Comparative clinical effectiveness and cost effectiveness of endovascular strategy v open repair for ruptured abdominal aortic aneurysm: three year results of the IMPROVE randomised trial.

Objective To assess the three year clinical outcomes and cost effectiveness of a strategy of endovascular repair (if aortic morphology is suitable, open repair if not) versus open repair for patients with suspected ruptured abdominal aortic aneurysm.Design Randomised controlled trial.Setting 30 vascular centres (29 in UK, one in Canada), 2009-16.Participants 613 eligible patients (480 men) with a clinical diagnosis of ruptured aneurysm, of whom 502 underwent emergency repair for rupture.Interventions 316 patients were randomised to an endovascular strategy (275 with confirmed rupture) and 297 to open repair (261 with confirmed rupture).Main outcome measures Mortality, with reinterventions after aneurysm repair, quality of life, and hospital costs to three years as secondary measures.Results The maximum follow-up for mortality was 7.1 years, with two patients in each group lost to follow-up by three years. After similar mortality by 90 days, in the mid-term (three months to three years) there were fewer deaths in the endovascular than the open repair group (hazard ratio 0.57, 95% confidence interval 0.36 to 0.90), leading to lower mortality at three years (48% v 56%), but by seven years mortality was about 60% in each group (hazard ratio 0.92, 0.75 to 1.13). Results for the 502 patients with repaired ruptures were more pronounced: three year mortality was lower in the endovascular strategy group (42% v 54%; odds ratio 0.62, 0.43 to 0.88), but after seven years there was no clear difference between the groups (hazard ratio 0.86, 0.68 to 1.08). Reintervention rates up to three years were not significantly different between the randomised groups (hazard ratio 1.02, 0.79 to 1.32); the initial rapid rate of reinterventions was followed by a much slower mid-term reintervention rate in both groups. The early higher average quality of life in the endovascular strategy versus open repair group, coupled with the lower mortality at three years, led to a gain in average quality adjusted life years (QALYs) at three years of 0.17 (95% confidence interval 0.00 to 0.33). The endovascular strategy group spent fewer days in hospital and had lower average costs of -£2605 (95% confidence interval -£5966 to £702) (about €2813; $3439). The probability that the endovascular strategy is cost effective was >90% at all levels of willingness to pay for a QALY gain.Conclusions At three years, compared with open repair, an endovascular strategy for suspected ruptured abdominal aortic aneurysm was associated with a survival advantage, a gain in QALYs, similar levels of reintervention, and reduced costs, and this strategy was cost effective. These findings support the increasing use of an endovascular strategy, with wider availability of emergency endovascular repair.Trial registration Current Controlled Trials ISRCTN48334791; ClinicalTrials NCT00746122

Experiences of running a stratified medicine adaptive platform trial : Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: FOCUS4 was co-funded by the Medical Research Council (MRC)/National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme and Cancer Research UK (CRUK) in April 2013. A subsequent AstraZeneca educational grant in 2017 funded the translational aspects of FOCUS4-C. Supply and distribution of AZD8931 for FOCUS-D and AZD1775 for FOCUS4-C were provided by AstraZeneca Ltd. Supply and distribution of aspirin and placebo for FOCUS4-B were provided by Bayer. The MRC Clinical Trials Unit at UCL receives core funding from the MRC within UK Research and Innovation (UKRI) (Budget: MC_UU_12023/20).Peer reviewedPublisher PD

Safety and efficacy of sonothrombolysis for acute ischaemic stroke : a multicentre, double-blind, phase 3, randomised controlled trial

Background Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score >= 10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4.5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov , number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1.05 (95% CI 0.77-1.45; p=0.74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1.24, 95% CI 0 .80-1. 92; 13=0.37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1.12, 0.79-1.60; p=0.53). Interpretation Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Copyright (C) 2019 Elsevier Ltd. All rights reserved.Peer reviewe

Enteral lactoferrin supplementation for very preterm infants: A randomised placebo-controlled trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods: In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding: UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial

Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke

Bayesian clinical trial designs : Another option for trauma trials?

The UK-REBOA Trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/199/09). PP was supported by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1-R/N/P/B1).Peer reviewedPublisher PD

Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux

BACKGROUND—Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS—In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim–sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS—Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim–sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS—Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.

Bayesian clinical trial designs:another option for trauma trials?

Conducting clinical trials in trauma care is challenging. As new treatments become available, we are faced with the dilemma of how to confirm their effectiveness, and strengthen the evidence base. Randomized controlled trials are the gold standard, but target groups in trauma care are often small and specialized, making the classical approach to trial design difficult. Bayesian designs represent an innovative means of increasing trial efficiency, and conducting trials with more realistic sample sizes. This article examines the design of such trials, using the UK-REBOA Trial as an example

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Publisher Copyright: © 2022 The AuthorsBackground: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.Peer reviewe

Endoscopic urethrotomy versus open urethroplasty for men with bulbar urethral stricture : the OPEN randomised trial cost-effectiveness analysis

Funding: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research, ref: 10/57/23. Acknowledgements: Contributors: Jing Shen, supervised by Luke Vale, led the health economic evaluation and analysis. Robert Pickard led the study, Beatriz Goulao supervised by Graeme MacLennan performed the statistical analysis, Sonya Carnell and Rebecca Forbes supported by Stephanie Currer and supervised by Jennifer Wilkinson managed the trial. John Norrie contributed to the funding application and statistical analysis plan. He also provided support to the statistical analysis team. Matt Breckons, supervised by Jing Shen, conducted a time trade off experiment reported separately. Paul Whybrow, supervised by Tim Rapley, carried out the qualitative research reported separately. Mark Forrest managed and maintained the trial database. Elaine McColl contributed to the funding application and protocol. Daniela Andrich, Anthony Mundy, James N’Dow and Stephen Payne provided clinician support to the funding application, acted as PIs at key sites. Stewart Barclay contributed a patient view to the trial, including the funding application, the protocol, and all aspects of the analysis. Jonathan Cook was involved in the design of the study and Nick Watkin co-wrote the funding application, contributed clinical insight to the trial management group. We thank the patients and health-care professionals for their participation in the study; Stewart Barclay, the patient and service user representative in the OPEN Trial Management Group; the Trial Steering committee members: Roger Kockelburg (chairperson), John Matthews, Alan McNeil, Howard Kynaston and Neil Campling; Data Monitoring Committee members: Gordon Murray (chairperson), Richard Martin and Thomas Pinkney. We also thank the following people who worked on the trial: Matthew Jackson, Research Fellow; Gladys McPherson, Data Manager; Lee Munro, Trial Manager; Rachel Stephenson, Trial Manager; Sue Tremble, Trial Manager; Robbie Brown, Trial Manager; Mark Deverill, Health Economist; Amy Collins, Project Secretary; Lavinia Miceli, Project Secretary; and Ann Payne, Project Secretary. Members of the Open Trial Group responsible for recruitment and who acted as principle investigators for their centres were: Trevor Dorkin, Freeman Hospital, Newcastle; Nick Watkin, St George’s Hospital, London; Anthony Mundy, University College London Hospitals NHS Foundation Trust, London; Paul Anderson, Russells Hall Hospital, Dudley; Suzie Venn, Queen Alexandra Hospital, Portsmouth; Ian Eardley, St James’s University Hospital, Leeds; Mr David Dickerson, Weston General Hospital, Westonsuper-Mare; Nikesh Thiruchelvam, Addenbrooke’s Hospital, Cambridge; Richard Inman and Chris Chapple, Royal Hallamshire Hospital, Sheeld; Andrew Baird, Aintree University Hospital NHS Foundation Trust, Liverpool; Andrew Sinclair, Stepping Hill Hospital, Stockport; Rajeshwar Krishnanm, Kent and Canterbury Hospital, Canterbury; Rowland Rees, University Hospital Southampton NHS Foundation Trust, Southampton; James N’dow, Aberdeen Royal Inrmary, Aberdeen; Bruce Montgomery, Frimley Park Hospital, Camberley; Michael Swinn, East Surrey Hospital, Redhill; Alastair Henderson and John Donohue, Maidstone Hospital, Maidstone; Suzie Venn, St Richard’s Hospital, Chichester; Robert Mason, Torbay Hospital, Torquay; Sanjeev Madaan, Darent Valley Hospital, Kent; Mustafa Hilmy, York Hospital, York; Vivienne Kirchin, Sunderland Royal Inrmary, Sunderland; Kim Davenport, Cheltenham General Hospital, Cheltenham; John McGrath, Exeter Hospital, Exeter; Tim Porter, Yeovil District Hospital, Yeovil; Ruaraidh MacDonagh and Amerdip Birring, Musgrove Park Hospital, Taunton; Ramachandran Ravi, Basildon University Hospital; Jawad Husain, Royal Albert Edward Inrmary, Wigan; Maj Shabbir, Guy’s Hospital, London; Omer Baldo, Airedale General Hospital, Keighley; Sadhanshu Chitale, Whittington Hospital, London; Mary Garthwaite, James Cook University Hospital, Middlesbrough; Shalom Srirangam, Royal Blackburn Hospital, Blackburn; Liaqat Chowoo, Bedford Hospital, Bedford; Tina Rashid, Charing Cross Hospital, London; Rob Skyrme; Jon Featherstone, Princess of Wales Hospital, Bridgend; Ammar Alhasso, Edinburgh; and Oleg Tatarov, Cardiff. We thank the following trusts for offering participant identication centre support: Basingstoke and Northamptonshire NHS Foundation Trust; Royal Liverpool and Broadgreen University Hospitals NHS Trust; Chelsea and Westminster NHS Foundation Trust; and Wirral University Teaching Hospital NHS Foundation Trust. We thank the following Trusts for offering PIC support: Basingstoke and Northamptonshire NHS Foundation Trust; Royal Liverpool and Broadgreen University Hospitals NHS Trust; Chelsea and Westminster NHS Foundation Trust; Wirral University Teaching Hospitals NHS Foundation Trust.Peer reviewedPublisher PDFPublisher PD