail according to the self-reported Groningen Frailty Indicator, and scheduled to undergo total hip or knee replacement at 2–3 hospitals in England and Wales will be recruited and randomly allocated on a 1:1 ratio to the intervention or usual care group. The usual care group will receive the standard care at their hospital. The intervention group will be given a daily protein supplement and will be asked to follow a home-based, tailored daily exercise programme for 12 weeks before their operation, in addition to usual care. Participants will be supported through six follow-up calls from a physiotherapist during the 12-week intervention period. Study questionnaires will be administered at baseline and 12 weeks after randomisation. Embedded qualitative research with patients will explore their experiences of participating, reasons for nonparticipation, and/or reasons for withdrawal or treatment discontinuation. Primary feasibility outcomes will be eligibility and recruitment rates, adherence to the intervention, and acceptability of the trial and the intervention. Discussion This study will generate important data regarding the feasibility of a RCT to evaluate a prehabilitation intervention for frail patients undergoing total hip and knee replacement. A future phase-3 RCT will determine if preoperative exercise and protein supplementation improve the recovery of frail patients after primary joint replacement. Trial registration ISRCTN11121506, registered 29 September 2022.

Background Randomised controlled trials (‘trials’) are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures Number of host trials funded. Results Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information. Plain language summary Aims of the research A Study Within A Trial is a research study nested inside a larger ‘host trial’, promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. Background The best way to test health and social care treatments is to do a randomised controlled trial (‘trial’), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Methods Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. Results We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found ‘pre-notifying’ before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Conclusions Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future. Scientific summary Background Many delivery aspects of randomised controlled trials (RCTs) have not been subjected to rigorous evaluation. Strategies to enhance recruitment and retention often tend to not be based on evidence. However, there is an increasing interest in embedding RCTs of such strategies. The Medical Research Council (MRC) funded systematic techniques for assisting recruitment to trials (START), which found it feasible to test two strategies for recruitment and retention across a number of trials by performing randomised ‘Studies Within A Trial (SWATs)’. Aims The aim of the PROMoting THE USE of Studies Within A Trial (PROMETHEUS) programme was to build on the START initiative and make embedding SWATs standard practice across Clinical Trials Units (CTUs). We intended to pump prime and facilitate the start of at least 25 SWATs across multiple CTUs within 30 months. The ultimate aim was to make the inclusion of SWATs routine when conducting a trial in a CTU. We share our experience of delivering the PROMETHEUS programme, along with the lessons learnt for undertaking randomised SWATs of recruitment and retention methods. Methods A network of 10 CTUs and one primary care research centre committed to conducting randomised controlled SWATs of recruitment and/or retention interventions was established by the PROMETHEUS team. We identified promising recruitment and retention interventions from a variety of sources including Cochrane systematic reviews, the Northern Ireland Network for Trial Methodology Research SWAT Repository Store, and existing prioritisation exercises. Promising strategies were reviewed by our patient and public (PPI) members to create an initial priority list of seven recruitment and eight retention interventions. The programme allowed host trial teams to apply for funding of up to £5000 and receive support from the PROMETHEUS team to design, implement and report SWATs. We also tested the feasibility of undertaking co-ordinated SWATs, across multiple host trials simultaneously. Results The PROMETHEUS programme funded 42 SWATs, embedded within 31 host trials, across 12 CTUs. The mean cost of a funded SWAT was £3535. Of the 42 SWATs, 12 tested the same SWAT across multiple host trials using a co-ordinated SWAT design and four tested more than one strategy in a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. In the space of just 4 years, PROMETHEUS will add 18% more SWATs to the Cochrane review of global recruitment strategies, and 79% more SWATs to the Cochrane review of global retention strategies. The results from the SWATs reported to date found there was no evidence of a significant difference in recruitment for any of the strategies tested. For retention, pre-notifying participants by card prior to sending questionnaires was effective [risk difference 3.3%, 95% confidence interval (CI) −3.0% to 9.6%]; as was pre-notifying participants by letter or e-mail (risk difference 3.8%, 95% CI −6.1% to 13.6%). Sending personalised text messages was more effective for improving the return of postal questionnaires compared to non-personalised text messages (risk ratio 1.16, 95% CI 1.00 to 1.33); and resulted in fewer completions via telephone compared with a non-personalised text [adjusted odds ratio (OR) 0.44, 95% CI 0.22 to 0.87]. Including a pen with a questionnaire probably increases retention and response rate (pooled OR 1.21, 95% CI 1.09 to 1.35). We highlight key lessons learnt below (see Recommendations section). Conclusions The PROMETHEUS programme significantly increased the international evidence base for both recruitment and retention strategies within RCTs. The funded SWATs evaluated a wide range of recruitment and retention strategies; however, the COVID-19 pandemic negatively impacted five funded SWATs, with two being delayed and three prematurely terminated. Through this project, we identified that when provided with both funding and practical support, host trial teams successfully implemented SWATs. PROMETHEUS led to an overall increase in the evidence base; however, ongoing ‘routine’ application of SWATs across RCTs employing the lessons learnt is required to ensure that efficient trial conduct strategies are identified. Recommendations Recommendations for funders All trial funders should contribute to the effort to improve the efficiency of trials. Funders should encourage the teams that they fund to undertake SWATs. Funding streams specifically designed to support SWATs must be made available to trial teams to continue building the trial process evidence base, for recruitment and retention as well as for other stages of the trial design and delivery process. This includes funding streams for undertaking specific SWATs, as well as infrastructure funding to support CTUs and other centres to undertake co-ordination activities that will support the design, conduct, reporting, and implementation of SWATs and their findings to inform the work of the National Institute for Health and Care Research (NIHR), the MRC, and other funders. PROMETHEUS has demonstrated that co-ordination of activity remains crucial to the delivery of SWATs. A central, national co-ordination point that provides hands-on support needs to continue and funding should be allocated for this. Additionally, CTUs should identify a lead for SWATs, to support SWAT activities and evidence-based trial conduct within the CTU, as well as links with others undertaking SWATs elsewhere to share best practice. The funding for both central and CTU-based support should be ongoing. SWAT priorities need to be identified and communicated clearly to funders, and funders should use these priorities to inform their funding decisions. Funders should develop a mechanism to promote SWAT questions that have been identified as a priority during the funding application process. The mean cost of funding requested for a standalone SWAT within PROMETHEUS was £3535 (range £500–5000). The co-ordinated SWATs cost was £10,668 (training SWAT) and £1306.40 (Christmas cards); however, these did not include costs for central co-ordination, data preparation and sharing by the host trial teams, data cleaning, analysis and write-up. These costs suggest that the £10,000 being offered by the NIHR for trial teams to include a SWAT should be sufficient for most planned SWATs. However, there may be occasions where trial teams may wish to test strategies that may be more expensive. When applying for SWAT funding, trial teams should be asked to indicate whether the question they are addressing is a priority SWAT question, and to provide a clear rationale for selecting that particular question. If teams are unable to undertake a SWAT, funders should ask that recruitment and retention methods are clearly reported to support the evidence base. Recommendations for Sponsors Our experience suggests that there is a need for clear, easily accessible information about the nature of SWATs, as well as the role of the funder in supporting SWATs. Any future changes proposed by the Health Research Authority (HRA) to the approvals process need to be communicated clearly and applied consistently to each SWAT. Recommendations for involving patient and public involvement partners in Studies Within A Trial research PPI should be considered when undertaking a SWAT, in the same way PPI is expected to be undertaken in the main trial. PPI partners should be involved to develop novel and untested recruitment and retention strategies, as well as to adapt existing strategies to the context of their specific host trial and the population being enrolled. Recommendations for oversight committees Our experience suggests that Trial Management Groups (TMGs) play a key role in decisions about whether a SWAT is undertaken and continued in the host trial or not. TMG members should encourage the uptake of SWATs in their trials. While the findings of SWATs may not always directly inform their host trial, the findings of SWATs undertaken during the early, or internal pilot, phase of the trial may inform the decisions about which strategies should be used at a later stage, such as in the main trial. Trial Steering Committees should review the SWAT activity and progress, in the same way that they review substudies in a trial. Data Monitoring Committee review is dependent on the specific host trial and SWAT strategy being evaluated. Recommendations for journals and reviewers Journal peer reviewer profiles should be updated to include methodological interests and expertise, to support evidence of suitability to undertake a peer review for a SWAT. When selecting peer reviewers, the SWAT and methodology interests as registered by reviewers should be used where possible. SWATs are a niche area and so to increase the pool of reviewers, journals should consider being more flexible when assessing reviewer credentials to review a SWAT, such as allowing relevant experience in place of a PhD. Reviewers should be advised that in many instances informed consent from participants need not be obtained when undertaking a SWAT, due to the low risk associated with the intervention and in the case of retention SWATs due to existing consent for further research being in place. This may depend on the jurisdiction. In the UK, this approach is supported by HRA guidance in relation to grading for SWAT interventions and approvals. Robust and transparent reporting is necessary, that is compliant with CONsolidated Standards Of Reporting Trials (CONSORT). Recommendations for trial teams and methodologists undertaking SWAT research There remains a need for continually updated research priorities to allow researchers to address the questions relevant at that time. When SWAT priorities are set, methodologists need to provide enough information to enable teams to make informed decisions about evaluating the priorities set. Further work is needed to help teams identify suitable SWAT strategies for their host trials. SWAT priorities need to be communicated clearly and consistently to trial teams. Recommendation for trial conduct and using SWAT evidence As the evidence base develops for effective and cost-effective recruitment and retention strategies, it will become increasingly important for trial teams to use this evidence base to inform their recruitment and retention activities. Trial teams need to actively engage with the evidence base to inform their practice. Funders will need to actively support the trials they fund to use evidence-informed recruitment and retention strategies. Recommendations for future research There remains a substantial need for more high-quality SWAT evidence and so Chief Investigators should be encouraged to consider the embedding of a SWAT at the funding stage. Further work is therefore needed to increase the awareness of the methodological importance of SWAT research with research teams, and to develop engagement strategies to increase SWAT activity. Future research needs to focus on identifying whether further replications are needed for existing evidence. If so, the gaps in the evidence base should be targeted. More co-ordination and replication of SWAT evaluations are encouraged. A ‘real-time’ and dynamic communication strategy including a clear cost and resource breakdown for each suggested SWAT should be developed. This will alleviate the burden on trials teams to begin costing exercises and enable them to make an informed decision more quickly as to whether they can embed a given SWAT. There is a need to aid teams to identify and select a suitable SWAT for their host trial populations. Pragmatic decisions on which SWAT may be appropriate and feasible to include should be taken as required. A mechanism to communicate SWAT research priorities is needed, and this information needs to be readily accessible for all trialists to refer to. Our findings demonstrate that within an individual host trial, there is often a capacity to address more than one SWAT question, either separately, or simultaneously using a factorial design. This suggests that there is a capacity to significantly speed up and strengthen the evidence base through teams undertaking more than one SWAT in their trials where relevant. For certain strategies, co-ordinated SWATs should be encouraged. This method could be used to rapidly replicate SWAT evaluations to plug the evidence gap, as well as to evaluate more complex recruitment and retention strategies that may be more challenging to undertake using individual SWATs. Materials should be developed to advise teams on how to undertake co-ordinated SWATs, as well as a method of networking to enable teams to promote their co-ordinated SWAT and collaborate. As the evidence base develops, it will become increasingly important for trialists to utilise the evidence base in a systematic way to identify both effective and ineffective strategies to inform their practice. Future work should therefore consider issues around the dissemination and implementation of SWATs and develop guidance to enable the wider trials community to undertake, report and adopt the findings of SWATs. Implementation science, the study of methods to promote the uptake of evidence-based practice, could be used to inform any such future work. Funders can also help by questioning strategies proposed by trial teams that are known to be either ineffective or not cost-effective. Improving the knowledge of the potential ‘harms’ from implementing interventions that have no evidence of benefit is an important next step to help improve uptake. While establishing the effectiveness of recruitment or retention strategies is important, the high costs of research waste and limited public finance mean that cost considerations around SWATs are just as important. With only one retention strategy having high Grading of Recommendations, Assessment, Development and Evaluations (GRADE) certainty of cost effectiveness, we encourage trial teams to undertake streamlined economic evaluations alongside all their SWATs in the future, for strategies shown to be effective, as well as those that are ineffective. For cost effectiveness, trial teams should look to report the cost per additional participant recruited or retained (i.e. the incremental cost-effectiveness ratio). Value of information analyses can help determine the need for further SWAT evidence where several SWATs already exist. Many trial teams wish to contribute to developing the evidence base by undertaking non-randomised SWATs. Future work that informs the development of guidance for undertaking non-randomised SWATs would be helpful. Working with trial teams to develop engagement strategies and training to undertake SWATs would be beneficial. Audience specific guidance should be developed to support SWAT research. Trial teams have expressed they want to undertake SWATs that are important and necessary to increase the evidence base. Collaboration with funders, working groups involved in priority setting, and trial teams is needed to develop a mechanism to communicate this dynamic and evolving information once priority SWATs have been identified. Work is needed to identify the barriers that teams have when undertaking a SWAT, and strategies and solutions for addressing these barriers should be identified and implemented. Continued and proactive collaboration is needed with working groups to enable networking, and collaboration with teams undertaking SWAT research. Reporting guidance is needed to support teams when writing publications to ensure sufficient information is included to GRADE evaluation can be undertaken. Study registration All SWATs in the PROMETHEUS programme had to be registered with the Northern Ireland Network for Trials Methodology Research SWAT Repository. Funding details This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

Introduction Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care.Methods and analysis The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted.Ethics and dissemination The trial received Research Ethics Committee (REC) approval from South Central – Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available.Trial registration ISRCTN31474800. Registered 14 April 2020.

Objectives To assess the effectiveness of injectable tissue pulmonary valve compared with standard pulmonary valve in patients requiring pulmonary valve replacement surgery.Design A multicentre, single-blind, parallel two-group randomised controlled trial. Participants were blind to their allocation. Follow-up continued for 6 months. Randomised allocations were generated by a computer using block randomisation, stratified by centre.Setting Two National Health Service secondary care centres in the UK.Participants People aged 12–80 years requiring pulmonary valve replacement.Interventions Participants were randomly allocated (1:1 ratio) to injectable pulmonary valve replacement (IPVR) without cardiopulmonary bypass (CPB) or standard pulmonary valve replacement (SPVR) with CPB.Primary and secondary outcome measures The primary outcome was chest drainage volume over the first 24 hours after surgery. Secondary outcomes included in-hospital clinical outcomes; valve and heart function 6 months postsurgery and health-related quality of life 6 weeks and 6 months postsurgery.Results Nineteen participants agreed to take part. Eleven were allocated to IPVR and eight to SPVR. The trial was stopped before the target sample size of 60 participants was reached due to challenges in recruitment. The primary analysis includes all randomised participants; there were no withdrawals. Chest drain volume 24 hours after surgery was on average 277.6 mL lower with IPVR (IPVR mean 340.0 mL; SPVR mean 633.8 mL; mean difference, −277.6; 95% CI, −484.0 to −71.2; p=0.005). There were no statistically significant differences in time to readiness for extubation (p=0.476), time to fitness for discharge (p=0.577) and time to first discharge from the intensive care unit (p=0.209). Six participants with IPVR required CPB. Safety profiles and quality of life scores were similar.Conclusions IPVR reduced chest drain volume despite >50% of participants requiring CPB. There was no evidence of any other benefit of IPVR.Trial registration number ISRCTN23538073.

Abstract Objective To narratively describe the challenges and solutions required in delivering a non-commercial study of children undergoing cardiac surgery using a novel subcutaneous hormone collection device. Results The challenges faced by the research team are divided into those of conducting healthcare research in children and those specific to this study. Many of the issues of conducting healthcare research in children can and have been overcome by structural and institutional culture change–normalising and embedding research as part of good clinical care. The issues specific to insertion and maintenance of the novel collection device can be overcome by education and support of the clinical teams. The increased incentives and resources of commercial research may have overcome many of these.

Introduction Brain injury is common following open heart valve surgery. Carbon dioxide insufflation (CDI) has been proposed to reduce the incidence of brain injury by reducing the number of air microemboli entering the bloodstream in surgery. The CO2 Study will evaluate the efficacy and safety of CDI in patients undergoing planned left-sided open heart valve surgery.Methods and analysis The CO2 Study is a multicentre, blinded, placebo-controlled, randomised controlled trial. Seven-hundred and four patients aged 50 years and over undergoing planned left-sided heart valve surgery will be recruited to the study, from at least eight UK National Health Service hospitals, and randomised in a 1:1 ratio to receive CDI or medical air insufflation (placebo) in addition to standard de-airing. Insufflation will be delivered at a flow rate of 5 L/min from before the initiation of cardiopulmonary bypass until 10 min after cardiopulmonary bypass weaning. Participants will be followed up until 3 months post-surgery. The primary outcome is acute ischaemic brain injury within 10 days post-surgery based on new brain lesions identified with diffusion-weighted MRI or clinical evidence of permanent brain injury according to the current definition of stroke.Ethics and dissemination The study was approved by the East Midlands–Nottingham 2 Research Ethics Committee in June 2020 and the Medicines and Healthcare products Regulatory Agency in May 2020. All participants will provide written informed consent prior to undertaking any study assessments. Consent will be obtained by the principal investigator or a delegated member of the research team who has been trained in the study and undergone Good Clinical Practice training. Results will be disseminated through peer-reviewed publications and presentations at national and international meetings. Study participants will be informed of results through study notifications and patient organisations.Trial registration number ISRCTN30671536.

Introduction More than 30 000 cardiac surgery procedures are performed in the UK each year, however, postoperative complications and long-term failure of interventions are common, leading to repeated surgeries. This represents a significant burden on the patient and health service.Routinely, patients are discharged to their general practitioner 6 weeks postoperatively and research studies typically only report short-term outcomes up to 1 year after surgery, together this makes long-term outcomes of cardiac surgery difficult to monitor. Further, traditional research methods have yet to advance understanding of what causes early complications and why surgical interventions fail.Methods and analysis This prospective cohort study will characterise participants undergoing cardiac surgery at baseline, describe short-term, medium-term and long-term health outcomes postoperatively and collect tissue samples.All eligible adult patients undergoing cardiac surgery at the Bristol Heart Institute, UK will be approached for consent. Recruitment is expected to continue for up to 10 years resulting in the largest cohort of cardiac patients reported to date. Blood, urine and waste tissue samples will be collected during admission. Samples, along with anonymised data, will be used to investigate outcomes and inform predictive models of complications associated with cardiac surgery.Data about the surgical admission will be obtained from hospital databases and medical notes. Participants may be monitored up to 5 years postoperatively using data obtained from NHS digital. Participants will complete health questionnaires 3 months and 12 months postoperatively.The analysis of data and tissue samples to address specific research questions will require separate research protocols and ethical approval.Ethics and dissemination This study was approved by the East Midlands Nottingham 2 Research Ethics Committee.Findings will be disseminated through peer-reviewed publications and presentation at national and international meetings. Participants will be informed of results in annual newsletters.Trial registration number ISRCTN90204321.

BackgroundMyocardial infarction induces elevation of progenitor cells in the circulation, a reparative response inhibited by type-2 diabetes.ObjectivesDetermine if myocardial infarct severity and diabetes interactively influence the migratory activity of CD34+/CXCR4+ progenitor cells and if the migratory test predicts cardiac outcomes.Materials and methodsA longitudinal study was conducted on patients with or without diabetes with a STEMI or NSTEMI. CD34+/CXCR4+ cells were measured in the peripheral blood using flow cytometry, and migratory activity was tested in vitro on cells isolated from samples collected on days 0 and 4 post-infarct. Cardiac function was assessed at three months using cardiac MRI.ResultsOf 1,149 patients screened, 71 (6.3%) were eligible and consented. Fifty had STEMI (16 with diabetes) and 21 NSTEMI (8 with diabetes). The proportion of CD34+/CXCR4+ cells within blood mononuclear cells was 1.96 times higher after STEMI compared with NSTEMI (GMR = 1.96, 95% CI 0.87, 4.37) and 1.55 times higher in patients with diabetes compared to patients without diabetes (GMR = 1.55, 95% CI 0.77, 3.13). In the latter, STEMI was associated with a 2.42-times higher proportion of migrated CD34 + /CXCR4 + cells compared with NSTEMI (GMR = 2.42, 95% CI 0.66, 8.81). In patients with diabetes, the association was the opposite, with a 55% reduction in the proportion of migrated CD34+/CXCR4+ cells. No statistically significant associations were observed between the frequency in peripheral blood or in vitro migration capacity of CD34+/CXCR4+ cells and MRI outcomes.ConclusionWe document the interaction between infarct and diabetes on the migratory activity of CD34+/CXCR4+ cells. The test did not predict functional outcomes in the studied cohort.

Abstract Background There has been little research to investigate whether the appearance of paper patient information leaflets (PILs) used to describe research studies to potential participants influences their decision to take part. Embedding a study within a trial (SWAT) is an efficient way of answering this type of methodological question. We included a randomised SWAT within a large cohort study, Outcome Monitoring after Cardiac Surgery (OMACS), to address this question. Methods Potential participants for the OMACS study were randomised to receive one of three PILs, which were identical in content but with varying formatting and use of colour: PIL A (enhanced format), PIL B (hybrid format) and PIL C (standard format). Consent to OMACS was the primary outcome. Consent rates using the three different PIL formats were collected and compared. Qualitative feedback on the different formats was obtained from a public and patient involvement (PPI) group. Results For the SWAT, 1517 PILs were sent to potential participants, of whom 640 (42%) consented to take part in OMACS. PIL B had the highest recruitment rate, with 45% of patients consenting to participation; 40% and 41% of patients consented to participation after receiving PILs A and C, respectively. Compared to PIL C, the consent rate was 4% higher with PIL B (45% versus 41%, 95% confidence interval (CI) -2% to + 10%, p = 0.16) and 1% lower with PIL A (40% versus 41%, 95% CI − 7% to + 5%, p = 0.72). Conclusions Consent rates were similar for all three PIL formats. PIL B is being used for the remainder of the host study and will be used to inform the design of PILs for other research studies, as it was the preferred format of the PPI group. Trial registration International Clinical Trials Registry, ISRCTN90204321. Registered on 21 January 2015.

Introduction Surgery to remove the gallbladder (laparoscopic cholecystectomy (LC)) is the standard treatment for symptomatic gallbladder disease. One potential complication of gallbladder disease is that gallstones can pass into the common bile duct (CBD) where they may remain dormant, pass spontaneously into the bowel or cause problems such as obstructive jaundice or pancreatitis. Patients requiring LC are assessed preoperatively for their risk of CBD stones using liver function tests and imaging. If the risk is high, guidelines recommend further investigation and treatment. Further investigation of patients at low or moderate risk of CBD stones is not standardised, and the practice of imaging the CBD using magnetic resonance cholangiopancreatography (MRCP) in these patients varies across the UK. The consequences of these decisions may lead to overtreatment or undertreatment of patients.Methods and analysis We are conducting a UK multicentre, pragmatic, open, randomised controlled trial with internal pilot phase to compare the effectiveness and cost-effectiveness of preoperative imaging with MRCP versus expectant management (ie, no preoperative imaging) in adult patients with symptomatic gallbladder disease undergoing urgent or elective LC who are at low or moderate risk of CBD stones. We aim to recruit 13 680 patients over 48 months. The primary outcome is any hospital admission within 18 months of randomisation for a complication of gallstones. This includes complications of endoscopic retrograde cholangiopancreatography for the treatment of gallstones and complications of LC. This will be determined using routine data sources, for example, National Health Service Digital Hospital Episode Statistics for participants in England. Secondary outcomes include cost-effectiveness and patient-reported quality of life, with participants followed up for a median of 18 months.Ethics and dissemination This study received approval from Yorkshire & The Humber – South Yorkshire Research Ethics Committee. Results will be submitted for publication in a peer-reviewed journal.Trial registration number ISRCTN10378861.

Background: In chronic central serous chorioretinopathy, fluid accumulates in the subretinal space and causes permanent vision loss in ≈ 30% of patients. There is no definitive treatment. Previous research suggests that the mineralocorticoid receptor antagonist eplerenone is effective but it is not licensed for chronic central serous chorioretinopathy. Objectives: The objective was to evaluate whether or not eplerenone was safe and superior to placebo for treating chronic central serous chorioretinopathy. We also aimed to set up a biobank of DNA, serum and plasma samples from treatment-naive participants for future research. Design: The trial was a parallel, randomised (1 : 1 ratio), multicentre, double-masked, placebo-controlled superiority trial comparing eplerenone plus usual care with placebo plus usual care. Participants were randomly allocated to eplerenone or placebo using a secure online system that returned a unique number corresponding to a bottle of the investigational medicinal product. Participants, clinical care teams, pharmacists, outcome assessors and the trial management group were masked. Setting: The trial took place in 22 NHS hospitals in the UK. Participants: Eligible participants were patients aged 18–60 years with treatment-naive chronic central serous chorioretinopathy of at least 4 months’ duration, a best corrected visual acuity score of 54–85 letters and no other conditions affecting visual acuity or contraindications to taking eplerenone or placebo. Interventions: The intervention was oral eplerenone (25 mg/day for 1 week, increased to 50 mg/day for up to 12 months). Placebo was a lactose-filled capsule that appeared identical to the overencapsulated eplerenone tablets. To maintain blinding, participants in the placebo group followed the same dose escalation schedule as the eplerenone group. Usual care was included in both groups and was administered at the discretion of clinicians. Main outcome measures: The primary outcome was best corrected visual acuity score at 12 months. Secondary outcomes were low-luminance visual acuity, central subfield retinal thickness, change in subretinal fluid thickness, systemic and ocular adverse events, macular atrophy of the retinal pigment epithelium, subfoveal choroidal thickness, choroidal permeability, resolution of subretinal fluid, time to recurrence of subretinal fluid, fundus fluorescein angiography phenotype, incidence of chronic central serous chorioretinopathy in the fellow eye, and patient-reported visual function. Results: Between 11 January 2017 and 22 February 2018, 57 participants were randomised to eplerenone and 57 to placebo; 57 and 54 participants, respectively, were included in the analysis of the primary outcome. The modelled mean best corrected visual acuity score at 12 months in the eplerenone and placebo groups was 80.4 letters (standard deviation 4.6 letters) and 79.5 letters (standard deviation 4.5 letters), with an estimated difference between groups of 1.73 letters (95% confidence interval –1.12 to 4.57 letters; p = 0.24). Hyperkalaemia occurred in eight participants in each group (14%). No serious adverse events occurred in the eplerenone group; three unrelated serious adverse events occurred in the placebo group. Limitations: Limitations included the inability to prevent co-treatments and discontinuation of the investigational medicinal product in the event of resolution or hyperkalaemia. Conclusions: Eplerenone was safe but not superior to placebo in improving best corrected visual acuity in people with chronic central serous chorioretinopathy during 12 months of follow-up. In future work, ophthalmologists should investigate alternative treatments for this condition, which remains complicated to treat. Trial registration: Current Controlled Trials ISRCTN92746680. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 2. See the NIHR Journals Library website for further project information.

Abstract Background Site performance is key to the success of large multicentre randomised trials. A standardised set of clear and accessible summaries of site performance could facilitate the timely identification and resolution of potential problems, minimising their impact. The aim of this study was to identify and agree a core set of key performance metrics for managing multicentre randomised trials. Methods We used a mixed methods approach to identify potential metrics and to achieve consensus about the final set, adapting methods that are recommended by the COMET Initiative for developing core outcome sets in health care. We used performance metrics identified from our systematic search and focus groups to create an online Delphi survey. We invited respondents to score each metric for inclusion in the final core set, over three survey rounds. Metrics scored as critical by ≥70% and unimportant by 50% of participants voting for inclusion were retained. Results Round 1 of the Delphi survey presented 28 performance metrics, and a further six were added in round 2. Of 294 UK-based stakeholders who registered for the Delphi survey, 211 completed all three rounds. At the consensus meeting, 17 metrics were discussed and voted on: 15 metrics were retained following survey round 3, plus two others that were preferred by consensus meeting participants. Consensus was reached on a final core set of eight performance metrics in three domains: (1) recruitment and retention, (2) data quality and (3) protocol compliance. A simple tool for visual reporting of the metrics is available from the Nottingham Clinical Trials Unit website. Conclusions We have established a core set of metrics for measuring the performance of sites in multicentre randomised trials. These metrics could improve trial conduct by enabling researchers to identify and address problems before trials are adversely affected. Future work could evaluate the effectiveness of using the metrics and reporting tool.

Abstract Background Dual antiplatelet therapy (DAPT) with aspirin (ASP) and a P2Y12 blocker is currently standard care after percutaneous coronary intervention (PCI) with stent insertion, and aims to inhibit platelet function in order to prevent stent thrombosis. The P2Y12 blocker ticagrelor (TIC) has greater antiplatelet effect than the previously used members of this class, such as clopidogrel. In healthy volunteers, TIC is sufficient to cause strong platelet inhibition, with little additional effect from ASP. Omission of ASP may improve the safety of antiplatelet regimes by reducing bleeding. However, the effect of single antiplatelet treatment with TIC, compared to DAPT with TIC + ASP, has not been studied in detail in patients with coronary artery disease. Methods To compare TIC with TIC + ASP, we have initiated a single centre, open-label randomised controlled trial (TEMPLATE study) in adults receiving DAPT following PCI with a sample size of 110 patients. Patients are invited to join the study when, as part of standard care, they are due to switch from DAPT (ASP + any P2Y12 blocker) to single antiplatelet treatment with ASP alone after 6–12 months. Patients are randomised to receive either TIC or TIC + ASP for 4 weeks. All patients then revert to standard care with ASP alone. Blood samples and clinical data are collected at three study visits: at baseline during treatment with ASP + any P2Y12 blocker (visit 1); approximately 4 weeks after visit 1 during treatment with either TIC or TIC + ASP (visit 2); and approximately 8 weeks after visit 1 when treatment has reverted to ASP alone (visit 3). The primary outcome is the extent of platelet inhibition, measured by light transmission aggregation, flow cytometry, flow chamber and plasma biomarker tests. The primary analysis will compare the extent of platelet inhibition between the TIC and TIC + ASP groups at visit 2, adjusted for baseline platelet reactivity. Secondary analyses will compare the extent of platelet inhibition at visit 2 with that at visit 3. Discussion This is the first study to compare in detail the extent of platelet inhibition in patients who are receiving TIC compared with TIC + ASP. The study findings will complement larger-scale trials of the clinical efficacy and safety of TIC compared to TIC + ASP. Trial registration ISRCTN registry, identifier ISRCTN84335288 . Registered on 23 June 2014.

BackgroundTransplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model. Methods and ResultsWe performed a blind, randomized, placebo‐controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone. ConclusionsImmunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.

Background: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the ‘parent’ molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5–10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. Objective: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. Design: Multicentre, factorial randomised controlled trial with within-trial cost–utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. Setting: Twenty-three ophthalmology departments in NHS hospitals. Participants: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. Interventions: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. Main outcome measures: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. Results: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [–1.37 letters, 95% confidence interval (CI) –3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (–1.63 letters, 95% CI –4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. Conclusions: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. Trial registration: Current Controlled Trials ISRCTN92166560. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.