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Abstract Background Laparoscopic surgery has become the preferred approach for many procedures because of reduced post-operative pain, better recovery, shorter hospital stay and improved cosmesis. Single incision laparoscopic surgery is one of the many recent variants where either standard ports or a specially designed single multi-channel port is introduced through a single skin incision. While the cosmetic advantage of this is obvious, the evidence base for claims of reduced morbidity and better post-operative recovery is weak. This study aims to compare the effectiveness of single port/incision laparoscopic appendicectomy with standard three-port laparoscopic appendicectomy in adult patients at six weeks post-surgery. We also wish to assess the feasibility of a multicentre randomised controlled trial comparing single port/incision laparoscopic surgery with standard three-port laparoscopic surgery for other surgical techniques. Methods and design Patients diagnosed with suspected appendicitis and requiring surgical treatment will be randomised to receive either standard three-port or single incision laparoscopic surgery. Data will be collected from clinical notes, operation notes and patient reported questionnaires. The following outcomes will be considered: 1. Effectiveness of the surgical procedure in terms of: •patient reported outcomes •clinical outcomes •resource use 2. Feasibility of conducting a randomised controlled trial (RCT) in the emergency surgical setting by quantifying: •patient eligibility •randomisation acceptability •feasibility of blinding participants to the intervention received •completion rates of case report forms and patient reported questionnaires Trial registration ISRCTN66443895 (assigned 10 March 2011, first patient randomised 09 January 2011)

Abstract Background Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care. EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care. Methods/Design EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible. The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events. A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate. Trial Registration: ISRCTN44464607.

Abstract Randomised controlled trials (RCTs) are generally regarded as the gold standard for evaluating health care interventions. The level of uncertainty around a trial's estimate of effect is, however, frequently linked to how successful the trial has been in recruiting and retaining participants. As recruitment is often slower or more difficult than expected, with many trials failing to reach their target sample size within the timescale and funding originally envisaged, the results are often less reliable than they could have been. The high number of trials that require an extension to the recruitment period in order to reach the required sample size potentially delays the introduction of more effective therapies into routine clinical practice. Moreover, it may result in less research being undertaken as resources are redirected to extending existing trials rather than funding additional studies. Poor recruitment to publicly-funded RCTs has been much debated but there remains remarkably little clear evidence as to why many trials fail to recruit well, which recruitment methods work, in which populations and settings and for what type of intervention. One proposed solution to improving recruitment and retention is to adopt methodology from the business world to inform and structure trial management techniques. We review what is known about interventions to improve recruitment to trials. We describe a proposed business approach to trials and discuss the implementation of using a business model, using insights gained from three case studies.

Abstract Background A full-thickness macular hole (FTMH) is a common retinal condition associated with impaired vision. Randomised controlled trials (RCTs) have demonstrated that surgery, by means of pars plana vitrectomy and post-operative intraocular tamponade with gas, is effective for stage 2, 3 and 4 FTMH. Internal limiting membrane (ILM) peeling has been introduced as an additional surgical manoeuvre to increase the success of the surgery; i.e. increase rates of hole closure and visual improvement. However, little robust evidence exists supporting the superiority of ILM peeling compared with no-peeling techniques. The purpose of FILMS (Full-thickness macular hole and Internal Limiting Membrane peeling Study) is to determine whether ILM peeling improves the visual function, the anatomical closure of FTMH, and the quality of life of patients affected by this disorder, and the cost-effectiveness of the surgery. Methods/Design Patients with stage 2–3 idiopathic FTMH of less or equal than 18 months duration (based on symptoms reported by the participant) and with a visual acuity ≤ 20/40 in the study eye will be enrolled in this FILMS from eight sites across the UK and Ireland. Participants will be randomised to receive combined cataract surgery (phacoemulsification and intraocular lens implantation) and pars plana vitrectomy with postoperative intraocular tamponade with gas, with or without ILM peeling. The primary outcome is distance visual acuity at 6 months. Secondary outcomes include distance visual acuity at 3 and 24 months, near visual acuity at 3, 6, and 24 months, contrast sensitivity at 6 months, reading speed at 6 months, anatomical closure of the macular hole at each time point (1, 3, 6, and 24 months), health related quality of life (HRQOL) at six months, costs to the health service and the participant, incremental costs per quality adjusted life year (QALY) and adverse events. Discussion FILMS will provide high quality evidence on the role of ILM peeling in FTMH surgery. Trial registration This trial is registered with Current Controlled Trials ISRCTN number 33175422 and Clinical Trials.gov identifier NCT00286507.

Abstract Background Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Methods Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. Results The case study demonstrates that trials need various categories of people to buy in – hence, to be successful, trialists must embrace marketing strategies to some extent. Conclusion The performance of future clinical trials could be enhanced if trialists routinely considered these factors.

Abstract Background Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). Methods In-depth semi-structured telephone interviews were conducted in 2003–04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. Results The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. Conclusion This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

Abstract Background A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. Methods The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. Results Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. Conclusion Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Background: Clinical trials commonly have a dedicated trial manager and effective trial management is essential to the successful delivery of high-quality trials. Trial managers have diverse experience and currently there is no standardised structured career pathway. The UK Trial Managers' Network (UKTMN) surveyed its members to understand what is important to them with respect to career development since this would be important in the development of any initiative intended to develop a skilled workforce.Methods: We conducted an online survey of UKTMN members, who are trial management professionals, working on academic-led trials in the UK. Members were asked what they perceive as opportunities and barriers to career development. Two reminders were sent to facilitate completion of the survey, and responders were offered the opportunity to enter a prize draw for waived fees at the UKTMN annual meeting. Data were analysed descriptively by using Stata (version 15.1), and free-text responses were reviewed for themes.Results: The survey was sent to 819 UKTMN members; 433 responses were received, although 13 were from non-UKTMN members; thus 420 respondents' data were included in analyses. Respondents were representative of UKTMN membership; however, more responses were received by trial managers based in registered clinical trials units (CTUs). The top three opportunities for career development were (i) training, (ii) helping design trials and (iii) undertaking relevant qualifications. The top three barriers were (i) funding, (ii) few opportunities to get involved in development activities aside from managing a trial and (iii) unclear organisational career pathway. Almost all respondents (401/420, 95.4%) considered career development either very or quite important. Although all respondents had a day-to-day role in managing trials, there was huge disparity between job titles.Conclusion: Career development is important to trial managers yet there is a lack of a structured pathway. The enablers and disablers to career development for trial managers should be clearly considered by the clinical trial community and, in particular, employers, sponsors and funders in order to develop a highly skilled workforce of trial managers, who are key to the delivery of trials. [ABSTRACT FROM AUTHOR]

Background: Heavy menstrual bleeding (HMB) is a common problem affecting approximately 1.5 million women in England and Wales with a major impact on their physical, emotional, social and material quality of life. It is the fourth most common reason why women attend gynaecology outpatient clinics and accounts for one-fifth of all gynaecology outpatient referrals. Initial treatment in primary care is medical - either by means of oral or injected medication or the levonorgestrel-intrauterine system (Mirena®). If medical treatment fails then surgical treatment can be offered, either endometrial ablation (EA), which destroys the lining of the cavity of the uterus (endometrium), or hysterectomy, i.e. surgical removal of the uterus. While effective, conventional hysterectomy is invasive and carries a risk of complications due to injury to other pelvic structures. The procedure can be simplified and complications minimised by undertaking a 'supracervical' hysterectomy where the cervix is left in situ and only the body of the uterus removed. Recent advances in endoscopic technologies have facilitated increased use of laparoscopic supracervical hysterectomy (LASH) which can be performed as a day-case procedure and is relatively easy for the surgeon to learn. HEALTH (Hysterectomy or Endometrial AbLation Trial for Heavy menstrual bleeding) aims to address the question 'Is LASH superior to second generation EA for the treatment of HMB in terms of clinical and cost effectiveness?'Methods/design: Women aged < 50 years, with HMB, in whom medical treatment has failed and who are eligible for EA will be considered for trial entry. We aim to recruit women from approximately 30 active secondary care centres in the UK NHS who carry out both surgical procedures. All women who consent will complete a diary of pain symptoms from day 1 to day 14 after surgery, postal questionnaires at six weeks and six months after surgery and 15 months post randomisation. Healthcare utilisation questions will also be completed at the six-week, six-month and 15-month time-points.Discussion: Measuring the comparative effectiveness of LASH vs EA will provide the robust evidence required to determine whether the new technique should be adopted widely in the NHS.Trial Registration: International Standard Randomised Controlled Trials, ISRCTN49013893 . Registered on 28 January 2014. [ABSTRACT FROM AUTHOR]

Background Urinary stone disease is common, with an estimated prevalence among the general population of 2% to 3%. Ureteric stones can cause severe pain and have a significant impact on quality of life, accounting for over 15,000 hospital admissions in England annually. Uncomplicated cases of smaller stones in the lower ureter are traditionally treated expectantly. Those who fail standard care or develop complications undergo active treatment, such as extracorporeal shock wave lithotripsy or ureteroscopy with stone retrieval. Such interventions are expensive, require urological expertise and carry a risk of complications. Growing understanding of ureteric function and pathophysiology has led to the hypothesis that drugs causing relaxation of ureteric smooth muscle, such as the selective α-blocker tamsulosin and the calcium-channel blocker nifedipine, can enhance the spontaneous passage of ureteric stones. The use of drugs in augmenting stone passage, reducing the morbidity and costs associated with ureteric stone disease, is promising. However, the majority of clinical trials conducted to date have been small, poor to moderate quality and lacking in comprehensive economic evaluation. This trial aims to determine the clinical and cost-effectiveness of tamsulosin and nifedipine in the management of symptomatic urinary stones. Methods/design The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial is a multicentre, double-blind, randomized controlled trial evaluating two medical expulsive therapy strategies (nifedipine or tamsulosin) versus placebo. Patients aged 18 to 65 with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder will be randomized to receive nifedipine, tamsulosin or placebo (400 participants per arm) for a maximum of 28 days. The primary clinical outcome is spontaneous passage of ureteric stones at 4 weeks (defined as no further intervention required to facilitate stone passage). The primary economic outcome is a reduction in the incremental cost per quality-adjusted life years, determined at 12 weeks. The analysis will be based on all participants as randomized (intention to treat). The trial has 90% power with a type I error rate of 5% to detect a 10% increase in primary outcome between the tamsulosin and nifedipine treatment groups. [ABSTRACT FROM AUTHOR]

Background Postal questionnaires are simple and economical for collecting outcome data for randomised controlled trials (RCTs) but are prone to non-response. In the RECORD trial (a large pragmatic publicly funded RCT in UK) non-responders were sent a reminder and another questionnaire at 1 year, of which 40% were returned. In subsequent years we investigated the effect of an advance telephone call to non-responders on responses rate to reminder questionnaires and the next questionnaire 4 months later. Methods Non-responders to annual questionnaires were randomised to receive a telephone call from the trial office ahead of the reminder questionnaire in addition to the usual reminder schedule (n = 390) or to a control group that received the usual reminder schedule only (n = 363). The primary outcome was response to the reminder questionnaire within 21 days; secondary outcomes were response to a questionnaire 4 months later; completeness of quality of life instruments; and the number of participants declining further follow-up. Results are presented as odds ratios from a logistic regression intention-to-treat (ITT) analysis and then percentage difference and 95% confidence intervals (CI) for both ITT and average treatment effect on the treated (ATT) analyses. Results The proportions that responded were 67.8% (265/390) in the intervention group compared to 62.5% (227/363) in the control group. The ITT estimate was a 5.4% increase (95% CI -1.4 to 12.2). Four months later percentages responding were 51.8% (202) and 42.7% (155). The ITT estimate was a 9.1% increase (95% CI 2.0 to 16.2). In the intervention group 12.3% (48/390) of participants were not telephoned because questionnaires were returned before the scheduled telephone call. ATT estimates adjusting for this were 6.2% (95% CI -1.6 to 14.0) and 10.4% (95% CI 2.2 to 18.5), respectively. Conclusions The telephone call resulted in a slight increase in response to the reminder questionnaire, however at 4 months later the proportion in the telephoned group responding was greater. This study suggests that pre-notification telephone calls may only be worthwhile if further questionnaires are to be sent out soon after reminder questionnaires. Trial registration Current Clinical Trials ISRCTN51647438 [ABSTRACT FROM AUTHOR]

Background: Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care.Methods/design: EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate.Trial Registration: ISRCTN44464607. [ABSTRACT FROM AUTHOR]

Background: Postal questionnaires are simple and economical for collecting outcome data for randomised controlled trials (RCTs) but are prone to non-response. In the RECORD trial (a large pragmatic publicly funded RCT in UK) non-responders were sent a reminder and another questionnaire at 1 year, of which 40% were returned. In subsequent years we investigated the effect of an advance telephone call to non-responders on responses rate to reminder questionnaires and the next questionnaire 4 months later.Methods: Non-responders to annual questionnaires were randomised to receive a telephone call from the trial office ahead of the reminder questionnaire in addition to the usual reminder schedule (n=390) or to a control group that received the usual reminder schedule only (n=363). The primary outcome was response to the reminder questionnaire within 21 days; secondary outcomes were response to a questionnaire 4 months later; completeness of quality of life instruments; and the number of participants declining further follow-up. Results are presented as odds ratios from a logistic regression intention-to-treat (ITT) analysis and then percentage difference and 95% confidence intervals (CI) for both ITT and average treatment effect on the treated (ATT) analyses.Results: The proportions that responded were 67.8% (265/390) in the intervention group compared to 62.5% (227/363) in the control group. The ITT estimate was a 5.4% increase (95% CI -1.4 to 12.2). Four months later percentages responding were 51.8% (202) and 42.7% (155). The ITT estimate was a 9.1% increase (95% CI 2.0 to 16.2). In the intervention group 12.3% (48/390) of participants were not telephoned because questionnaires were returned before the scheduled telephone call. ATT estimates adjusting for this were 6.2% (95% CI -1.6 to 14.0) and 10.4% (95% CI 2.2 to 18.5), respectively.Conclusions: The telephone call resulted in a slight increase in response to the reminder questionnaire, however at 4 months later the proportion in the telephoned group responding was greater. This study suggests that pre-notification telephone calls may only be worthwhile if further questionnaires are to be sent out soon after reminder questionnaires.Trial Registration: Current Clinical Trials ISRCTN51647438. [ABSTRACT FROM AUTHOR]

Background: Urinary stone disease is common, with an estimated prevalence among the general population of 2% to 3%. Ureteric stones can cause severe pain and have a significant impact on quality of life, accounting for over 15,000 hospital admissions in England annually. Uncomplicated cases of smaller stones in the lower ureter are traditionally treated expectantly. Those who fail standard care or develop complications undergo active treatment, such as extracorporeal shock wave lithotripsy or ureteroscopy with stone retrieval. Such interventions are expensive, require urological expertise and carry a risk of complications.Growing understanding of ureteric function and pathophysiology has led to the hypothesis that drugs causing relaxation of ureteric smooth muscle, such as the selective α-blocker tamsulosin and the calcium-channel blocker nifedipine, can enhance the spontaneous passage of ureteric stones. The use of drugs in augmenting stone passage, reducing the morbidity and costs associated with ureteric stone disease, is promising. However, the majority of clinical trials conducted to date have been small, poor to moderate quality and lacking in comprehensive economic evaluation.This trial aims to determine the clinical and cost-effectiveness of tamsulosin and nifedipine in the management of symptomatic urinary stones.Methods/design: The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial is a multicentre, double-blind, randomized controlled trial evaluating two medical expulsive therapy strategies (nifedipine or tamsulosin) versus placebo.Patients aged 18 to 65 with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder will be randomized to receive nifedipine, tamsulosin or placebo (400 participants per arm) for a maximum of 28 days. The primary clinical outcome is spontaneous passage of ureteric stones at 4 weeks (defined as no further intervention required to facilitate stone passage). The primary economic outcome is a reduction in the incremental cost per quality-adjusted life years, determined at 12 weeks. The analysis will be based on all participants as randomized (intention to treat). The trial has 90% power with a type I error rate of 5% to detect a 10% increase in primary outcome between the tamsulosin and nifedipine treatment groups.Trial Registration: ISRCTN69423238; EudraCT number: 2010-019469-26. [ABSTRACT FROM AUTHOR]

Background: A full-thickness macular hole (FTMH) is a common retinal condition associated with impaired vision. Randomised controlled trials (RCTs) have demonstrated that surgery, by means of pars plana vitrectomy and post-operative intraocular tamponade with gas, is effective for stage 2, 3 and 4 FTMH. Internal limiting membrane (ILM) peeling has been introduced as an additional surgical manoeuvre to increase the success of the surgery; i.e. increase rates of hole closure and visual improvement. However, little robust evidence exists supporting the superiority of ILM peeling compared with no-peeling techniques. The purpose of FILMS (Full-Thickness Macular Hole and Internal Limiting Membrane Peeling Study) is to determine whether ILM peeling improves the visual function, the anatomical closure of FTMH, and the quality of life of patients affected by this disorder, and the cost-effectiveness of the surgery.Methods/design: Patients with stage 2-3 idiopathic FTMH of less or equal than 18 months duration (based on symptoms reported by the participant) and with a visual acuity Discussion: FILMS will provide high quality evidence on the role of ILM peeling in FTMH surgery.Trial Registration: This trial is registered with Current Controlled Trials ISRCTN number 33175422 and Clinical Trials.gov identifier NCT00286507. [ABSTRACT FROM AUTHOR]