Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial.

OBJECTIVE: To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. DESIGN: Parallel group, pragmatic randomised, superiority trial. SETTING: 20 secondary care centres in the UK. PARTICIPANTS: 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. INTERVENTIONS: Conservative management or surgical removal of the gallbladder. MAIN OUTCOME MEASURES: The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. RESULTS: Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval -1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference -£1033, (-$1334; -€1205), 95% credible interval -£1413 to -£632) and QALYs did not differ (mean difference -0.019, 95% credible interval -0.06 to 0.02). CONCLUSIONS: In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN55215960.

Assessment of Joint and Interactive Effects of Multimorbidity and Chronic Pain on ADRD Risk in the Elder Population.

Objective: Multimorbidity and non-cancer chronic pain conditions (NCPC) are independently linked to elevated risk for cognitive impairment and incident Alzheimer's Disease and Related Dementias (ADRD)-both - We present the study of potential joint and interactive effects of these conditions on the risk of incident ADRD in older population. Methods: This retrospective-cohort study drew baseline and 2-year follow-up data from linked Medicare claims and Medicare Current Beneficiary Survey (MCBS). Baseline multimorbidity and NCPC were ascertained using claims data. ADRD was ascertained at baseline and follow-up. Results: NCPC accompanied by multimorbidity (vs. absence of NCPC or multimorbidity) had a significant and upward association with incident ADRD (adjusted odds ratio (AOR): 1.72, 95% CI 1.38, 2.13, p < 0.0001). Secondary analysis by number of comorbid conditions suggested that the joint effects of NCPC and multimorbidity on ADRD risk may increase with rising number contributing chronic conditions. Interaction analyses indicated significantly elevated excess risk for incident ADRD.

Using re-randomisation designs to increase the efficiency and applicability of retention studies within trials: a case study.

BACKGROUND: Poor retention in randomised trials can lead to serious consequences to their validity. Studies within trials (SWATs) are used to identify the most effective interventions to increase retention. Many interventions could be applied at any follow-up time point, but SWATs commonly assess interventions at a single time point, which can reduce efficiency. METHODS: The re-randomisation design allows participants to be re-enrolled and re-randomised whenever a new retention opportunity occurs (i.e. a new follow-up time point where the intervention could be applied). The main advantages are as follows: (a) it allows the estimation of an average effect across time points, thus increasing generalisability; (b) it can be more efficient than a parallel arm trial due to increased sample size; and (c) it allows subgroup analyses to estimate effectiveness at different time points. We present a case study where the re-randomisation design is used in a SWAT. RESULTS: In our case study, the host trial is a dental trial with two available follow-up points. The Sticker SWAT tests whether adding the trial logo's sticker to the questionnaire's envelope will result in a higher response rate compared with not adding the sticker. The primary outcome is the response rate to postal questionnaires. The re-randomisation design could double the available sample size compared to a parallel arm trial, resulting in the ability to detect an effect size around 28% smaller. CONCLUSION: The re-randomisation design can increase the efficiency and generalisability of SWATs for trials with multiple follow-up time points.

The Effects of Cannabidiol on the Driving Performance of Healthy Adults: A Pilot RCT.

Introduction: A common side effect of cannabidiol is drowsiness, which could impact safe driving. This study's purpose was to determine the feasibility and whether cannabidiol impacts simulated driving performance. Methods: This was a randomized, parallel-group, sex-stratified, double-blind, pilot trial that consisted of a volunteer sample of healthy, currently driving college students. Participants were randomized and allocated to receive a placebo (n=19) or 300 mg cannabidiol (n=21) by oral syringe. Participants completed a ~40-minute driving simulation. A post-test survey assessed acceptability. The primary outcomes were mean SD of lateral position, total percent time the individual drove outside travel lanes, total collisions, time to initial collision, and mean brake reaction time. Outcomes were compared between groups using Student's t-tests and Cox proportional hazards models. Results: None of the relationships were statistically significant, but the study was underpowered. Those receiving cannabidiol experienced slightly more collisions (0.90 vs 0.68, p=0.57) and had slightly higher mean SD of lateral position and slower brake reaction times (0.60 vs 0.58 seconds, p=0.61) than those who received placebo. Participants were satisfied with their experiences. Conclusions: The design was feasible. Larger trials may be warranted because it is unclear whether the small differences in performance seen in the cannabidiol group were clinically relevant.

The effects of cannabidiol on subjective states, cognition, and psychomotor function in healthy adults: A randomized clinical trial.

Despite being added to numerous products, little is known about cannabidiol. Drowsiness is a self-reported side effect, which could impact cognitive functioning. To determine whether cannabidiol impacts cognition and psychomotor function, a volunteer sample of healthy, college students were recruited for this randomized, parallel-group, double-blind, feasibility trial from April-November 2021. Participants completed a baseline survey, the Stanford Sleepiness Scale, Visual Analog Mood Scale, Digit Symbol Substitution Test, Trail Making Test, Psychomotor Vigilance Test, and Simple Reaction Time Tests. Participants were then randomized and allocated to receive 300 mg cannabidiol oil (N = 21) or placebo (N = 19). After 120 min, participants retook the tests. Performance between groups was compared using Analysis of Covariance and multi-level Negative Binomial regression. Participants averaged 21 ± 3 years of age, and 52% were female. Self-reported anxiety did not change posttreatment. Performances on the Stanford Sleepiness Scale, Visual Analog Mood Scale, and Psychomotor Vigilance Test increased for both groups. After accounting for baseline scores, attention lapse duration significantly increased for those receiving cannabidiol compared to placebo in the Psychomotor Vigilance Test (76 vs. 66 ms; p = 0.02). Auditory reaction time improved in the cannabidiol group versus placebo for one sound emitted during the Simple Reaction Time Test (241 vs. 245 ms; p = 0.02), but the number of early responses increased from 0.3 to 0.8 for those receiving cannabidiol. While performance on most tests was similar between those receiving cannabidiol and placebo, cannabidiol might affect certain aspects of vigilance. More research and larger trials are needed.

Core outcome set for symptomatic uncomplicated gallstone disease.

BACKGROUND: Heterogeneity of outcomes is a problem for assessing intervention effectiveness when considering treatments for uncomplicated symptomatic gallstone disease. The value to all stakeholders of outcomes that have been measured and reported to date is also unclear. The aim of this study was to develop a core outcome set for symptomatic uncomplicated gallstone disease. METHODS: An in person-meeting was held with patients to prioritize potentially important outcomes from a previously developed longlist of outcomes. This was followed by an online three-round Delphi survey that was conducted with healthcare professionals. The results of each consensus process were compared and combined to produce the final core outcome set. RESULTS: A total of 82 participants enrolled in round 1 of the Delphi survey, with a final sample of 40 participants contributing to round 3. Five patients contributed to the in-person group meeting. Following the consensus processes, 11 outcomes were considered to be core by patients and healthcare professionals, and included in the core outcome set. These were: quality of life; overall health state; overall satisfaction; overall pain; common bile duct injury; biliary leak; haemorrhage; need for endoscopic retrograde cholangiopancreatography; intra-abdominal collections; admission/readmission for problems; and reoperation. CONCLUSION: A core outcome set for symptomatic uncomplicated gallstone disease has been developed with patients and healthcare professionals. Eleven outcomes across four key domains have been identified. These represent the minimum set of outcomes that should be reported in trials evaluating interventions for gallstone disease.

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.

Bah humbug! Association between sending Christmas cards to trial participants and trial retention: randomised study within a trial conducted simultaneously across eight host trials.

OBJECTIVES: To determine the effectiveness of sending Christmas cards to participants in randomised controlled trials to increase retention rate at follow-ups, and to explore the feasibility of doing a study within a trial (SWAT) across multiple host trials simultaneously. DESIGN: Randomised SWAT conducted simultaneously across eight host trials. SETTING: Eight randomised controlled trials researching various areas including surgery and smoking cessation. PARTICIPANTS: 3223 trial participants who were still due at least one follow-up from their host randomised controlled trial. INTERVENTION: Participants were randomised (1:1, separately by each host trial) to either received a Christmas card in mid-December 2019 or to not receive a card. MAIN OUTCOME MEASURE: Proportion of participants completing their next follow-up (retention rate) within their host randomised controlled trial. RESULTS: 1469 participants (age 16-94 years; 70% (n=1033) female; 96% (813/847) white ethnicity) across the eight host randomised controlled trials were involved in the analysis (cut short owing to covid-19). No evidence was found of a difference in retention rate between the two arms for any of the host trials when analysed separately or when the results were combined (85.3% (639/749) for cards versus 85.4% (615/720) for no card; odds ratio 0.96, 95% confidence interval 0.71 to 1.29; P=0.77). No difference was observed when comparing just participants who were due a follow-up in the 30 days after receiving the card (odds ratio 0.96, 0.42 to 2.21). No evidence of a difference in time to complete the questionnaire was found (hazard ratio 1.01, 95% confidence interval 0.91 to 1.13; P=0.80). These results were robust to post hoc sensitivity analyses. The cost of this intervention was £0.76 (€0.91; $1.02) per participant, and it will have a carbon footprint of approximately 140 g CO2 equivalent per card. One benefit of this approach was the need to only submit one ethics application. CONCLUSIONS: Sending Christmas cards to participants in randomised controlled trials does not increase retention. Undertaking a SWAT within multiple randomised controlled trials at the same time is, however, possible. This approach should be used more often to build an evidence base to support selection of recruitment and retention strategies. Although no evidence of a boost to retention was found, embedding a SWAT in multiple host trials simultaneously has been shown to be possible. STUDY REGISTRATION: SWAT repository https://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,846275,en.pdf#search=SWAT%2082.

Identification and categorisation of relevant outcomes for symptomatic uncomplicated gallstone disease: in-depth analysis to inform the development of a core outcome set.

BACKGROUND: Many completed trials of interventions for uncomplicated gallstone disease are not as helpful as they could be due to lack of standardisation across studies, outcome definition, collection and reporting. This heterogeneity of outcomes across studies hampers useful synthesis of primary studies and ultimately negatively impacts on decision making by all stakeholders. Core outcome sets offer a potential solution to this problem of heterogeneity and concerns over whether the 'right' outcomes are being measured. One of the first steps in core outcome set generation is to identify the range of outcomes reported (in the literature or by patients directly) that are considered important. OBJECTIVES: To develop a systematic map that examines the variation in outcome reporting of interventions for uncomplicated symptomatic gallstone disease, and to identify other outcomes of importance to patients with gallstones not previously measured or reported in interventional studies. RESULTS: The literature search identified 794 potentially relevant titles and abstracts of which 137 were deemed eligible for inclusion. A total of 129 randomised controlled trials, 4 gallstone disease specific patient-reported outcome measures (PROMs) and 8 qualitative studies were included. This was supplemented with data from 6 individual interviews, 1 focus group (n=5 participants) and analysis of 20 consultations. A total of 386 individual recorded outcomes were identified across the combined evidence: 330 outcomes (which were reported 1147 times) from trials evaluating interventions, 22 outcomes from PROMs, 17 outcomes from existing qualitative studies and 17 outcomes from primary qualitative research. Areas of overlap between the evidence sources existed but also the primary research contributed new, unreported in this context, outcomes. CONCLUSIONS: This study took a rigorous approach to catalogue and map the outcomes of importance in gallstone disease to enhance the development of the COS 'long' list. A COS for uncomplicated gallstone disease that considers the views of all relevant stakeholders is needed.

Providing trial results to participants in phase III pragmatic effectiveness RCTs: a scoping review.

BACKGROUND: There is an ethical imperative to offer the results of trials to those who participated. Existing research highlights that less than a third of trials do so, despite the desire of participants to receive the results of the trials they participated in. This scoping review aimed to identify, collate, and describe the available evidence relating to any aspect of disseminating trial results to participants. METHODS: A scoping review was conducted employing a search of key databases (MEDLINE, EMBASE, PsycINFO, and the Cumulative Index to Nursing & Allied Health Literature (CINAHL) from January 2008 to August 2019) to identify studies that had explored any aspect of disseminating results to trial participants. The search strategy was based on that of a linked existing review. The evidence identified describes the characteristics of included studies using narrative description informed by analysis of relevant data using descriptive statistics. RESULTS: Thirty-three eligible studies, including 12,700 participants (which included patients, health care professionals, trial teams), were identified and included. Reporting of participant characteristics (age, gender, ethnicity) across the studies was poor. The majority of studies investigated dissemination of aggregate trial results. The most frequently reported mode of disseminating of results was postal. Overall, the results report that participants evaluated receipt of trial results positively, with reported benefits including improved communication, demonstration of appreciation, improved retention, and engagement in future research. However, there were also some concerns about how well the dissemination was resourced and done, worries about emotional effects on participants especially when reporting unfavourable results, and frustration about the delay between the end of the trial and receipt of results. CONCLUSIONS: This scoping review has highlighted that few high-quality evaluative studies have been conducted that can provide evidence on the best ways to deliver results to trial participants. There have been relatively few qualitative studies that explore perspectives from diverse populations, and those that have been conducted are limited to a handful of clinical areas. The learning from these studies can be used as a platform for further research and to consider some core guiding principles of the opportunities and challenges when disseminating trial results to those who participated.

Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial).

BACKGROUND: Gallstone disease (cholelithiasis) is common. In most people it is asymptomatic and does not require treatment, but in about 20% it can become symptomatic, causing pain and other complications requiring medical attention and/or surgery. A proportion of symptomatic people with uncomplicated gallstone disease do not experience further episodes of pain and, therefore, could be treated conservatively. Moreover, surgery carries risks of perioperative and postoperative complications. METHODS AND ANALYSIS: C-Gall is a pragmatic, multicentre, randomised controlled trial and economic evaluation to assess whether cholecystectomy is cost-effective compared with observation/ conservative management (here after referred to as medical management) at 18 months post-randomisation (with internal pilot). PRIMARY OUTCOME MEASURE: Patient-reported quality of life (QoL) (36-Item Short Form Survey (SF-36) bodily pain domain) up to 18 months after randomisation.The primary economic outcome is incremental cost per quality-adjusted life year gained at 18 months. SECONDARY OUTCOME MEASURES: Secondary outcome measures include condition-specific QoL, SF-36 domains, complications, further treatment, persistent symptoms, healthcare resource use, and costs assessed at 18 and 24 months after randomisation. The bodily pain domain of the SF-36 will also be assessed at 24 months after randomisation.A sample size of 430 participants was calculated. Computer-generated 1:1 randomisation was used.The C-Gall Study is currently in follow-up in 20 UK research centres. The first patient was randomised on 1 August 2016, with follow-up to be completed by 30 November 2021. STATISTICAL ANALYSIS: Statistical analysis of the primary outcome will be intention-to-treat and a per-protocol analysis. The primary outcome, area under the curve (AUC) for the SF-36 bodily pain up to 18 months, will be generated using the Trapezium rule and analysed using linear regression with adjustment for the minimisation variables (recruitment site, sex and age). For the secondary outcome, SF-36 bodily pain, AUC up to 24 months will be analysed in a similar way. Other secondary outcomes will be analysed using generalised linear models with adjustment for minimisation and baseline variables, as appropriate. Statistical significance will be at the two-sided 5% level with corresponding CIs. ETHICS AND DISSEMINATION: The North of Scotland Research Ethics Committee approved this study (16/NS/0053). The dissemination plans include Health Technology Assessment monograph, international scientific meetings and publications in high-impact, open-access journals. TRIAL REGISTRATION NUMBER: ISRCTN55215960; pre-results.

Effect of hands-on interprofessional simulation training for local emergencies in Scotland: the THISTLE stepped-wedge design randomised controlled trial.

OBJECTIVE: To assess whether the implementation of an intrapartum training package (PROMPT (PRactical Obstetric Multi-Professional Training)) across a health service reduced the proportion of term babies born with Apgar score <7 at 5 min (<75mins). DESIGN: Stepped-wedge cluster randomised controlled trial. SETTING: Twelve randomised maternity units with ≥900 births/year in Scotland. Three additional units were included in a supplementary analysis to assess the effect across Scotland. The intervention commenced in March 2014 with follow-up until September 2016. INTERVENTION: The PROMPT training package (Second edition), with subsequent unit-level implementation of PROMPT courses for all maternity staff. MAIN OUTCOME MEASURES: The primary outcome was the proportion of term babies with Apgar<75mins. RESULTS: 87 204 eligible births (99.2% with an Apgar score), of which 1291 infants had an Apgar<75mins were delivered in the 12 randomised maternity units. Two units did not implement the intervention. The overall Apgar<75mins rate observed in the 12 randomised units was 1.49%, increasing from 1.32% preintervention to 1.59% postintervention. Once adjusted for a secular time trend, the 'intention-to-treat' analysis indicated a moderate but non-significant reduction in the rate of term babies with an Apgar scores <75mins following PROMPT training (OR=0.79 95%CI(0.63 to 1.01)). However, some units implemented the intervention earlier than their allocated step, whereas others delayed the intervention. The content and authenticity of the implemented intervention varied widely at unit level. When the actual date of implementation of the intervention in each unit was considered in the analysis, there was no evidence of improvement (OR=1.01 (0.84 to 1.22)). No intervention effect was detected by broadening the analysis to include all 15 large Scottish maternity units. Units with a history of higher rates of Apgar<75mins maintained higher Apgar rates during the study (OR=2.09 (1.28 to 3.41)) compared with units with pre-study rates aligned to the national rate. CONCLUSIONS: PROMPT training, as implemented, had no effect on the rate of Apgar <75mins in Scotland during the study period. Local implementation at scale was found to be more difficult than anticipated. Further research is required to understand why the positive effects observed in other single-unit studies have not been replicated in Scottish maternity units, and how units can be best supported to locally implement the intervention authentically and effectively. TRIAL REGISTRATION NUMBER: ISRCTN11640515.

Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT.

BACKGROUND: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. DESIGN: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. SETTING: The trial was conducted in 121 UK primary and secondary care sites. PARTICIPANTS: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year. INTERVENTIONS: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. PRIMARY OUTCOME: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. RESULTS: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. LIMITATIONS: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. CONCLUSION: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. FUTURE WORK: To promote consideration of the findings of this trial in national and international COPD guidelines. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620. 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. 23, No. 37. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that cannot be cured. The main symptom is shortness of breath on exertion. In the UK, about 1.2 million people have COPD. It is a major cause of death and costs the NHS > £1B a year. Sudden 'flare-ups' of symptoms often need emergency treatment, shorten life expectancy and reduce people's ability to get on with their lives. Theophylline is a drug that has been around for decades. In the past, it was used in high doses to treat COPD by opening up airways. However, its benefits were limited and it often caused unpleasant side effects. High-dose theophylline has been replaced by drugs administered by inhalers, such as inhaled corticosteroids (ICSs). Recent work in the laboratory and in animal models suggests that, at low dose, theophylline could make ICSs work better in COPD with none of the side effects of high-dose theophylline. The Theophylline With Inhaled CorticoSteroid (TWICS) trial tested whether or not adding low-dose theophylline reduces flare-ups in people with COPD taking ICSs. A total of 1578 people with COPD from 121 centres all over the UK took part. Participants were randomly divided into two groups: one group took low-dose theophylline and the other took dummy placebo pills. Participants were asked to attend visits at 6 and 12 months. A total of 791 participants were prescribed low-dose theophylline and 787 were prescribed dummy placebo pills. Although not everyone took the tablets for a whole year, it was possible to count the number of flare-ups in 98% of those taking part. In total, there were 3430 flare-ups. On average, the people taking low-dose theophylline had 2.24 flare-ups and the people taking placebo had 2.23 flare-ups. Overall, the trial showed that, for people with COPD, taking low-dose theophylline on top of steroid inhalers makes no real difference.

Estimating Site Performance (ESP): can trial managers predict recruitment success at trial sites? An exploratory study.

BACKGROUND: Multicentre randomised trials provide some of the key evidence underpinning healthcare practice around the world. They are also hard work and generally expensive. Some of this work and expense are devoted to sites that fail to recruit as many participants as expected. Methods to identify sites that will recruit to target would be helpful. METHODS: We asked trial managers at the Centre for Healthcare Randomised Trials (CHaRT), University of Aberdeen to predict whether a site would recruit to target. Predictions were made after a site initiation visit and were collected on a form comprising a simple 'Yes/No' prediction and a reason for the prediction. We did not provide guidance as to what trial managers might want to think about when making predictions. After a minimum of eight months of recruitment at each site for which a prediction had been made, all trial mangers in CHaRT were invited to a group discussion where predictions were presented together with sites' actual recruitment performance over that period. Individual trial managers reflected on their predictions and there was a general discussion about predicting site recruitment. The prediction reasons from the forms and the content of the group discussion were used to identify features linked to correct predictions of recruitment failure. RESULTS: Ten trial managers made predictions for 56 site visits recruiting to eight trials. Trial managers' sensitivity was 82% and their specificity was 32%, correctly identifying 65% of sites that would hit their recruitment target and 54% of those that did not. Eight 'red flags' for recruitment failure were identified: previous poor site performance; slow approvals process; strong staff/patient preferences; the site recruitment target; the trial protocol and its implementation at the site; lack of staff engagement; lack of research experience among site staff; and busy site staff. We used these red flags to develop a guided prediction form. CONCLUSIONS: Trial managers' unguided recruitment predictions were not bad but were not good enough for decision-making. We have developed a modified prediction form that includes eight flags to consider before making a prediction. We encourage anyone interested in contributing to its evaluation to contact us.

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.

Relative importance of informational items in participant information leaflets for trials: a Q-methodology approach.

OBJECTIVES: To identify which information items potential participants and research nurses rank as the most important, and the reasons for this, when considering participation in a randomised controlled trial. DESIGN: Q-methodology approach alongside a think-aloud process. Using a vignette outlining a hypothetical trial, participants were asked to rank statements about informational items usually included in a participant information leaflet (PIL) on a Q-grid, while undertaking a real-time think-aloud process to elicit the underpinning decision processes. Analysis of quantitative data was conducted using descriptive statistics and qualitative data was coded using content analysis. PARTICIPANTS: 20 participants (10 potential trial participants and 10 research nurses). SETTING: UK-based participants. RESULTS: Ten research nurses and 10 potential trial participants provided data for the study. Both stakeholder groups ranked similar statements in their top three most important statements, with 'What are the possible disadvantages and risks of taking part?' featuring in both. However, considerable variability existed between the groups with regard to their ranking of statements of least importance. Participants identified that sufficient information to make a decision was secured using around 14 items. Participants also identified other items of importance not routinely included in PILs. CONCLUSIONS: This study has provided a unique insight into how and why different trial stakeholder groups rank informational items currently contained within PILs. These results have implications for those developing future PILs and those who develop guidance on their content; PILs should focus most on the information items that potential trial participants want and need to make an informed choice about trial participation.

The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial.

BACKGROUND: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. METHODS/DESIGN: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). DISCUSSION: Final results of RESTART will be analysed and disseminated in 2019. TRIAL REGISTRATION: ISRCTN71907627 ( www.isrctn.com/ISRCTN71907627 ). Prospectively registered on 25 April 2013.

THISTLE: trial of hands-on Interprofessional simulation training for local emergencies: a research protocol for a stepped-wedge clustered randomised controlled trial.

BACKGROUND: Many adverse pregnancy outcomes in the UK could be prevented with better intrapartum care. Training for intrapartum emergencies has been widely recommended but there are conflicting data about their effectiveness. Observational studies have shown sustained local improvements in perinatal outcomes associated with the use of the PRactical Obstetric Multi-Professional Training - (PROMPT) training package. However this effect needs to be investigated in the context of randomised study design in settings other than enthusiastic early adopter single-centres. The main aim of this study is to determine the effectiveness of PROMPT to reduce the rate of term infants born with low APGAR scores. METHODS: THISTLE (Trial of Hands-on Interprofessional Simulation Training for Local Emergencies) is a multi-centre stepped-wedge clustered randomised controlled superiority trial conducted across 12 large Maternity Units in Scotland. On the basis of prior observational findings all Units have been offered the intervention and have been randomly allocated in groups of four Units, to one of three intervention time periods, each six months apart. Teams of four multi-professional clinicians from each participating Unit attended a two-day PROMPT Train the Trainers (T3) programme prior to the start of their allocated intervention step. Following the T3 training, the teams commenced the implementation of local intrapartum emergency training in their own Units by the start of their allocated intervention period. Blinding has not been possible due to the nature of the intervention. The aim of the study is to follow up each Unit for at least 12-months after they have commenced their local courses. The primary outcome for the study is the proportion of Apgar scores <7 at 5 min for term vaginal or emergency caesarean section births (≥37 weeks) occurring in each of the study Units. These data will be extracted from the Information Services Division Scottish Morbidity Record 02, a national routine data collection on pregnancy and births. Mixed or marginal logistic regression will be employed for the main analysis. DISCUSSION: THISTLE is the first stepped wedge cluster randomised trial to evaluate the effectiveness of an intrapartum emergencies training programme. The results will inform training, trainers and policy going forward. TRIAL REGISTRATION: ISRCTN11640515 (registered on 09/09/2013).

Perfluoroalkyl substances and beta cell deficient diabetes.

AIMS: Perfluoroalkyl substances (PFAS) are synthetic hydrocarbons shown to preserve pancreatic islet cell viability and reduce islet cell hypoxia and apoptosis. We investigated the relationship of serum PFAS with diabetes, and whether this varied by diabetes type. METHODS: 6,460 individuals with and 60,439 without diabetes from the C8 Health Project, were categorized into three groups: type 1 (n=820), type 2 (n=4,291), or uncategorized diabetes (n=1,349, missing data on diabetes type or diabetes based on blood sugar at study entry). Four PFAS were investigated: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononaoic acid (PFNA). RESULTS: PFAS levels were significantly lower in those with diabetes, and lowest in those with type 1 diabetes. In age and sex adjusted analyses, ORs (CI) for type 1, type 2, and uncategorized diabetes compared to no diabetes were 0.59 (0.54-0.64), 0.74 (0.71-0.77), 0.84 (0.78-0.90), respectively for PFHxS; 0.69 (0.65-0.74), 0.87 (0.89-0.91), 0.92 (0.88-0.97), respectively for PFOA; 0.65 (0.61-0.70), 0.86 (0.82-0.90), 0.93 (0.86-1.03), respectively for PFOS; and 0.65 (0.57-0.74), 0.94 (0.88-1.00), 0.95 (0.85-1.06), respectively for PFNA. Further adjustment for eGFR and other covariates did not eliminate these inverse associations. CONCLUSIONS: PFAS levels were negatively associated with diabetes. This inverse relationship was strongest for type 1 diabetes, suggesting the relationship with serum PFAS may vary with the severity of islet cell deficiency.

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.

BACKGROUND: Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset. METHODS: In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518. FINDINGS: 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group). INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients. FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.