UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.

BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m2), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.

Use of heart failure medical therapy before and after a cancer diagnosis: A longitudinal study.

AIMS: We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). METHODS AND RESULTS: We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35-1.68; beta-blockers: OR = 1.22, 95% CI = 1.08-1.37; MRAs: OR = 1.31, 95% CI = 1.08-1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75-2.37; beta-blockers: OR = 1.35, 95% CI = 1.12-1.63; MRAs: OR = 1.49, 95% CI = 1.16-1.93), and higher risks for dose down-titration for RASIs (OR = 1.69, 95% CI = 1.40-2.04) and beta-blockers (OR = 1.31, 95% CI = 1.05-1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. CONCLUSIONS: Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.

Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes: the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study.

Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14-1.86] and 0.96 [95% CI 0.70-1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18-2.22] and 0.66 [95% CI 0.44-1.00] per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events. Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a 'misaligned' dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.

Impact of Post Manufacturing Handling of Protein-Based Biologic Drugs on Product Quality and User Centricity.

This article evaluates the current gaps around the impact of post-manufacturing processes on the product qualities of protein-based biologics, with a focus on user centricity. It includes the evaluation of the regulatory guidance available, describes a collection of scientific literature and case studies to showcase the impact of post-manufacturing stresses on product and dosing solution quality. It also outlines the complexity of clinical handling and the need for communication, and alignment between drug providers, healthcare professionals, users, and patients. Regulatory agencies provide clear expectations for drug manufacturing processes, however, guidance supporting post-product manufacturing handling is less defined and often misaligned. This is problematic as the pharmaceutical products experience numerous stresses and processes which can potentially impact drug quality, safety and efficacy. This article aims to stimulate discussion amongst pharmaceutical developers, health care providers, device manufacturers, and public researchers to improve these processes. Patients and caregivers' awareness can be achieved by providing relevant educational material on pharmaceutical product handling.

Effect of statin treatment on the risk of cancer in patients with heart failure: A target trial emulation study.

PURPOSE: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. METHODS: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses. CONCLUSIONS: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF.

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease: the ALL-HEART RCT and economic evaluation.

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting: Four hundred and twenty-four UK primary care practices. Participants: Aged 60 years and over with ischaemic heart disease but no gout. Interventions: Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work: The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration: This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths.

Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

Impact of beta-blockers on mortality and cardiovascular disease outcomes in patients with obstructive sleep apnoea: a population-based cohort study in target trial emulation framework.

Background: There is no real-world evidence regarding the association between beta-blocker use and mortality or cardiovascular outcomes in patients with obstructive sleep apnoea (OSA). We aimed to investigate the impact of beta-blocker use on all-cause mortality and cardiovascular diseases (CVDs) in patients with OSA. Methods: We conducted a target trial emulation study of 37,581 patients with newly diagnosed OSA from 1st January 2000 to 30th November 2021 using the IMRD-UK database (formerly known as the THIN database). We compared the treatment strategies of initiating beta-blocker treatment within one year versus non-beta-blocker treatment through the method of clone-censor-weight. Covariates, including patients' demographics, lifestyle, comorbidities, and recent medications, were measured and controlled. Patients were followed up for all-cause mortality or composite CVD outcomes (angina, myocardial infarction, stroke/transient ischaemic attack, heart failure, or atrial fibrillation). We estimated the five-year absolute risks, risk differences and risk ratio with 95% confidence intervals (CIs) with standardised, weighted pooled logistic regression, which is a discrete-time hazard model for survival analysis. Several sensitivity analyses were performed, including multiple imputation addressing the missing data. Findings: The median follow-up time was 4.1 (interquartile range, 1.9-7.8) years. The five-year absolute risk of all-cause mortality and CVD outcomes were 4.9% (95% CI, 3.8-6.0) and 13.0% (95% CI, 11.4-15.0) among beta-blocker users, and 4.0% (95% CI, 3.8-4.2) and 9.4% (95% CI, 9.1-9.7) among non-beta-blocker users, respectively. The five-year absolute risk difference and risk ratio between the two groups for all-cause mortality and CVD outcomes were 0.9% (95% CI, -0.2 to 2.1) and 1.22 (95% CI, 0.96-1.54), and 3.5% (95% CI, 2.1-5.5) and 1.37 (95% CI, 1.22-1.62), respectively. Findings were consistent across the sensitivity analyses. Interpretation: Beta-blocker treatment was associated with an increased risk of CVD and a trend for an increased risk of mortality among patients with OSA. Further studies are needed to confirm our findings. Funding: Innovation and Technology Commission of the Hong Kong Special Administration Region Government.

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial.

BACKGROUND: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. METHODS: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. FINDINGS: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. INTERPRETATION: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. FUNDING: British Heart Foundation.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research.

A cross-sectional survey on the early impact of COVID-19 on the uptake of decentralised trial methods in the conduct of clinical trials.

BACKGROUND: The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19. METHODS: A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private "Trials@Home" consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions). RESULTS: The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials. CONCLUSIONS: Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

The Prognostic Value of Derivatives-Reactive Oxygen Metabolites (d-ROMs) for Cardiovascular Disease Events and Mortality: A Review.

Oxidative stress participates in the development and exacerbation of cardiovascular diseases (CVD). The ability to promptly quantify an imbalance in an individual reductive-oxidative (RedOx) state could improve cardiovascular risk assessment and management. Derivatives-reactive oxygen metabolites (d-ROMs) are an emerging biomarker of oxidative stress quantifiable in minutes through standard biochemical analysers or by a bedside point-of-care test. The current review evaluates available data on the prognostic value of d-ROMs for CVD events and mortality in individuals with known and unknown CVD. Outcome studies involving small and large cohorts were analysed and hazard ratio, risk ratio, odds ratio, and mean differences were used as measures of effect. High d-ROM plasma levels were found to be an independent predictor of CVD events and mortality. Risk begins increasing at d-ROM levels higher than 340 UCARR and rises considerably above 400 UCARR. Conversely, low d-ROM plasma levels are a good negative predictor for CVD events in patients with coronary artery disease and heart failure. Moreover, combining d-ROMs with other relevant biomarkers routinely used in clinical practice might support a more precise cardiovascular risk assessment. We conclude that d-ROMs represent an emerging oxidative-stress-related biomarker with the potential for better risk stratification both in primary and secondary cardiovascular prevention.

A secondary qualitative analysis of stakeholder views about participant recruitment, retention, and adherence in decentralised clinical trials (DCTs).

BACKGROUND: Decentralised clinical trials (DCTs) are clinical trials where all or most trial activities occur in or near participants' homes instead of hospitals or research sites. While more convenient for participants, DCTs may offer limited opportunities to build trust with investigators and trial teams. This qualitative analysis explored DCT stakeholder views to inform strategies for maximising participant recruitment, retention, and adherence. METHODS: A secondary analysis of original interview transcripts focused on participant engagement: recruitment, retention, and adherence. Semi-structured interviews were conducted with a purposive sample of stakeholders, including trial managers and administrators, investigators, nurses, vendors, and patient representatives. Interview data were coded using a thematic approach to generate descriptive themes. RESULTS: Forty-eight stakeholders were interviewed. Three components of participant engagement in DCTs were identified: identifying and attracting potential participants, retaining participants and encouraging adherence, and involvement of patients and the public. Interviewees believed that a potential participant's beliefs about research value and their trust in the research team strongly influenced the likelihood of taking part in a DCT. Early involvement of patients was identified as one way to gauge participant priorities. However, perceived burden was seen as a barrier to recruitment. Factors influencing retention and adherence were related to the same underlying motivators that drove recruitment: personal values, circumstances, and burden. Being part of a DCT should not conflict with the original motivations to participate. CONCLUSION: Recruitment, retention, and adherence in DCTs are driven by factors that have previously been found to affect conventional clinical trials. Increasing patient and public involvement can address many of these factors. In contrast to conventional trials, DCTs are perceived as requiring greater emphasis on communication, and contact, to engender trust between participants and researchers despite a relative lack of in-person interaction.

Adverse events and overall health and well-being after COVID-19 vaccination: interim results from the VAC4COVID cohort safety study.

OBJECTIVES: To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination. DESIGN: VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease. SETTING: The study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK. PARTICIPANTS: 16 265 adult (18 years or older) UK residents with a valid email address and internet access. INTERVENTIONS: Any UK-authorised COVID-19 vaccination. MAIN OUTCOME MEASURES: The outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being. RESULTS: 11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected. CONCLUSIONS: The study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed. TRIAL REGISTRATION NUMBER: ISRCTN95881792; Pre-results.

Evaluating Diuretics in Normal Care (EVIDENCE): a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension.

BACKGROUND: Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK. METHODS: Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies. RESULTS: This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch. CONCLUSION: The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN46635087 . Registered on 11 August 2017.

A systematic review of methods used to conduct decentralised clinical trials.

AIMS: To evaluate, using quantitative and qualitative approaches, published data on the design and conduct of decentralised clinical trials (DCTs). METHODS: We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, ProQuest Dissertations and Theses, ClinicalTrials.gov, OpenGrey and Google Scholar for publications reporting, discussing, or evaluating decentralised clinical research methods. Reports of randomised clinical trials using decentralised methods were included in a focused quantitative analysis with a primary outcome of number of randomised participants. All publications discussing or evaluating DCTs were included in a wider qualitative analysis to identify advantages, disadvantages, facilitators, barriers and stakeholder opinions of decentralised clinical trials. Quantitative data were summarised using descriptive statistics, and qualitative data analysed using a thematic approach. RESULTS: Initial searches identified 19 704 articles. After removal of duplicates, 18 553 were screened, resulting in 237 eligible for full-text assessment. Forty-five trials were included in the quantitative analysis; 117 documents were included in the qualitative analysis. Trials were widely heterogeneous in design and reporting, precluding meta-analysis of the effect of DCT methods on the primary recruitment outcome. Qualitative analysis formulated 4 broad themes: value, burden, safety and equity. Participant and stakeholder experiences of DCTs were incompletely represented. CONCLUSION: DCTs are developing rapidly. However, there is insufficient evidence to confirm which methods are most effective in trial recruitment, retention, or overall cost. The identified advantages, disadvantages, facilitators and barriers should inform the development of DCT methods. We recommend further research on how DCTs are experienced and perceived by participants and stakeholders to maximise potential benefits.

Learning from remote decentralised clinical trial experiences: A qualitative analysis of interviews with trial personnel, patient representatives and other stakeholders.

AIMS: The aim of the study was to identify actionable learning points from stakeholders in remote decentralised clinical trials (RDCTs) to inform their future design and conduct. METHODS: Semistructured interviews were carried out with a purposive sample of stakeholders, including senior managers, trial managers, technology experts, principal investigators, clinical investigators, research scientists, research nurses, vendors, patient representatives and project assistants. The interview data were coded using a thematic approach, identifying similarities, differences and clustering to generate descriptive themes. Further refinement of themes was guided by empirical phenomenology, grounding explanation in the meanings that interviewees gave to their experiences. RESULTS: Forty-eight stakeholders were interviewed. Actionable learning points were generated from the thematic analysis. Patient involvement and participant engagement were seen as critical to the success of RDCTs where in-person contact is minimal or nonexistent. Involving patients in identifying the research question, creating recruitment materials, apps and websites, and providing ongoing feedback to trial participants were regarded as facilitating recruitment and engagement. Building strong relationships early with trial partners was thought to support RDCT conduct. Multiple modes of capturing information, including patient-reported outcomes (PROs) and routinely collected data, were felt to contribute to data completeness. However, RDCTs may transfer trial activity burden onto participants and remote-working research staff, therefore additional support may be needed. CONCLUSION: RDCTs will continue to face challenges in implementing novel technologies. However, maximising patient and partner involvement, reducing participant and staff burden, and simplifying how participants and staff interact with the RDCT may facilitate their implementation.

Home blood pressure monitors owned by participants in a large decentralised clinical trial in hypertension: the Treatment In Morning versus Evening (TIME) study.

Various home blood pressure monitors (HBPMs) are available to the public for purchase but only some are validated against standardised protocols. This study aimed to assess whether HBPMs owned by participants taking part in a clinical trial were validated models. The TIME study is a decentralised randomised trial investigating the effect of antihypertensive medication dosing time on cardiovascular outcomes in adults with hypertension. No HBPMs were provided to participants in this trial but patients were asked to report if they already owned one. We identified the model of HBPM reported by participants, then cross-referenced this against lists of validated HBPMs produced by dabl Educational Trust and the British and Irish Hypertension Society (BIHS). Of 21,104 participants, 10,464 (49.6%) reported their model of HBPM. 7464 (71.3%) of these participants owned a monitor that could be identified from the participants' entry. Of these, 6066 (81.3%) participants owned a monitor listed as validated by either dabl (n = 5903) or BIHS (n = 5491). Some were listed as validated by both. 1398 (18.7%) participants owned an identifiable HBPM that lacked clear evidence of validation. 6963 (93.3%) participants owned an upper arm HBPM and 501 (6.7%) owned a wrist HBPM. Validated HBPMs had a higher median online retail price of £45.00 compared to £20.00 for HBPMs lacking clear evidence of validation. A significant number of participants own HBPMs lacking evidence of validation.