Delivering clinical studies of exercise in the COVID-19 pandemic: challenges and adaptations using a feasibility trial of isometric exercise to treat hypertension as an exemplar.

The COVID-19 pandemic has significantly impacted on the delivery of clinical trials in the UK, posing complicated organisational challenges and requiring adaptations, especially to exercise intervention studies based in the community. We aim to identify the challenges of public involvement, recruitment, consent, follow-up, intervention and the healthcare professional delivery aspects of a feasibility study of exercise in hypertensive primary care patients during the COVID-19 pandemic. While these challenges elicited many reactive changes which were specific to, and only relevant in the context of 'lockdown' requirements, some of the protocol developments that came about during this unprecedented period have great potential to inform more permanent practices for carrying out this type of research. To this end, we detail the necessary adaptations to many elements of the feasibility study and critically reflect on our approach to redesigning and amending this ongoing project in order to maintain its viability to date. Some of the more major protocol adaptations, such as moving the study to remote means wherever possible, had further unforeseen and undesirable outcomes (eg, additional appointments) with regards to extra resources required to deliver the study. However, other changes improved the efficiency of the study, such as the remote informed consent and the direct advertising with prescreening survey. The adaptations to the study have clear links to the UK Plan for the future of research delivery. It is intended that this specific documentation and critical evaluation will help those planning or delivering similar studies to do so in a more resource efficient and effective way. In conclusion, it is essential to reflect and respond with protocol changes in the current climate in order to deliver clinical research successfully, as in the case of this particular study. [Abstract copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Management of blood pressure in adults, children and young people on dialysis: UK kidney association clinical practice guideline

People with end stage kidney disease receiving dialysis have a very risk of cardiovascular disease and mortality. Hypertension is a modifiable risk factor for cardiovascular disease and mortality, affecting around 90% of dialysis patients. Conversely, intradialytic hypotension in haemodialysis patients is associated with debilitating symptoms as well as the risk of cardiovascular disease and mortality. Blood pressure management in dialysis patients involves accurate measurement of blood pressure, setting a target blood pressure, adequate fluid volume management, lifestyle changes, modification of dialysis and dialysate, and the use of medication with proven efficacy in these patients. However, globally there is no published contemporary clinical practice guideline to assist health care professionals to manage blood pressure in dialysis patients. This is mainly because of a dearth of good quality evidence to inform guideline recommendations. Here, we present a comprehensive guideline to manage blood pressure in dialysis patients based on a thorough systematic review of literature. The guideline development committee comprised a multidisciplinary group of nephrology healthcare professionals and a patient. The evidence underpinning the guidance is often of moderate to low quality, influencing the strength of the recommendations. Therefore, the committee have come up with a list of research recommendations with a view to informing future guidelines. It is envisaged that this guideline will improve the care and outcomes of dialysis patients in the UK and elsewhere

Acute Renal Failure in Association with Community-Acquired Clostridium difficile Infection and McKittrick-Wheelock Syndrome

We report the case of a 65-year-old Caucasian woman who experienced two separate episodes of acute renal failure within an 18-month period, both requiring emergency admission and complicated treatment. Each episode was precipitated by hypovolaemia from intestinal fluid losses, but from two rare and independent pathologies. Her first admission was attributed to community-acquired Clostridium difficile-associated diarrhoea (CDAD) and was treated in the intensive therapy unit. She returned 18 months later with volume depletion and electrolyte disturbances, but on this occasion a giant hypersecretory villous adenoma of the rectum (McKittrick-Wheelock syndrome) was diagnosed following initial abnormal findings on digital rectal examination by a junior physician. Unlike hospital-acquired C. difficile, community-acquired infection is not common, although increasing numbers are being reported. Whilst community-acquired CDAD can be severe, it rarely causes acute renal failure. This case report highlights the pathological mechanisms whereby C. difficile toxin and hypersecretory villous adenoma of the rectum can predispose to acute renal failure, as well as the values of thorough clinical examination in the emergency room, and early communication with intensivist colleagues in dire situations

Call to action: British and Irish hypertension society position statement on blood pressure treatment thresholds and targets.

In this position statement the British and Irish Hypertension Society (BIHS) present a review of the current evidence for blood pressure (BP) treatment thresholds and targets. The BIHS recommend initiating pharmacological antihypertensive therapy, irrespective of cardiovascular disease risk, following a confirmed diagnosis of hypertension (sustained out-of-office BP ≥ 135/85 mmHg despite diet and lifestyle advice). The BIHS recommend an on-treatment BP target < 130/80 mmHg or as low as reasonably achievable without causing unacceptable side-effects, within 6-months of initiating treatment, for all adults. Possible subgroups to whom this may not apply are those who are frail and/or have limited life expectancy where higher targets may be appropriate based on clinical judgement and the individuals' tolerance to treatment. The BIHS believe that this simple 2-step approach will facilitate practitioners deliver evidence-based best practice, discourage therapeutic inertia around BP lowering and improve heath outcomes for all adults living with high BP

Randomised controlled effectiveness study (RCT) of isometric exercise (IE) in adults with stage 1 and 2 hypertension – ISOFITTER study [version 1; peer review: 1 approved]

Background High blood pressure (BP) affects more than one in four adults in England and only one in three patients are being treated effectively. Treatment of high BP includes changes to lifestyle such as more physical activity and/or taking medication. However, low adoption and high attrition rates are common with current large targets for recommended exercise (>150 minutes moderate exercise per week plus 2 strength sessions). Evidence suggests that isometric exercise (IE), holding a fixed body position for a period of time, for example a wall squat, lowers BP a greater amount, with less time and effort, than other recommended exercise. This ISOFITTER study will provide robust effectiveness evidence of IE for hypertension. Methods A multi-centre, randomised, controlled trial of isometric exercise wall squat intervention for hypertension: an effectiveness-implementation hybrid type-1 design. Adults (n=542) with Stage 1 or Stage 2 hypertension, on no more than one antihypertensive, and no other medical contra-indications will be randomised to either a standard care plus IE intervention group or standard care control group. Blood pressure readings, fidelity measurements, medications, adverse events, quality of life, participant satisfaction and health service use will be collected at baseline, week 4, month 3 and month 6 with a subgroup of n=50 invited up to month 12. Qualitative participant focus groups and interviews with wider stakeholders will collect implementation data. Results The ISOFITTER study will establish effectiveness of a self-administered, home IE intervention in lowering blood pressure in people with uncomplicated stage 1 and 2 hypertension. Implementation evidence will support patient delivery, context for scaling up of the intervention and intervention cost. Conclusion Lifestyle changes for the treatment of hypertension in the absence of other risk factors should not be overlooked. For long term hypertension management, easily adopted, evidenced exercise interventions are needed. This study will help to address this evidence gap

Delivering clinical studies of exercise in the COVID-19 pandemic: challenges and adaptations using a feasibility trial of isometric exercise to treat hypertension as an exemplar

The COVID-19 pandemic has significantly impacted on the delivery of clinical trials in the UK, posing complicated organisational challenges and requiring adaptations, especially to exercise intervention studies based in the community. We aim to identify the challenges of public involvement, recruitment, consent, follow-up, intervention and the healthcare professional delivery aspects of a feasibility study of exercise in hypertensive primary care patients during the COVID-19 pandemic. While these challenges elicited many reactive changes which were specific to, and only relevant in the context of ‘lockdown’ requirements, some of the protocol developments that came about during this unprecedented period have great potential to inform more permanent practices for carrying out this type of research. To this end, we detail the necessary adaptations to many elements of the feasibility study and critically reflect on our approach to redesigning and amending this ongoing project in order to maintain its viability to date. Some of the more major protocol adaptations, such as moving the study to remote means wherever possible, had further unforeseen and undesirable outcomes (eg, additional appointments) with regards to extra resources required to deliver the study. However, other changes improved the efficiency of the study, such as the remote informed consent and the direct advertising with prescreening survey. The adaptations to the study have clear links to the UK Plan for the future of research delivery. It is intended that this specific documentation and critical evaluation will help those planning or delivering similar studies to do so in a more resource efficient and effective way. In conclusion, it is essential to reflect and respond with protocol changes in the current climate in order to deliver clinical research successfully, as in the case of this particular study

The predictive role of symptoms in COVID-19 diagnostic models : A longitudinal insight

Acknowledgements 2019nCoV-302 Study Group Members: The NVX-CoV2373-2019nCoV-302 clinical trial was a collective group effort across multiple institutions and locations. Below is a list of sites and staff that significantly contributed to the implementation and conduct of the NVX-CoV2373-2019nCoV-302 clinical trial.Peer reviewe

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial

Acknowledgements The study and article were funded by Novavax. We would like to thank all the study participants for their commitment to this study. We also acknowledge the investigators and their study teams for their hard work and dedication. In addition, we would like to thank the National Institute for Health Research, representatives from the Department of Health and Social Care laboratories and NHS Digital and the members of the UK Vaccine Task Force. Editorial support was provided by Kelly Cameron of Ashfield MedComms, an Inizio company Funding This work was funded by Novavax, and the sponsor had primary responsibility for study design, study vaccines, protocol development, study monitoring, data management, and statistical analyses. All authors reviewed and approved the manuscript before submission. LF reports a position as a prior full-time employee, now contractor to Novavax re-imbursed hourly for work performed on this study and in analyses and drafting this report. IC reports providing medical writing support for this work as an employee of NovavaxPeer reviewedPublisher PD

Safety and efficacy of the NVX-CoV2373 coronavirus disease 2019 vaccine at completion of the placebo-controlled phase of a randomized controlled trial

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. Methods: Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. Clinical Trials Registration: EudraCT, 2020-004123-16

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Background Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. Methods In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. Findings Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). Interpretation Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia