Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents.

INTRODUCTION: The A allele of rs1042713 (Arg16 amino acid) in the ß2-adrenoreceptor is associated with poor response to long-acting ß2-agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ). METHODS: We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12-18 years with asthma taking inhaled corticosteroids. 241 participants (mean±sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. RESULTS: Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00-0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02-0.81; p=0.041). CONCLUSION: This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such ß2-adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.

Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging.

The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT.

Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 µg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?

BACKGROUND: Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test-Lung Cancer Scotland Study). METHODS: Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n = 95) and normal CT groups (n = 174) at 3 and 6 months follow-up. RESULTS: No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3- and 6-month time points: 3.04, 95% CI: 0.95, 9.73; P = 0.06). CONCLUSION: Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation.

Prevalence and Distribution of Atherosclerosis in a Low- to Intermediate-Risk Population: Assessment with Whole-Body MR Angiography.

Purpose To quantify the burden and distribution of asymptomatic atherosclerosis in a population with a low to intermediate risk of cardiovascular disease. Materials and Methods Between June 2008 and February 2013, 1528 participants with 10-year risk of cardiovascular disease less than 20% were prospectively enrolled. They underwent whole-body magnetic resonance (MR) angiography at 3.0 T by using a two-injection, four-station acquisition technique. Thirty-one arterial segments were scored according to maximum stenosis. Scores were summed and normalized for the number of assessable arterial segments to provide a standardized atheroma score (SAS). Multiple linear regression was performed to assess effects of risk factors on atheroma burden. Results A total of 1513 participants (577 [37.9%] men; median age, 53.5 years; range, 40-83 years) completed the study protocol. Among 46 903 potentially analyzable segments, 46 601 (99.4%) were interpretable. Among these, 2468 segments (5%) demonstrated stenoses, of which 1649 (3.5%) showed stenosis less than 50% and 484 (1.0%) showed stenosis greater than or equal to 50%. Vascular stenoses were distributed throughout the body with no localized distribution. Seven hundred forty-seven (49.4%) participants had at least one stenotic vessel, and 408 (27.0%) participants had multiple stenotic vessels. At multivariable linear regression, SAS correlated with age (B = 3.4; 95% confidence interval: 2.61, 4.20), heart rate (B = 1.23; 95% confidence interval: 0.51, 1.95), systolic blood pressure (B = 0.02; 95% confidence interval: 0.01, 0.03), smoking status (B = 0.79; 95% confidence interval: 0.44, 1.15), and socioeconomic status (B = -0.06; 95% confidence interval: -0.10, -0.02) (P < .01 for all). Conclusion Whole-body MR angiography identifies early vascular disease at a population level. Although disease prevalence is low on a per-vessel level, vascular disease is common on a per-participant level, even in this low- to intermediate-risk cohort. © RSNA, 2018 Online supplemental material is available for this article.

Systemic arteriosclerosis is associated with left ventricular remodeling but not atherosclerosis: a TASCFORCE study.

BACKGROUND: Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events, with this effect postulated to be due to its effect on cardiac afterload, atherosclerosis (plaque formation) progression or both, but with limited evidence examining these early in disease formation. The aim of the current study is to examine the association between arteriosclerosis, atherosclerosis and ventricular remodelling in a population at low-intermediate cardiovascular risk. METHODS: One thousand six hundred fifty-one subjects free of clinical cardiovascular disease and with a < 20% 10 year cardiovascular risk score underwent a cardiovascular magnetic resonance (CMR) study and whole body CMR angiogram. Arteriosclerosis was measured using total arterial compliance (TAC) - calculated as the indexed stroke volume divided by the pulse pressure. Atherosclerosis was quantified using a standardised atheroma score (SAS) which was calculated by scoring 30 arterial segments within the body based on the degree of stenosis, summating these scores and normalising it to the number of assessable segments. Left ventricular remodelling was measured using left ventricular mass to volume ratio (LVMVR). RESULTS: One thousand five hundred fifteen (38% male, 53.8 ± 8.2 years old) completed the study. On univariate analysis TAC was associated with SAS but this was lost after accounting for cardiovascular risk factors in both males (B = - 0.001 (- 0.004-0.002),p = 0.62) and females (B = 0.000(95%CI -0.002--0.002),p = 0.78). In contrast compliance correlated with LVMVR after accounting for cardiovascular risk factors (B = - 0.12(95%CI -0.16--0.091),p < 0.001 in males; B = - 0.12(95%CI -0.15--0.086),p < 0.001 in females). CONCLUSION: Systemic arteriosclerosis is associated with left ventricular remodelling but not atherosclerosis. Future efforts in cardiovascular risk prevention should thus seek to address both arteriosclerosis and atherosclerosis individually.

Determinants of motivation to quit in smokers screened for the early detection of lung cancer: a qualitative study.

BACKGROUND: The promotion of smoking cessation within lung cancer screening could lead to benefits for smoking-related disease and improve cost-effectiveness of screening. Little is known about how smokers respond to lung cancer screening and how this impacts smoking behaviour. We aimed to understand how lung cancer screening influences individual motivations about smoking, including in those who have stopped smoking since screening. METHODS: Thirty one long-term smokers aged 51-74 took part in semi-structured interviews about smoking. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test Lung Cancer Scotland Study. They were purposively sampled for interview based on their self-reported post-screening smoking behaviour. Eleven participants had stopped smoking since screening. Verbatim interview transcripts were analysed using thematic analysis. RESULTS: Two key overarching themes were interpretations of screening test results and emotional responses to those interpretations. Participants' understanding of the risk implied by their test result was often inaccurate, for example a negative result interpreted as an 'all-clear' from lung cancer and a positive result as meaning lung cancer would definitely develop. Those interpretations led to emotional responses (fear, shock, worry, relief, indifference) influencing motivations about smoking. Other themes included a wake-up call causing changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking and family influences. There was no clear pattern in smoking motivations in those who received positive or negative test results. Of those who had stopped smoking, some cited screening experiences as the sole motivation, some cited screening along with other coinciding factors, and others cited non-screening reasons. Cues to change were experienced at different stages of the screening process. Some participants indicated they underwent screening to try and stop smoking, while others expressed little or no desire to stop. CONCLUSIONS: We observed complex and individualised motivations about smoking following lung cancer screening. To be most effective, smoking cessation support in this context should explore understanding of screening test results and may need to be highly tailored to individual emotional responses to screening.

Detection in blood of autoantibodies to tumour antigens as a case-finding method in lung cancer using the EarlyCDT®-Lung Test (ECLS): study protocol for a randomized controlled trial.

BACKGROUND: Lung cancer is the most common cause of cancer related death worldwide. The majority of cases are detected at a late stage when prognosis is poor. The EarlyCDT®-Lung Test detects autoantibodies to abnormal cell surface proteins in the earliest stages of the disease which may allow tumour detection at an earlier stage thus altering prognosis. The primary research question is: Does using the EarlyCDT®-Lung Test to identify those at high risk of lung cancer, followed by X-ray and computed tomography (CT) scanning, reduce the incidence of patients with late-stage lung cancer (III & IV) or unclassified presentation (U) at diagnosis, compared to standard practice? METHODS: A randomised controlled trial of 12 000 participants in areas of Scotland targeting general practices serving patients in the most deprived quintile of the Scottish Index of Multiple Deprivation. Adults aged 50-75 who are at high risk of lung cancer and healthy enough to undergo potentially curative therapy (Performance Status 0-2) are eligible to participate. The intervention is the EarlyCDT®-Lung Test, followed by X-ray and CT in those with a positive result. The comparator is standard clinical practice in the UK. The primary outcome is the difference, after 24 months, between the rates of patients with stage III, IV or unclassified lung cancer at diagnosis. The secondary outcomes include: all-cause mortality; disease specific mortality; a range of morbidity outcomes; cost-effectiveness and measures examining the psychological and behavioural consequences of screening. Participants with a positive test result but for whom the CT scan does not lead to a lung cancer diagnosis will be offered 6 monthly thoracic CTs for 24 months. An initial chest X-ray will be used to determine the speed and the need for contrast in the first screening CT. Participants who are found to have lung cancer will be followed-up to assess both time to diagnosis and stage of disease at diagnosis. DISCUSSION: The study will determine the clinical and cost effectiveness of EarlyCDT®-Lung Test for early lung cancer detection and assess its suitability for a large-scale, accredited screening service. The study will also assess the potential psychological and behavioural harms arising from false positive or false negative results, as well as the potential benefits to patients of true negative EarlyCDT lung test results. A cost-effectiveness model of lung cancer screening based on the results of the EarlyCDT Lung Test study will be developed. TRIAL REGISTRATION: NCT01925625 . August 19, 2013.

3T MRI investigation of cardiac left ventricular structure and function in a UK population: The tayside screening for the prevention of cardiac events (TASCFORCE) study.

PURPOSE: To scan a volunteer population using 3.0T magnetic resonance imaging (MRI). MRI of the left ventricular (LV) structure and function in healthy volunteers has been reported extensively at 1.5T. MATERIALS AND METHODS: A population of 1528 volunteers was scanned. A standardized approach was taken to acquire steady-state free precession (SSFP) LV data in the short-axis plane, and images were quantified using commercial software. Six observers undertook the segmentation analysis. RESULTS: Mean values (±standard deviation, SD) were: ejection fraction (EF) = 69 ± 6%, end diastolic volume index (EDVI) = 71 ± 13 ml/m2 , end systolic volume index (ESVI) = 22 ± 7 ml/m2 , stroke volume index (SVI) = 49 ± 8 ml/m2 , and LV mass index (LVMI) = 55 ± 12 g/m2 . The mean EF was slightly larger for females (69%) than for males (68%), but all other variables were smaller for females (EDVI 68v77 ml/m2 , ESVI 21v25 ml/m2 , SVI 46v52 ml/m2 , LVMI 49v64 g/m2 , all P < 0.05). The mean LV volume data mostly decreased with each age decade (EDVI males: -2.9 ± 1.3 ml/m2 , females: -3.1 ± 0.8 ml/m2 ; ESVI males: -1.3 ± 0.7 ml/m2 , females: -1.7 ± 0.5 ml/m2 ; SVI males: -1.7 ± 0.9 ml/m2 , females: -1.4 ± 0.6 ml/m2 ; LVMI males: -1.6 ± 1.1 g/m2 , females: -0.2 ± 0.6 g/m2 ) but the mean EF was virtually stable in males (0.6 ± 0.6%) and rose slightly in females (1.2 ± 0.5%) with age. CONCLUSION: LV reference ranges are provided in this population-based MR study at 3.0T. The variables are similar to those described at 1.5T, including variations with age and gender. These data may help to support future population-based MR research studies that involve the use of 3.0T MRI scanners. J. Magn. Reson. Imaging 2016;44:1186-1196.

Levetiracetam for the treatment of mild cognitive impairment in Parkinson's disease: a double-blind controlled proof-of-concept trial protocol.

BACKGROUND: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. METHODS: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. RESULTS: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. CONCLUSIONS: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Tayside Screening For Cardiac Events (TASCFORCE) study: a prospective cardiovascular risk screening study.

PURPOSE: Risk factor-based models struggle to accurately predict the development of cardiovascular disease (CVD) at the level of the individual. Ways of identifying people with low predicted risk who will develop CVD would allow stratified advice and support informed treatment decisions about the initiation or adjustment of preventive medication, and this is the aim of this prospective cohort study. PARTICIPANTS: The Tayside Screening for Cardiac Events (TASCFORCE) study recruited men and women aged≥40 years, free from known CVD, with a predicted 10-year risk of coronary heart disease<20%. If B-type natriuretic peptide (BNP) was greater than their gender median, participants were offered a whole-body contrast-enhanced MRI (WBCE-MRI) scan (cardiac imaging, whole-body angiography to determine left ventricular parameters, delayed gadolinium enhancement, atheroma burden). Blood, including DNA, was stored for future biomarker assays. Participants are being followed up using electronic record-linkage cardiovascular outcomes. FINDINGS TO DATE: 4423 (1740, 39.3% men) were recruited. Mean age was 52.3 years with a median BNP of 7.50 ng/L and 15.30 ng/L for men and women, respectively. 602 had a predicted 10-year risk of 10%-19.9%, with the remainder<10%. Age, female sex, ex-smoking status, lower heart rate, higher high-density lipoprotein and lower total cholesterol were independently associated with higher log10 BNP levels. Mean left ventricular mass was 129.2 g and 87.0 g in men and women, respectively. FUTURE PLANS: The TASCFORCE study is investigating the ability of a screening programme, using BNP and WBCE-MRI, at the time of enrolment, to evaluate prediction of CVD in a population at low/intermediate risk. Blood stored for future biomarker analyses will allow testing/development of novel biomarkers. We believe this could be a new UK Framingham study allowing study for many years to come. CLINICAL TRIAL REGISTRATION: ISRCTN38976321.

Consumer perspectives on simplified, layered consent for a low risk, but complex pragmatic trial.

BACKGROUND: For decades, the research community has called for participant information sheets/consent forms (PICFs) to be improved. Recommendations include simplifying content, reducing length, presenting information in layers and using multimedia. However, there are relatively few studies that have evaluated health consumers' (patients/carers) perspectives on the type and organisation of information, and the level of detail to be included in a PICF to optimise an informed decision to enter a trial. We aimed to elicit consumers' views on a layered approach to consent that provides the key information for decision-making in a short PICF (layer 1) with additional optional information that is accessed separately (layer 2). We also elicited consumers' views on the optimal content and layout of the layered consent materials for a large and complex Bayesian adaptive platform trial (the SNAP trial). METHODS: We conducted a qualitative multicentre study (4 focus groups and 2 semi-structured interviews) involving adolescent and adult survivors of Staphylococcus aureus bloodstream infection (22) and their carers (2). Interview transcripts were examined using inductive thematic analysis. RESULTS: Consumers supported a layered approach to consent. The primary theme that emerged was the value of agency; the ability to exert some control over the amount of information read before the consent form is signed. Three other themes emerged; the need to prioritise participants' information needs; the importance of health literacy; the importance of information about a trial's benefits (over its risks) for decision-making and the interplay between the two. CONCLUSIONS: Our findings suggest that consumers may challenge the one-size-fits-all approach currently applied to the development of PICFs in countries like Australia. Consumers supported a layered approach to consent that offers choice in the amount of information to be read before deciding whether to enter a trial. A 3-page PICF was considered sufficient for decision-making for the SNAP trial, provided that further information was available and accessible.

Ceftolozane-tazobactam versus meropenem for definitive treatment of bloodstream infection due to extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales ("MERINO-3"): study protocol for a multicentre, open-label randomised non-inferiority trial.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli. METHODS: This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5 days and a maximum of 14 days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. DISCUSSION: Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible E. coli and Klebsiella spp. or Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens. They will be randomised 1:1 to ceftolozane-tazobactam 3 g versus meropenem 1 g, both every 8 h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, C. difficile infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024. TRIAL REGISTRATION: The MERINO-3 trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT04238390 . Registered on 23 January 2020.

Associations between frailty, physical performance, and renal biomarkers in older people with advanced chronic kidney disease.

PURPOSE: Impaired physical performance and frailty are common in older people with advanced chronic kidney disease but it is unclear which metabolic derangements contribute to these impairments. We, therefore, examined associations between renal biochemical markers and both physical performance and frailty in older people with advanced chronic kidney disease. METHODS: Secondary analysis of data from the BiCARB trial, which enrolled non-dialysing patients aged 60 and over, with chronic kidney disease stage 4/5, with serum bicarbonate < 22 mmol/L. Participants undertook the Short Physical Performance Battery, maximum grip strength and six-minute walk test at baseline, 3, 6, 12 and 24 months. Renal biochemistry (serum creatinine, cystatin C, phosphate, and bicarbonate), haemoglobin, 25-hydroxyvitamin D and NT-pro-B-type natriuretic peptide were measured at baseline. Associations between baseline renal biochemistry and physical performance, and between baseline biochemistry and the monthly rate of change in physical performance were assessed. RESULTS: We analysed data from 300 participants (mean age 74 years; 86 [29%] women). 148 (49%) were pre-frail, 86 (29%) were frail. In multivariable cross-sectional baseline analyses, only age and BMI were significantly associated with baseline short physical performance battery; age, sex, body mass index, NT-pro-BNP and 25-hydroxyvitamin D were significantly associated with baseline six-minute walk distance. No significant associations were found between biochemical markers and change in physical performance over time, except between baseline 25-hydroxyvitamin D concentration and change in six-minute walk distance. CONCLUSIONS: Biochemical markers associated with chronic kidney disease did not consistently associate with baseline physical performance or the rate of change of physical performance measures. TRIAL REGISTRATION: ISRCTN09486651.

Unconditional and conditional monetary incentives to increase response to mailed questionnaires: A randomized controlled study within a trial (SWAT).

RATIONALE, AIMS, AND OBJECTIVES: High response rates to research questionnaires can help to ensure results are more representative of the population studied and provide increased statistical power, on which the study may have been predicated. Improving speed and quality of response can reduce costs. METHOD: We conducted a randomized study within a trial (SWAT) to assess questionnaire response rates, reminders sent, and data completeness with unconditional compared with conditional monetary incentives. Eligible individuals were mailed a series of psychological questionnaires as a follow-up to a baseline host trial questionnaire. Half received a £5 gift voucher with questionnaires (unconditional), and half were promised the voucher after returning questionnaires (conditional). RESULTS: Of 1079 individuals, response rates to the first follow-up questionnaire were 94.2% and 91.7% in the unconditional and conditional monetary incentive groups, respectively (OR 1.78; 95% CI, 0.85-3.72). There were significantly greater odds of returning repeat questionnaires in the unconditional group at 6 months (OR 2.97; 95% CI, 1.01-8.71; .047) but not at 12 months (OR 1.12; 95% CI, 0.44-2.85). Incentive condition had no impact at any time point on the proportion of sent questionnaires that needed reminders. Odds of incomplete questionnaires were significantly greater at 3 months in the unconditional compared with the conditional incentive group (OR 2.45; 95% CI, 1.32-4.55; .004). CONCLUSIONS: Unconditional monetary incentives can produce a transitory greater likelihood of mailed questionnaire response in a clinical trial participant group, consistent with the direction of effect in other settings. However, this could have been a chance finding. The use of multiple strategies to promote response may have created a ceiling effect. This strategy has potential to reduce administrative and postage costs, weighed against the cost of incentives used, but could risk compromising the completeness of data.

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT.

BACKGROUND: Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. OBJECTIVES: The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. DESIGN: A parallel-group, double-blind, placebo-controlled randomised trial. SETTING: The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. PARTICIPANTS: Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of < 22 mmol/l. INTERVENTIONS: Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was < 22 mmol/l at 3 months. MAIN OUTCOME MEASURES: The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. RESULTS: In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (-0.4 points, 95% confidence interval -0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of -0.05 (95% confidence interval -0.08 to -0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. LIMITATIONS: The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. CONCLUSIONS: Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

Patients with advanced chronic kidney disease often have excessive levels of acid in their blood (acidosis). Acidosis has been associated with a range of other problems that particularly affect patients with chronic kidney disease, including weaker muscles, weaker bones, worse blood vessel health and kidney disease that worsens more quickly. For decades, acidosis has been treated with sodium bicarbonate tablets (the ingredient found in baking soda) to neutralise the excess acid. However, sodium bicarbonate is awkward to take, may cause side effects and may increase blood pressure. To clarify whether or not sodium bicarbonate caused an overall improvement in health, we carried out a study involving 300 people aged ≥ 60 years with advanced chronic kidney disease and mild acidosis. Half received sodium bicarbonate capsules and half received dummy capsules (placebo), for up to 2 years. The treatments were chosen randomly by a computer and the participants, their doctors and the researchers were not aware of the treatment received until the end of the study. We measured physical function (walking speed, ability to stand from a chair, balance) alongside quality of life, kidney function, bone and blood vessel health, side effects and health service use over 2 years. We found that sodium bicarbonate did not improve physical function or quality of life compared with placebo. Sodium bicarbonate also did not improve kidney function, bone health or blood vessel health compared with placebo. More people in the sodium bicarbonate group than in the placebo group had side effects, although blood pressure was the same in both groups. Health-care costs were higher in the sodium bicarbonate group than in the placebo group. We conclude that oral sodium bicarbonate did not significantly improve health measures compared with placebo for older people (aged ≥ 60 years) with advanced chronic kidney disease associated with mild acidosis.

Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT).

PURPOSE: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. PATIENTS AND METHODS: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3ß, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. RESULTS: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3ß (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. CONCLUSIONS: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort.

OBJECTIVE: To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial. METHODS: We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats. RESULTS: We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed t test t = -3.7, p = 0.0019). CONCLUSIONS: Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.