An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.

Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Two commonly performed surgical interventions are available for severe (grade II-IV) haemorrhoids; traditional excisional surgery and stapled haemorrhoidopexy. Uncertainty exists as to which is most effective. The eTHoS trial was designed to establish the clinical effectiveness and cost-effectiveness of stapled haemorrhoidopexy compared with traditional excisional surgery. METHODS: The eTHoS trial was a large, open-label, multicentre, parallel-group, pragmatic randomised controlled trial done in adult participants (aged 18 years or older) referred to hospital for surgical treatment for grade II-IV haemorrhoids. Participants were randomly assigned (1:1) to receive either traditional excisional surgery or stapled haemorrhoidopexy. Randomisation was minimised according to baseline EuroQol 5 dimensions 3 level score (EQ-5D-3L), haemorrhoid grade, sex, and centre with an automated system to stapled haemorrhoidopexy or traditional excisional surgery. The primary outcome was area under the quality of life curve (AUC) measured with the EQ-5D-3L descriptive system over 24 months, assessed according to the randomised groups. The primary outcome measure was analysed using linear regression with adjustment for the minimisation variables. This trial is registered with the ISRCTN registry, number ISRCTN80061723. FINDINGS: Between Jan 13, 2011, and Aug 1, 2014, 777 patients were randomised (389 to receive stapled haemorrhoidopexy and 388 to receive traditional excisional surgery). Stapled haemorrhoidopexy was less painful than traditional excisional surgery in the short term and surgical complication rates were similar between groups. The EQ-5D-3L AUC score was higher in the traditional excisional surgery group than the stapled haemorrhoidopexy group over 24 months; mean difference -0·073 (95% CI -0·140 to -0·006; p=0·0342). EQ-5D-3L was higher for stapled haemorrhoidopexy in the first 6 weeks after surgery, the traditional excisional surgery group had significantly better quality of life scores than the stapled haemorrhoidopexy group. 24 (7%) of 338 participants who received stapled haemorrhoidopexy and 33 (9%) of 352 participants who received traditional excisional surgery had serious adverse events. INTERPRETATION: As part of a tailored management plan for haemorrhoids, traditional excisional surgery should be considered over stapled haemorrhoidopexy as the surgical treatment of choice. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Individualised pelvic floor muscle training in women with pelvic organ prolapse (POPPY): a multicentre randomised controlled trial.

BACKGROUND: Pelvic organ prolapse is common and is strongly associated with childbirth and increasing age. Women with prolapse are often advised to do pelvic floor muscle exercises, but evidence supporting the benefits of such exercises is scarce. We aimed to establish the effectiveness of one-to-one individualised pelvic floor muscle training for reducing prolapse symptoms. METHODS: We did a parallel-group, multicentre, randomised controlled trial at 23 centres in the UK, one in New Zealand, and one in Australia, between June 22, 2007, and April 9, 2010. Female outpatients with newly-diagnosed, symptomatic stage I, II, or III prolapse were randomly assigned (1:1), by remote computer allocation with minimsation, to receive an individualised programme of pelvic floor muscle training or a prolapse lifestyle advice leaflet and no muscle training (control group). Outcome assessors, and investigators who were gynaecologists at trial sites, were masked to group allocation; the statistician was masked until after data analysis. Our primary endpoint was participants' self-report of prolapse symptoms at 12 months. Analysis was by intention-to-treat analysis. This trial is registered, number ISRCTN35911035. FINDINGS: 447 eligible patients were randomised to the intervention group (n=225) or the control group (n=222). 377 (84%) participants completed follow-up for questionnaires at 6 months and 295 (66%) for questionnaires at 12 months. Women in the intervention group reported fewer prolapse symptoms (ie, a significantly greater reduction in the pelvic organ prolapse symptom score [POP-SS]) at 12 months than those in the control group (mean reduction in POP-SS from baseline 3.77 [SD 5.62] vs 2.09 [5.39]; adjusted difference 1.52, 95% CI 0.46-2.59; p=0.0053). Findings were robust to missing data. Eight adverse events (six vaginal symptoms, one case of back pain, and one case of abdominal pain) and one unexpected serious adverse event, all in women from the intervention group, were regarded as unrelated to the intervention or to participation in the study. INTERPRETATION: One-to-one pelvic floor muscle training for prolapse is effective for improvement of prolapse symptoms. Long-term benefits should be investigated, as should the effects in specific subgroups. FUNDING: Chief Scientist Office of the Scottish Government Health and Social Care Directorates, New Zealand Lottery Board, and National Health and Medical Research Council (Australia).

Evaluating pharmacological THRomboprophylaxis in Individuals undergoing superficial endoVEnous treatment across NHS and private clinics in the UK: a multi-centre, assessor-blind, randomised controlled trial-THRIVE trial.

INTRODUCTION: Endovenous therapy is the first choice management for symptomatic varicose veins in NICE guidelines, with 56-70 000 procedures performed annually in the UK. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a known complication of endovenous therapy, occurring at a rate of up to 3.4%. Despite 73% of UK practitioners administering pharmacological thromboprophylaxis to reduce VTE, no high-quality evidence supporting this practice exists. Pharmacological thromboprophylaxis may have clinical and cost benefit in preventing VTE; however, further evidence is needed. This study aims to establish whether when endovenous therapy is undertaken: a single dose or course of pharmacological thromboprophylaxis alters the risk of VTE; pharmacological thromboprophylaxis is associated with an increased rate of bleeding events; pharmacological prophylaxis is cost effective. METHODS AND ANALYSIS: A multi-centre, assessor-blind, randomised controlled trial (RCT) will recruit 6660 participants from 40 NHS and private sites across the UK. Participants will be randomised to intervention (single dose or extended course of pharmacological thromboprophylaxis plus compression) or control (compression alone). Participants will undergo a lower limb venous duplex ultrasound scan at 21-28 days post-procedure to identify asymptomatic DVT. The duplex scan will be conducted locally by blinded assessors. Participants will be contacted remotely for follow-up at 7 days and 90 days post-procedure. The primary outcome is imaging-confirmed lower limb DVT with or without symptoms or PE with symptoms within 90 days of treatment. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, using a repeated measures analysis of variance, adjusting for any pre-specified strongly prognostic baseline covariates using a mixed effects logistic regression. ETHICS AND DISSEMINATION: Ethical approval was granted by Brent Research Ethics Committee (22/LO/0261). Results will be disseminated in a peer-reviewed journal and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN18501431.

Examining the benefit of graduated compression stockings in the prevention of hospital-associated venous thromboembolism in low-risk surgical patients: a multicentre cluster randomised controlled trial (PETS trial).

INTRODUCTION: Hospital-acquired thrombosis (HAT) is defined as any venous thromboembolism (VTE)-related event during a hospital admission or occurring up to 90 days post discharge, and is associated with significant morbidity, mortality and healthcare-associated costs. Although surgery is an established risk factor for VTE, operations with a short hospital stay (<48 hours) and that permit early ambulation are associated with a low risk of VTE. Many patients undergoing short-stay surgical procedures and who are at low risk of VTE are treated with graduated compression stockings (GCS). However, evidence for the use of GCS in VTE prevention for this cohort is poor. METHODS AND ANALYSIS: A multicentre, cluster randomised controlled trial which aims to determine whether GCS are superior in comparison to no GCS in the prevention of VTE for surgical patients undergoing short-stay procedures assessed to be at low risk of VTE. A total of 50 sites (21 472 participants) will be randomised to either intervention (GCS) or control (no GCS). Adult participants (18-59 years) who undergo short-stay surgical procedures and are assessed as low risk of VTE will be included in the study. Participants will provide consent to be contacted for follow-up at 7-days and 90-days postsurgical procedure. The primary outcome is the rate of symptomatic VTE, that is, deep vein thrombosis or pulmonary embolism during admission or within 90 days. Secondary outcomes include healthcare costs and changes in quality of life. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, measured at an individual level, using hierarchical (multilevel) logistic regression. ETHICS AND DISSEMINATION: Ethical approval was granted by the Camden and Kings Cross Research Ethics Committee (22/LO/0390). Findings will be published in a peer-reviewed journal and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13908683.

The ALLEGRO trial: a placebo controlled randomised trial of intravenous lidocaine in accelerating gastrointestinal recovery after colorectal surgery.

BACKGROUND: Return of gastrointestinal (GI) function is fundamental to patient recovery after colorectal surgery and is required before patients can be discharged from hospital safely. Up to 40% of patients suffer delayed return of GI function after colorectal surgery, causing nausea, vomiting and abdominal discomfort, resulting in longer hospital stay. Small, randomised studies have suggested perioperative intravenous (IV) lidocaine, which has analgesic and anti-inflammatory effects, may accelerate return of GI function after colorectal surgery. The ALLEGRO trial is a pragmatic effectiveness study to assess the benefit of perioperative IV lidocaine in improving return of GI function after elective minimally invasive (laparoscopic or robotic) colorectal surgery. METHODS: United Kingdom (UK) multi-centre double blind placebo-controlled randomised controlled trial in 562 patients undergoing elective minimally invasive colorectal resection. IV lidocaine or placebo will be infused for 6-12 h commencing at the start of surgery as an adjunct to usual analgesic/anaesthetic technique. The primary outcome will be return of GI function. DISCUSSION: A 6-12-h perioperative intravenous infusion of 2% lidocaine is a cheap addition to usual anaesthetic/analgesic practice in elective colorectal surgery with a low incidence of adverse side-effects. If successful in achieving quicker return of gut function for more patients, it would reduce the rate of postoperative ileus and reduce the duration of inpatient recovery, resulting in reduced pain and discomfort with faster recovery and discharge from hospital. Since colorectal surgery is a common procedure undertaken in every acute hospital in the UK, a reduced length of stay and reduced rate of postoperative ileus would accrue significant cost savings for the National Health Service (NHS). TRIAL REGISTRATION: EudraCT Number 2017-003835-12; REC Number 17/WS/0210 the trial was prospectively registered (ISRCTN Number: ISRCTN52352431 ); date of registration 13 June 2018; date of enrolment of first participant 14 August 2018.

Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial.

BACKGROUND: The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. METHODS: RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. FINDINGS: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 µg budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3·1% (-11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). INTERPRETATION: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. FUNDING: National Institute for Health Research.

A pragmatic multi-centre randomised controlled trial of fluid loading in high-risk surgical patients undergoing major elective surgery--the FOCCUS study.

INTRODUCTION: Fluid strategies may impact on patient outcomes in major elective surgery. We aimed to study the effectiveness and cost-effectiveness of pre-operative fluid loading in high-risk surgical patients undergoing major elective surgery. METHODS: This was a pragmatic, non-blinded, multi-centre, randomised, controlled trial. We sought to recruit 128 consecutive high-risk surgical patients undergoing major abdominal surgery. The patients underwent pre-operative fluid loading with 25 ml/kg of Ringer's solution in the six hours before surgery. The control group had no pre-operative fluid loading. The primary outcome was the number of hospital days after surgery with cost-effectiveness as a secondary outcome. RESULTS: A total of 111 patients were recruited within the study time frame in agreement with the funder. The median pre-operative fluid loading volume was 1,875 ml (IQR 1,375 to 2,025) in the fluid group compared to 0 (IQR 0 to 0) in controls with days in hospital after surgery 12.2 (SD 11.5) days compared to 17.4 (SD 20.0) and an adjusted mean difference of 5.5 days (median 2.2 days; 95% CI -0.44 to 11.44; P = 0.07). There was a reduction in adverse events in the fluid intervention group (P = 0.048) and no increase in fluid based complications. The intervention was less costly and more effective (adjusted average cost saving: £2,047; adjusted average gain in benefit: 0.0431 quality adjusted life year (QALY)) and has a high probability of being cost-effective. CONCLUSIONS: Pre-operative intravenous fluid loading leads to a non-significant reduction in hospital length of stay after high-risk major surgery and is likely to be cost-effective. Confirmatory work is required to determine whether these effects are reproducible, and to confirm whether this simple intervention could allow more cost-effective delivery of care. TRIAL REGISTRATION: Prospective Clinical Trials, ISRCTN32188676.

Emergency contraception from the pharmacy 20 years on: a mystery shopper study.

BACKGROUND: Emergency contraception (EC) was approved in the UK as a pharmacy medicine for purchase without prescription in 2001. Twenty years later we conducted a study to characterise routine practice pharmacy provision of EC. STUDY DESIGN: Mystery shopper study of 30 pharmacies in Edinburgh, Dundee and London participating in a clinical trial of contraception after EC. METHODS: Mystery shoppers, aged ≥16 years, followed a standard scenario requesting EC. After the pharmacy visit, they completed a proforma recording the duration of the consultation, where it took place, and whether advice was given to them about the importance of ongoing contraception after EC. RESULTS: Fifty-five mystery shopper visits were conducted. The median reported duration of the consultation with the pharmacist was 6 (range 1-18) min. Consultations took place in a private room in 34 cases (62%) and at the shop counter in the remainder. In 27 cases (49%) women received advice about ongoing contraception. Eleven women (20%) left the pharmacy without EC due to lack of supplies or of a trained pharmacist. Most women were generally positive about the consultation. CONCLUSIONS: While availability of EC from UK pharmacies has undoubtedly improved access, the necessity to have a consultation, however helpful, with a pharmacist introduces delays and around one in five of our mystery shoppers left without getting EC. Consultations in private are not always possible and little advice is given about ongoing contraception. It is time to make EC available without a pharmacy consultation.

Examining the impact of oral hygiene advice and/or scale and polish on periodontal disease: the IQuaD cluster factorial randomised controlled trial.

Objective To compare the clinical effectiveness and cost benefit of different frequencies of scale and polish (S&P) treatments in combination with different types of oral hygiene advice (OHA).Design Multi-centre, multi-level cluster randomised factorial open trial with blinded outcome evaluation. UK dental practices were cluster randomised to deliver OHA as usual or personalised. In a separate randomisation, patients were allocated to receive S&P 6-monthly, 12-monthly or never.Setting UK primary dental care.Participants Practices providing NHS care and adults who had received regular dental check-ups.Main outcome measures The percent of sites with bleeding on probing, patient confidence in self-care, incremental net benefits (INB) over three years.Results Sixty-three practices and 1,877 adult patients were randomised and 1,327 analysed (clinical outcome). There was no statistically significant or clinically important difference in gingival bleeding between the three S&P groups (for example, six-monthly versus none: difference 0.87% sites, 95% CI: 1.6 to 3.3, p = 0.48) or between personalised or usual OHA groups (difference -2.5% sites, -95%CI: -8.3 to 3.3, p = 0.39), or oral hygiene self-efficacy (cognitive impact) between either group (for example, six-monthly versus none: difference -0.028, 95% CI -0.119 to 0.063, p = 0.543). The general population place a high value on, and are willing to pay for, S&P services. However, from a dental health perspective, none of the interventions were cost-effective.Conclusion Results suggest S&P treatments and delivering brief personalised OHA provide no clinical benefit and are therefore an inefficient approach to improving dental health (38% of sites were bleeding whatever intervention was received). However, the general population value both interventions.

Outcomes of a Noninferiority Randomised Controlled Trial of Surgery for Men with Urodynamic Stress Incontinence After Prostate Surgery (MASTER).

BACKGROUND: Stress urinary incontinence (SUI) is common after radical prostatectomy and likely to persist despite conservative treatment. The sling is an emerging operation for persistent SUI, but randomised controlled trial (RCT) comparison with the established artificial urinary sphincter (AUS) is lacking. OBJECTIVE: To compare the outcomes of surgery in men with bothersome urodynamic SUI after prostate surgery. DESIGN, SETTING, AND PARTICIPANTS: A noninferiority RCT was conducted among men with bothersome urodynamic SUI from 27 UK centres. Blinding was not possible due the surgeries. INTERVENTION: Participants were randomly assigned (1:1) to the male transobturator sling (n = 190) or the AUS (n = 190) group. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was patient-reported SUI 12 mo after randomisation, collected from postal questionnaire using a composite outcome from two items in validated International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form questionnaire (ICIQ-UI SF). Noninferiority margin was 15%, thought to be of acceptable lower effectiveness, in return for reduced adverse events (AEs) and easier operation, for the sling. Secondary outcomes were operative and postoperative details, patient-reported measures, and AEs, up to 12 mo after surgery. RESULTS AND LIMITATIONS: A total of 380 participants were included. At 12 mo after randomisation, incontinence rates were 134/154 (87.0%) for male sling versus 133/158 (84.2%) for AUS (difference 3.6% [95% confidence interval {CI} -11.6 to 4.6], pNI = 0.003), showing noninferiority. Incontinence symptoms (ICIQ-UI SF) reduced from scores of 16.1 and 16.4 at baseline to 8.7 and 7.5 for male sling and AUS, respectively (mean difference 1.4 [95% CI 0.2-2.6], p =  0.02). Serious AEs (SAEs) were few: n = 6 and n = 13 for male sling and AUS (one man had three SAEs), respectively. Quality of life scores improved, and satisfaction was high in both groups. All other secondary outcomes that show statistically significant differences favour the AUS. CONCLUSIONS: Using a strict definition, urinary incontinence rates remained high, with no evidence of difference between male sling and AUS. Symptoms and quality of life improved significantly in both groups, and men were generally satisfied with both procedures. Overall, secondary and post hoc analyses were in favour of AUS. PATIENT SUMMARY: Urinary incontinence after prostatectomy has considerable effect on men's quality of life. MASTER shows that if surgery is needed, both surgical options result in fewer symptoms and high satisfaction, despite most men not being completely dry. However, most other results indicate that men having an artificial urinary sphincter have better outcomes than those who have a sling.

Early diagnosis of brain tumours using a novel spectroscopic liquid biopsy.

Early diagnosis of brain tumours is challenging and a major unmet need. Patients with brain tumours most often present with non-specific symptoms more commonly associated with less serious diagnoses, making it difficult to determine which patients to prioritize for brain imaging. Delays in diagnosis affect timely access to treatment, with potential impacts on quality of life and survival. A test to help identify which patients with non-specific symptoms are most likely to have a brain tumour at an earlier stage would dramatically impact on patients by prioritizing demand on diagnostic imaging facilities. This clinical feasibility study of brain tumour early diagnosis was aimed at determining the accuracy of our novel spectroscopic liquid biopsy test for the triage of patients with non-specific symptoms that might be indicative of a brain tumour, for brain imaging. Patients with a suspected brain tumour based on assessment of their symptoms in primary care can be referred for open access CT scanning. Blood samples were prospectively obtained from 385 of such patients, or patients with a new brain tumour diagnosis. Samples were analysed using our spectroscopic liquid biopsy test to predict presence of disease, blinded to the brain imaging findings. The results were compared to the patient's index brain imaging delivered as per standard care. Our test predicted the presence of glioblastoma, the most common and aggressive brain tumour, with 91% sensitivity, and all brain tumours with 81% sensitivity, and 80% specificity. Negative predictive value was 95% and positive predictive value 45%. The reported levels of diagnostic accuracy presented here have the potential to improve current symptom-based referral guidelines, and streamline assessment and diagnosis of symptomatic patients with a suspected brain tumour.

The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix: the STOPPIT 2 RCT.

BACKGROUND: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. OBJECTIVE: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. DESIGN: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group - the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. SETTING: Antenatal clinics in the UK and elsewhere in Europe. PARTICIPANTS: Women with twin pregnancy at < 21 weeks' gestation with known chorionicity and gestation established by scan at ≤ 16 weeks' gestation. INTERVENTIONS: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0-20+ 6 weeks' gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. MAIN OUTCOME MEASURES: Obstetric - all births before 34+ 0 weeks' gestation following the spontaneous onset of labour; and neonatal - composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. RESULTS: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal 'easy' or 'fairly easy' in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. LIMITATIONS: There was the possibility of a type II error around smaller than anticipated benefit. CONCLUSIONS: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. FUTURE WORK: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. 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. 25, No. 44. See the NIHR Journals Library website for further project information.

Women who are pregnant with twins have a much higher risk of going into labour early and having an early (preterm) birth than women who are pregnant with only one baby. For this reason, babies who are twins are much more likely to die or to have serious health complications in the first months of life. Although we know that women with twin pregnancy are at risk, there are no treatments that are recommended to prevent early births. Some studies have suggested that the Arabin pessary can help. The Arabin pessary is a silicone ring that fits around the cervix (neck of the womb). The pessary can be put in place in a clinic without any need for an anaesthetic. Some studies have suggested that the Arabin pessary helps and others have suggested that it does not. It appears to be most helpful when the cervix (neck of the womb) is already shortening. Shortening of the neck of the womb is a sign that early birth is even more likely. We asked women with twin pregnancy to take part in STOPPIT 2. Women who agreed had an ultrasound scan of the neck of the womb, which measured its length. Those with a short cervix were randomised to be offered the Arabin pessary (in addition to standard care) or standard care alone. This allocation was carried out 'at random' by a computer. We followed women up until the end of their pregnancy and collected information on the babies' health after birth. We found that the Arabin pessary did not reduce the risk of an early birth; nor did it reduce the risk of health complications for the baby. We conclude that the Arabin pessary should not be used for this purpose.

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception: the Bridge-it RCT.

INTRODUCTION: Unless women start effective contraception after using emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies that are unable to provide ongoing contraception (apart from barrier methods which have high failure rates). This means that women need an appointment with a general practitioner or at a sexual and reproductive health clinic. We conducted a pragmatic cluster randomised cohort crossover trial to determine whether or not pharmacist provision of a bridging supply of a progestogen-only pill plus the invitation to attend a sexual and reproductive health clinic resulted in increased subsequent use of effective contraception (hormonal or intrauterine). METHODS: Twenty-nine pharmacies in three UK cities recruited women receiving emergency contraception (levonorgestrel). In the intervention, women received a 3-month supply of the progestogen-only pill (75 µg of desogestrel) plus a card that provided rapid access to a local sexual and reproductive health clinic. In the control arm, pharmacists advised women to attend their usual contraceptive provider. The primary outcome was reported use of an effective contraception (hormonal and intrauterine methods) at 4 months. Process evaluation was also conducted to inform any future implementation. RESULTS: The study took place December 2017 and June 2019 and recruited 636 women to the intervention (n = 316) and control groups (n = 320). There were no statistically significant differences in demographic characteristics between the groups. Four-month follow-up data were available for 406 participants: 63% (198/315) of the control group and 65% (208/318) of the intervention group. The proportion of participants reporting use of effective contraception was 20.1% greater (95% confidence interval 5.2% to 35.0%) in the intervention group (58.4%, 95% confidence interval 48.6% to 68.2%) than in the control group (40.5%, 95% confidence interval 29.7% to 51.3%) (adjusted for recruitment period, treatment arm and centre; p = 0.011). The proportion of women using effective contraception remained statistically significantly larger, when adjusted for age, current sexual relationship and history of past use of effective contraception, and was robust to the missing data. There were no serious adverse events. CONCLUSION: Provision of a bridging supply of the progestogen-only pill with emergency contraception from a pharmacist and the invitation to a sexual and reproductive health clinic resulted in a significant increase in self-reported subsequent use of effective contraception. This simple intervention has the potential to prevent more unintended pregnancies for women after emergency contraception. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70616901. 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. 25, No. 27. See the NIHR Journals Library website for further project information.

The emergency contraceptive pill can prevent pregnancy following unprotected sex or a burst condom; however, unless women start a regular method of contraception they remain at risk of pregnancy. Most women obtain emergency contraception from a community pharmacy (chemist), but then require an appointment with a general practitioner or at a sexual and reproductive health clinic for ongoing contraception. Getting an appointment can take time and unintended pregnancies can occur during this time. If a pharmacist could give women a small supply of a progestogen-only pill or 'mini-pill' with their emergency contraception, together with help to get an appointment at a clinic, then this might help more women to start effective contraception. We undertook a study in 29 pharmacies in Lothian, Tayside and London among women receiving emergency contraception. Pharmacists provided either their standard advice about contraception (control group) or the intervention. The intervention was a 3-month supply of the progestogen-only pill plus a rapid-access card, which, if presented at a sexual and reproductive health clinic, would help women get an appointment for contraception. The order in which the pharmacy provided either control or intervention was randomised. We conducted telephone interviews with the women 4 months later to find out what contraception they were using. A total of 636 women took part in the study, 316 in the intervention group and 320 in the control group. The proportion who said that they were using an effective method of contraception was around 20% larger in the intervention group. In addition, fewer women in this group said that they had used emergency contraception again. This study shows that community pharmacy provision of a small supply of progestogen-only pills and the invitation to attend a sexual and reproductive health clinic results in a large increase in the use of effective contraception after emergency contraception. If this became routine practice then it could help prevent unintended pregnancies.

Shockwave Lithotripsy Versus Ureteroscopic Treatment as Therapeutic Interventions for Stones of the Ureter (TISU): A Multicentre Randomised Controlled Non-inferiority Trial.

BACKGROUND: Renal stone disease is common and can cause emergency presentation with acute pain due to ureteric colic. International guidelines have stated the need for a multicentre randomised controlled trial (RCT) to determine whether a non-invasive outpatient (shockwave lithotripsy [SWL]) or surgical (ureteroscopy [URS]) intervention should be the first-line treatment for those needing active intervention. This has implications for shaping clinical pathways. OBJECTIVE: To report a pragmatic multicentre non-inferiority RCT comparing SWL with URS. DESIGN, SETTING, AND PARTICIPANTS: This trial tested for non-inferiority of up to two sessions of SWL compared with URS as initial treatment for ureteric stones requiring intervention. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was whether further intervention was required to clear the stone, and secondary outcomes included quality of life assessment, severity of pain, and serious complications; these were based on questionnaires at baseline, 8 wk, and 6 mo. We included patients over 16 yr with a single ureteric stone clinically deemed to require intervention. Intention-to-treat and per-protocol analyses were planned. RESULTS AND LIMITATIONS: The study recruited between July 1, 2013 and June 30, 2017. We recruited 613 participants from a total of 1291 eligible patients, randomising 306 to SWL and 307 to URS. Sixty-seven patients (22.1%) in the SWL arm needed further treatment compared with 31 patients (10.3%) in the URS arm. The absolute risk difference was 11.7% (95% confidence interval 5.6%, 17.8%) in favour of URS, which was inside the 20% threshold we set for demonstrating noninferiority of SWL. CONCLUSIONS: This RCT was designed to test whether SWL is non-inferior to URS and confirmed this; although SWL is an outpatient noninvasive treatment with potential advantages both for patients and for reducing the use of inpatient health care resources, the trial showed a benefit in overall clinical outcomes with URS compared with SWL, reflecting contemporary practice. The Therapeutic Interventions for Stones of the Ureter (TISU) study provides new evidence to help guide the choice of modality for this common health condition. PATIENT SUMMARY: We present the largest trial comparing ureteroscopy versus extracorporeal shockwave lithotripsy for ureteric stones. While ureteroscopy had marginally improved outcome in terms of stone clearance, as expected, shockwave lithotripsy had better results in terms of health care costs. These results should enable patients and health care providers to optimise treatment pathways for this common urological condition.

Study of progesterone for the prevention of preterm birth in twins (STOPPIT): findings from a trial-based cost-effectiveness analysis.

OBJECTIVES: Preterm birth contributes to a range of healthcare problems amongst infants surmounting to sizeable healthcare costs. Twin pregnancies are at particular risk of preterm birth. The objective of this study was to assess the cost-effectiveness of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies. METHODS: An economic evaluation was conducted alongside a randomized placebo controlled trial (the STOPPIT trial) of vaginal progesterone gel for the prevention of preterm birth in twin pregnancies. Five hundred women were recruited from nine maternity hospitals in the United Kingdom. The outcomes of the economic evaluation were presented in terms of net benefit statistics, cost-effectiveness acceptability curves, generated using the nonparametric bootstrap method, and the expected value of perfect information. RESULTS: Mean health service costs between the period of randomization and discharge for mother and infant were 28,031 pound sterling in the progesterone group and 25,972 pound sterling in the placebo group, generating a mean nonsignificant cost difference of 2,059 pound sterling (bootstrap mean cost difference 2,334 pound sterling; 95 percent confidence interval: -5,023 pound sterling, 9,142 pound sterling; p = .33). The probability of progesterone being cost-effective was 20 percent at a willingness to pay threshold of 30,000 pound sterling per preterm birth prevented. There is little economic justification for conducting further research into the use of vaginal progesterone gel in twin pregnancies for the prevention of preterm birth. CONCLUSIONS: Further studies of preventive interventions for preterm birth more generally are required given the scale of the clinical and economic burden of this condition. These studies should be sufficiently powered for economic endpoints and extend beyond hospital discharge.

Graduated compression stockings as adjuvant to pharmaco-thromboprophylaxis in elective surgical patients (GAPS study): randomised controlled trial.

OBJECTIVES: To investigate whether the use of graduated compression stockings (GCS) offers any adjuvant benefit when pharmaco-thromboprophylaxis is used for venous thromboembolism prophylaxis in patients undergoing elective surgery. DESIGN: Open, multicentre, randomised, controlled, non-inferiority trial. SETTING: Seven National Health Service tertiary hospitals in the United Kingdom. PARTICIPANTS: 1905 elective surgical inpatients (≥18 years) assessed as being at moderate or high risk of venous thromboembolism were eligible and consented to participate. INTERVENTION: Participants were randomly assigned (1:1) to receive low molecular weight heparin (LMWH) pharmaco-thromboprophylaxis alone or LMWH pharmaco-thromboprophylaxis and GCS. OUTCOME MEASURES: The primary outcome was imaging confirmed lower limb deep vein thrombosis with or without symptoms, or pulmonary embolism with symptoms within 90 days of surgery. Secondary outcome measures were quality of life, compliance with stockings and LMWH, lower limb complications related to GCS, bleeding complications, adverse reactions to LMWH, and all cause mortality. RESULTS: Between May 2016 and January 2019, 1905 participants were randomised. 1858 were included in the intention to treat analysis (17 were identified as ineligible after randomisation and 30 did not undergo surgery). A primary outcome event occurred in 16 of 937 (1.7%) patients in the LMWH alone group compared with 13 of 921 (1.4%) in the LMWH and GCS group. The risk difference between the two groups was 0.30% (95% confidence interval -0.65% to 1.26%). Because the 95% confidence interval did not cross the non-inferiority margin of 3.5% (P<0.001 for non-inferiority), LMWH alone was confirmed to be non-inferior. CONCLUSIONS: For patients who have elective surgery and are at moderate or high risk of venous thromboembolism, administration of pharmaco-thromboprophylaxis alone is non-inferior to a combination of pharmaco-thromboprophylaxis and GCS. These findings indicate that GCS might be unnecessary in most patients undergoing elective surgery. TRIAL REGISTRATION: ISRCTN13911492.

Surgical interventions for uterine prolapse and for vault prolapse: the two VUE RCTs.

BACKGROUND: New surgical approaches for apical prolapse have gradually been introduced, with few prospective randomised controlled trial data to evaluate their safety and efficacy compared with traditional methods. OBJECTIVE: To compare surgical uterine preservation with vaginal hysterectomy in women with uterine prolapse and abdominal procedures with vaginal procedures in women with vault prolapse in terms of clinical effectiveness, adverse events, quality of life and cost-effectiveness. DESIGN: Two parallel randomised controlled trials (i.e. Uterine and Vault). Allocation was by remote web-based randomisation (1 : 1 ratio), minimised on the need for concomitant anterior and/or posterior procedure, concomitant incontinence procedure, age and surgeon. SETTING: UK hospitals. PARTICIPANTS: Uterine trial - 563 out of 565 randomised women had uterine prolapse surgery. Vault trial - 208 out of 209 randomised women had vault prolapse surgery. INTERVENTIONS: Uterine trial - uterine preservation or vaginal hysterectomy. Vault trial - abdominal or vaginal vault suspension. MAIN OUTCOME MEASURES: The primary outcome measures were women's prolapse symptoms (as measured using the Pelvic Organ Prolapse Symptom Score), prolapse-specific quality of life and cost-effectiveness (as assessed by incremental cost per quality-adjusted life-year). RESULTS: Uterine trial - adjusting for baseline and minimisation covariates, the mean Pelvic Organ Prolapse Symptom Score at 12 months for uterine preservation was 4.2 (standard deviation 4.9) versus vaginal hysterectomy with a Pelvic Organ Prolapse Symptom Score of 4.2 (standard deviation 5.3) (mean difference -0.05, 95% confidence interval -0.91 to 0.81). Serious adverse event rates were similar between the groups (uterine preservation 5.4% vs. vaginal hysterectomy 5.9%; risk ratio 0.82, 95% confidence interval 0.38 to 1.75). There was no difference in overall prolapse stage. Significantly more women would recommend vaginal hysterectomy to a friend (odds ratio 0.39, 95% confidence interval 0.18 to 0.83). Uterine preservation was £235 (95% confidence interval £6 to £464) more expensive than vaginal hysterectomy and generated non-significantly fewer quality-adjusted life-years (mean difference -0.004, 95% confidence interval -0.026 to 0.019). Vault trial - adjusting for baseline and minimisation covariates, the mean Pelvic Organ Prolapse Symptom Score at 12 months for an abdominal procedure was 5.6 (standard deviation 5.4) versus vaginal procedure with a Pelvic Organ Prolapse Symptom Score of 5.9 (standard deviation 5.4) (mean difference -0.61, 95% confidence interval -2.08 to 0.86). The serious adverse event rates were similar between the groups (abdominal 5.9% vs. vaginal 6.0%; risk ratio 0.97, 95% confidence interval 0.27 to 3.44). The objective anterior prolapse stage 2b or more was higher in the vaginal group than in the abdominal group (odds ratio 0.38, 95% confidence interval 0.18 to 0.79). There was no difference in the overall prolapse stage. An abdominal procedure was £570 (95% confidence interval £459 to £682) more expensive than a vaginal procedure and generated non-significantly more quality-adjusted life-years (mean difference 0.004, 95% confidence interval -0.031 to 0.041). CONCLUSIONS: Uterine trial - in terms of efficacy, quality of life or adverse events in the short term, no difference was identified between uterine preservation and vaginal hysterectomy. Vault trial - in terms of efficacy, quality of life or adverse events in the short term, no difference was identified between an abdominal and a vaginal approach. FUTURE WORK: Long-term follow-up for at least 6 years is ongoing to identify recurrence rates, need for further prolapse surgery, adverse events and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86784244. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 13. See the National Institute for Health Research Journals Library website for further project information.

About 1 in 10 women has pelvic organ prolapse (POP) surgery, and around three of these women require a further operation. The aim of this study was to identify the most appropriate surgery for two different types of POP found in women: (1) when the uterus itself has come down ­ the Uterine trial ­ and (2) when a previous hysterectomy has resulted in the top of the vagina coming down ­ the Vault trial. In the Uterine trial, preserving the uterus was compared with removing it vaginally. In the Vault trial, uplifting and supporting the vault prolapse using an abdominal approach was compared with a vaginal approach. Women were asked about their prolapse and other symptoms affecting their quality of life (QoL). The majority of women reported that their prolapse symptoms and QoL improved after surgery. The women's prolapse was also measured by clinical examination before and 12 months after their operation. All of these results were compared between the different procedures. It was found that all the surgical procedures were successful within the 12-month review period. Abdominal surgery in the Vault trial as well as any that was required in the Uterine trial, was, however, slightly less cost-effective. Serious complications and the need for further prolapse surgery were similar in all groups. A small number of women did require additional surgery for prolapse recurrence or for small mesh exposure when additional or prolapse procedures had involved mesh. Women in both trials will be followed up for at least 6 years to determine longer-term costs and consequences.

Informing prevention of stillbirth and preterm birth in Malawi: development of a minimum dataset for health facilities participating in the DIPLOMATIC collaboration.

OBJECTIVE: The global research group, DIPLOMATIC (Using eviDence, Implementation science, and a clinical trial PLatform to Optimise MATernal and newborn health in low Income Countries), aims to reduce stillbirths and preterm births and optimise outcomes for babies born preterm. Minimum datasets for routine data collection in healthcare facilities participating in DIPLOMATIC (initially in Malawi) were designed to assist understanding of baseline maternal and neonatal care processes and outcomes, and facilitate evaluation of improvement interventions and pragmatic clinical trials. DESIGN: Published and grey literature was reviewed alongside extensive in-country consultation to define relevant clinical best practice guidance, and the existing local data and reporting infrastructure, to identify requirements for the minimum datasets. Data elements were subjected to iterative rounds of consultation with topic experts in Malawi and Scotland, the relevant Malawian professional bodies and the Ministry of Health in Malawi to ensure relevance, validity and feasibility. SETTING: Antenatal, maternity and specialist neonatal care in Malawi. RESULTS: The resulting three minimum datasets cover the maternal and neonatal healthcare journey for antenatal, maternity and specialist neonatal care, with provision for effective linkage of records for mother/baby pairs. They can facilitate consistent, precise recording of relevant outcomes (stillbirths, preterm births, neonatal deaths), risk factors and key care processes. CONCLUSIONS: Poor quality routine data on care processes and outcomes constrain healthcare system improvement. The datasets developed for implementation in DIPLOMATIC partner facilities reflect, and hence support delivery of, internationally agreed best practice for maternal and newborn care in low-income settings. Informed by extensive consultation, they are designed to integrate with existing local data infrastructure and reporting as well as meeting research data needs. This work provides a transferable example of strengthening data infrastructure to underpin a learning healthcare system approach in low-income settings.DIPLOMATIC is funded by the UK National Institute for Health Research.