Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.

INTRODUCTION: Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs? METHODS AND ANALYSIS: We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study. ETHICS AND DISSEMINATION: The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums. TRANSLATIONAL ASPECTS: The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns. ARTICLE SUMMARY: The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns. TRIAL REGISTRATION NUMBERS: EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.

Comparative costs and activity from a sample of UK clinical trials units.

BACKGROUND: The costs of medical research are a concern. Clinical Trials Units (CTUs) need to better understand variations in the costs of their activities. METHODS: Representatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over 1.5 years. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5-year, nonpharmacological randomized controlled trial (RCT) conducted at 20 centres. Direct and indirect costs, the number of full time equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen's κ. RESULTS: Median full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU, which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair (κ = 0.21-0.40) for statisticians/data managers and poor for other roles (κ < 0.20). CONCLUSIONS: Some variation in costs is due to factors outside the control of CTUs such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies.

An external pilot study to test the feasibility of a randomised controlled trial comparing eye muscle surgery against active monitoring for childhood intermittent exotropia [X(T)].

INTRODUCTION: The evidence base for the treatment of strabismus (squint) is poor. Our main aim is to improve this evidence base for the treatment of a common type of childhood squint {intermittent exotropia, [X(T)]}. We conducted an external pilot study in order to inform the design and conduct of a future full randomised controlled trial (RCT). METHODS: Children of between 6 months and 16 years with a recent diagnosis of X(T) were eligible for recruitment. Participants were recruited from secondary care at the ophthalmology departments at four UK NHS foundation trusts. Participants were randomised to either active monitoring or surgery. This report describes the findings of the Pilot Rehearsal Trial and Qualitative Study, and assesses the success against the objectives proposed. RECRUITMENT AND RETENTION: The experience gained during the Pilot Rehearsal Trial demonstrates the ability to recruit and retain sites that are willing to randomise children to both trial arms, and for parents to agree to randomisation of their children to such a study. One child declined the group allocation. A total of 231 children were screened (expected 240), of whom 138 (60%) were eligible (expected 228: 95%) and 49 (35% of eligible) children were recruited (expected 144: 63% of eligible). Strategies that improved recruitment over the course of the trial are discussed, together with the reasons why fewer children were eligible for recruitment than initially anticipated. Attrition was low. Outcome data were obtained for 47 of 49 randomised children. TRIAL PROCESSES AND DATA COLLECTION: The Trial Management processes proved effective. There were high levels of completion on all of the data collection forms. However, the feedback from the treatment orthoptists revealed that some modifications should be made to the length and frequency of the health service assessment and travel assessment questionnaires, thus reducing the burden on participants in the main trial. Modifications to the wording of the questions also need to be made. MONITORING OF BIAS: Children who recruited to the trial were older and had more severe strabismus than those children eligible but declining participation. Strategies to account for this in a full trial are proposed. REASONS FOR PARTICIPATION OR DECLINING STUDY: These were identified using qualitative interviews. The principal reasons for declining entry into the study were strong preferences for and against surgical treatment. HARMS: There were no serious unexpected adverse events. Two children had overcorrection of their X(T) with reduction in binocular vision following surgery, which is in line with previous studies. No children in the active monitoring arm developed a constant strabismus although two showed some reduction in control. CONCLUSIONS: The SamExo study has demonstrated that it is possible to recruit and retain participants to a randomised trial of surgery compared with active monitoring for X(T). For longer-term full RCTs, in order to maximise the generalisability of future studies, consideration needs to be given to planning more time and clinic appointments to assess eligibility and to allow consideration of participation; the greater use of research nurses for recruitment; and accommodating the strong preferences of some parents both for and against surgical intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44114892. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 39. See the NIHR Journals Library website for further project information.

Surrendering control, or nothing to lose: Parents' preferences about participation in a randomised trial of childhood strabismus surgery.

BACKGROUND: Intermittent exotropia is the most common form of divergent strabismus (squint) in children. Evidence regarding its optimum management is limited. A pilot randomised controlled trial has recently been completed (Surgery versus Active Monitoring in Intermittent Exotropia trial) to determine the feasibility of a full randomised controlled trial. PURPOSE: To identify drivers for and barriers against parents' participation in Surgery versus Active Monitoring in Intermittent Exotropia and to seek their views on information received, the need for randomisation, and enhancing acceptability. METHODS: Multiple method qualitative study using semi-structured telephone interviews to explore parents' motivations and trial screening logs to provide an indication of common barriers. Exploratory thematic analysis identified key themes. RESULTS: A total of 48 interviews were conducted (14 participants; 34 non-participants). Barriers included no desire for surgery/preference to 'wait and see', wanting surgery immediately, feeling uncomfortable about 'surrendering control' over decision-making/being managed 'at random', lack of confidence in the effectiveness of surgery, believing the risks outweighed the benefits, and lack of trust. Drivers included desiring surgery, 'nothing to lose', benefits offsetting the risks, and being in a trial would result in better care. Some also mentioned 'doing their bit' for research. Suggestions for enhancing acceptability included allowing choice of treatment group, giving more time for decision-making, expanding on information given, and improving communication. Many felt the necessity of randomisation was adequately explained, but there was some indication that it was misunderstood. Information extracted from the screening logs of 80/89 eligible non-participants indicated the most prevalent barrier was not wanting surgery/preferring to observe (56%), followed by desiring surgery straightaway (15%). Opposition to randomisation/wanting to retain control was recorded in 9% of cases as was the belief that the child's squint was not severe enough to warrant surgery. LIMITATIONS: Interviews were not audio-recorded. Not all who consented to interview could be contacted, although the response/contact rate was good (48/62). A few parents did not provide reasons for refusing the trial. CONCLUSION: Opposition to surgery and concerns about surrendering control were common obstacles to participation, whereas parents keen for their child to undergo the operation but happy to defer tended to embrace a 'nothing to lose' attitude. Many non-participants would have consented if allowed to choose group, although most of these would have chosen observation. While most parents felt happy with information given and that randomisation was adequately explained, it is of concern that there may be some misunderstanding, which should be addressed in any trial. These findings will inform future trials in childhood exotropia, for example, consideration of preference arms and improving communication. Lessons learnt from the Surgery versus Active Monitoring in Intermittent Exotropia trial could prove valuable to paediatric and surgical trials generally.

Intervention to reduce excessive alcohol consumption and improve comorbidity outcomes in hypertensive or depressed primary care patients: two parallel cluster randomized feasibility trials.

BACKGROUND: Many primary care patients with raised blood pressure or depression drink potentially hazardous levels of alcohol. Brief interventions (BI) to reduce alcohol consumption may improve comorbid conditions and reduce the risk of future alcohol problems. However, research has not established their effectiveness in this patient population. This study aimed to establish the feasibility of definitive trials of BI to reduce excessive drinking in primary care patients with hypertension or mild to moderate depression. METHODS: Thirteen general practices in North East England were randomized to the intervention or control arm of one of two parallel pilot trials. Adult patients drinking excessively and diagnosed with hypertension or mild-to-moderate depression received the Alcohol Use Disorders Identification Test (AUDIT) by postal survey. Consenting respondents scoring more than 7 on AUDIT (score range 0 to 40) received brief alcohol consumption advice plus an information leaflet (intervention) or an information leaflet alone (control) with follow-up at six months. Measurements included the numbers of patients eligible, recruited, and retained, and the AUDIT score and systolic/diastolic blood pressure of each patient or the nine-item Patient Health Questionnaire (PHQ-9) score. Acceptability was assessed via practitioner feedback and patient willingness to be screened, recruited, and retained at follow-up. RESULTS: In the hypertension trial, 1709 of 33,813 adult patients (5.1%) were eligible and were surveyed. Among the eligible patients, 468 (27.4%) returned questionnaires; 166 (9.6% of those surveyed) screened positively on AUDIT and 83 (4.8% of those surveyed) were recruited (50.0% of positive screens). Sixty-seven cases (80.7% of recruited patients) completed follow-up at six months. In the depression trial, 1,044 of 73,146 adult patients (1.4%) were eligible and surveyed. Among these eligible patients, 215 (20.6%) responded; 104 (10.0% of those surveyed) screened positively on AUDIT and 29 (2.8% of those surveyed) were recruited (27.9% of positive screens). Nineteen cases (65.5% of recruited patients) completed follow-up at six months. CONCLUSIONS: Recruitment and retention rates were higher in the hypertension trial than in the depression trial. A full brief intervention trial appears feasible for primary care patients with hypertension who drink excessively. High AUDIT scores in the depression trial suggest the importance of alcohol intervention in this group. However, future work may require alternative screening and measurement procedures. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89156543; registered 21 October 2013.

The missing dimension: the relevance of people's conception of time.

While a timely conceptual innovation for the digital age, the "map" proposed by Bentley et al. would benefit from strengthening through the inclusion of a non-clock-time perspective. In this way, there could be new hypotheses developed which could be applied and tested relevant to more diverse societies, cultures, and individuals.

Improving collection efficiency through remote monitoring of charity assets.

Collection costs associated with servicing a major UK charity's donation banks and collecting unsold goods from their retail shops can account for up to 20% of the overall income gained. Bank and shop collections are commingled and are typically made on fixed days of the week irrespective of the amounts of materials waiting to be collected. Using collection records from a major UK charity, this paper considers what vehicle routing and scheduling benefits could accrue if bank and shop servicing requirements were monitored, the former using remote sensing technology to allow more proactive collection scheduling. A vehicle routing and scheduling algorithm employing tabu search methods was developed, and suggested time and distance savings of up to 30% over the current fixed schedules when a minimum bank and shop fill level of between 50% and 60% was used as a collection trigger. For the case study investigated, this led to a potential revenue gain of 5% for the charity and estimated CO2 savings of around 0.5 tonnes per week across the fleet of six heterogeneous vehicles.

Study protocol for the randomised controlled trial: antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study).

BACKGROUND: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service. METHODS/DESIGN: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. DISCUSSION: Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

The FiCTION dental trial protocol - filling children's teeth: indicated or not?

BACKGROUND: There is a lack of evidence for effective management of dental caries (decay) in children's primary (baby) teeth and an apparent failure of conventional dental restorations (fillings) to prevent dental pain and infection for UK children in Primary Care. UK dental schools' teaching has been based on British Society of Paediatric Dentistry guidance which recommends that caries in primary teeth should be removed and a restoration placed. However, the evidence base for this is limited in volume and quality, and comes from studies conducted in either secondary care or specialist practices. Restorations provided in specialist environments can be effective but the generalisability of this evidence to Primary Care has been questioned. The FiCTION trial addresses the Health Technology Assessment (HTA) Programme's commissioning brief and research question "What is the clinical and cost effectiveness of restoration caries in primary teeth, compared to no treatment?" It compares conventional restorations with an intermediate treatment strategy based on the biological (sealing-in) management of caries and with no restorations. METHODS/DESIGN: This is a Primary Care-based multi-centre, three-arm, parallel group, patient-randomised controlled trial. Practitioners are recruiting 1461 children, (3-7 years) with at least one primary molar tooth where caries extends into dentine. Children are randomized and treated according to one of three treatment approaches; conventional caries management with best practice prevention, biological management of caries with best practice prevention or best practice prevention alone. Baseline measures and outcome data (at review/treatment during three year follow-up) are assessed through direct reporting, clinical examination including blinded radiograph assessment, and child/parent questionnaires. The primary outcome measure is the incidence of either pain or infection related to dental caries. Secondary outcomes are; incidence of caries in primary and permanent teeth, patient quality of life, cost-effectiveness, acceptability of treatment strategies to patients and parents and their experiences, and dentists' preferences. DISCUSSION: FiCTION will provide evidence for the most clinically-effective and cost-effective approach to managing caries in children's primary teeth in Primary Care. This will support general dental practitioners in treatment decision making for child patients to minimize pain and infection in primary teeth. The trial is currently recruiting patients. TRIAL REGISTRATION: Protocol ID: NCTU: ISRCTN77044005.

Brief intervention to prevent hazardous drinking in young people aged 14-15 in a high school setting (SIPS JR-HIGH): study protocol for a randomized controlled trial.

BACKGROUND: Whilst the overall proportion of young people drinking alcohol in the United Kingdom has decreased in recent years, those who do drink appear to drink a larger amount, and more frequently. Early and heavy drinking by younger adolescents is a significant public health problem linked to intellectual impairment, increased risk of injuries, mental health issues, unprotected or regretted sexual experience, violence, and sometimes accidental death, which leads to high social and economic costs. This feasibility pilot trial aims to explore the feasibility of delivering brief alcohol intervention in a school setting with adolescents aged 14 and 15 and to examine the acceptability of study measures to school staff, young people and parents. METHODS AND DESIGN: Seven schools across one geographical area in the North East of England will be recruited. Schools will be randomly allocated to one of three conditions: provision of an advice leaflet (control condition, n = 2 schools); a 30-minute brief interactive session, which combines structured advice and motivational interviewing techniques delivered by the school learning mentor (level 1 condition, n = 2 schools); and a 60-minute session involving family members delivered by the school learning mentor (level 2 condition, n = 3 schools). Participants will be year 10 school pupils (aged 14 and 15) who screen positively on a single alcohol screening question and who consent to take part in the trial. Year 10 pupils in all seven schools will be followed up at 6 and 12 months. Secondary outcome measures include the ten-question Alcohol-Use Disorders Identification Test. The EQ-5D-Y and a modified short service use questionnaire will inform the health and social resource costs for any future economic evaluation.Young people recruited into the trial will also complete a 28-day timeline follow back questionnaire at 12-month follow-up. A qualitative evaluation (with young people, school staff, learning mentors, and parents) will examine facilitators and barriers to the use of screening and brief intervention approaches in the school setting in this age group. TRIAL REGISTRATION: Trial reference number ISRCTN07073105.

The management of dental caries in primary teeth - involving service providers and users in the design of a trial.

BACKGROUND: There is a lack of evidence for the effective management of dental caries in children's primary teeth. The trial entitled 'Filling Children's Teeth: Indicated Or Not?' (FiCTION) was designed to examine the clinical and cost effectiveness, in primary dental care, of three different approaches to the management of caries in primary teeth. However, before the FiCTION main trial commenced, a pilot trial was designed. Service provider (dentists and other members of the team including dental nurses and practice managers) and participant (child participants and their parents) involvement was incorporated into the pilot trial. The aim of this study is to describe service providers' and users' perspectives on the pilot trial to identify improvements to the conduct and design of the FiCTION main trial. METHODS: Qualitative interviews (individual and group) were held with dentists, dental team members, children and parents involved in the FiCTION pilot trial. Individual interviews were held with four dentists and a group interview was held with 17 dental team members. Face-to-face interviews were held with four parents and children (four- to eight-years old) representing the three arms of the trial and five telephone interviews were conducted with parents. All interviews were transcribed verbatim. Framework analysis was used. RESULTS: Overall, service providers, children and parents found the pilot trial to be well conducted and an interesting experience. Service providers highlighted the challenges of adhering to research protocols, especially managing the documentation and undertaking new clinical techniques. They indicated that the time and financial commitments were greater than they had anticipated. Particular difficulties were found recruiting suitable patients within the timeframe. For parents recruitment was apparently more related to trusting their dentist than the content of information packs. While some of the older children understood what a study was, others did not understand or were not aware they were enrolled. CONCLUSIONS: The findings provided valuable recommendations to improve the method of recruitment of dental practices and patients, the timing and content of the training, the type of support dentists would value and ways to further engage children and parents in the FiCTION main trial. TRIAL REGISTRATION: ISRCTN77044005.

Using a business model approach and marketing techniques for recruitment to clinical trials.

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.

A pragmatic cluster randomised controlled trial of a Diabetes REcall And Management system: the DREAM trial.

BACKGROUND: Following the introduction of a computerised diabetes register in part of the northeast of England, care initially improved but then plateaued. We therefore enhanced the existing diabetes register to address these problems. The aim of the trial was to evaluate the effectiveness and efficiency of an area wide 'extended,' computerised diabetes register incorporating a full structured recall and management system, including individualised patient management prompts to primary care clinicians based on locally-adapted, evidence-based guidelines. METHODS: The study design was a pragmatic, cluster randomised controlled trial, with the general practice as the unit of randomisation. Set in 58 general practices in three Primary Care Trusts in the northeast of England, the study outcomes were the clinical process and outcome variables held on the diabetes register, patient-reported outcomes, and service and patient costs. The effect of the intervention was estimated using generalised linear models with an appropriate error structure. To allow for the clustering of patients within practices, population averaged models were estimated using generalized estimating equations. RESULTS: Patients in intervention practices were more likely to have at least one diabetes appointment recorded (OR 2.00, 95% CI 1.02, 3.91), to have a recording of a foot check (OR 1.87, 95% CI 1.09, 3.21), have a recording of receiving dietary advice (OR 2.77, 95% CI 1.22, 6.29), and have a recording of blood pressure (BP) (OR 2.14, 95% CI 1.06, 4.36). There was no difference in mean HbA1c or BP levels, but the mean cholesterol level in patients from intervention practices was significantly lower (-0.15 mmol/l, 95% CI -0.25, -0.06). There were no differences in patient-reported outcomes or in patient-reported use of drugs, or uptake of health services. The average cost per patient was not significantly different between the intervention and control groups. Costs incurred in administering the system at the register and in general practice were in addition to these. CONCLUSION: This study has shown benefits from an area-wide, computerised diabetes register incorporating a full structured recall and individualised patient management system. However, these benefits were achieved at a cost. In future, these costs may fall as electronic data exchange becomes a reliable reality. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN32042030.

Development of a series of patient information leaflets for constipation using a range of cognitive interview techniques: LIFELAX.

BACKGROUND: The aim of the LIFELAX randomised controlled trial (diet and lifestyle vs. laxatives in the management of chronic constipation) is to develop and evaluate a cost effective intervention to promote diet and lifestyle in the treatment and management of chronic constipation for older people in Primary Care. Constipation affects the quality of life in around 20% of older people in the community. In the 65 years plus population, a significant proportion of men and women both living in institutions (81% and 75% respectively) and free living (30% and 37% respectively) use laxatives. Approximately 42 million pounds is spent each year on prescribed laxatives in England in addition to laxatives purchased over the counter. Although bowel problems are often multifactorial, diet and lifestyle have an extremely important role in their management. This paper describes one aspect of the main study, the development and piloting of the Patient information leaflets (PILs). METHODS: Following review of the literature and interviews with practitioners and patients, 8 PILs were designed on: constipation, activity, bowel health, fruit and vegetables, fibre, fluid, alternative therapies and laxatives. To check the patient's understanding of terms used in the PILS and the clarity and accessibility of the information understanding, cognitive interviews (CI) were used with nine patients (selected from 3 GP surgeries), aged > or = 55 years, who had received > or = 3 prescriptions of laxatives over 12 months. Interviews were recorded and transcribed. RESULTS: Changes made following the CI process included the lay-out, words used (e.g. 'exercise' was changed to 'activity', 'gut motility' changed to 'bowel movement') and descriptions and examples were adapted to be more appropriate for the target population. CONCLUSION: Pilot testing with CIs resulted in improvements in the PILs, which emphasises the need to pilot PILs with the target population before use. The techniques employed are relatively inexpensive and could be routinely used when preparing literature for research or clinical use including those intended for use with healthcare professionals and patients.

Protocol for north of England and Scotland study of tonsillectomy and adeno-tonsillectomy in children (NESSTAC). A pragmatic randomised controlled trial comparing surgical intervention with conventional medical treatment in children with recurrent sore throats.

BACKGROUND: Uncertainties surrounding the effectiveness and cost-effectiveness of childhood tonsillectomy for recurrent sore throat led the NHS Health Technology Assessment Programme to commission this research to evaluate the effectiveness and cost-effectiveness of tonsillectomy and adeno-tonsillectomy in comparison with standard non-surgical management in children aged under 16 with recurrent throat infections. The aim is to evaluate if tonsillectomy and adeno-tonsillectomy reduces the number of episodes of sore throats among children to a clinically significant extent. METHODS/DESIGN: A simple prospective pragmatic randomised controlled trial with economic analysis and prospective cohort study of non-trial participants comparing surgical intervention with conventional medical treatment. The treatment arm will receive tonsillectomy and adeno-tonsillectomy while in the control arm non-surgical conventional medical treatment only will be used. The primary outcome measure will be reported number of episodes of sore throat over two years with secondary outcomes measures of reported number of episodes of sore throat, otitis media and upper respiratory tract infection which invoke a GP consultation; reported number of symptom-free days; reported severity of sore throats and surgical and anaesthetic morbidity. The study will take place in five hospitals in the UK. The trial population will be 406 children aged 4-15 on their last birthday with recurrent sore throat referred by primary care to the 5 otolaryngology departments. The duration of the study is seven years (July 2001-July 2008). DISCUSSION: As with all pragmatic randomised controlled trials it is impossible to control the external environment in which the research is taking place. Since this trial began a number of factors have arisen which could affect the outcome including; a reduction in the incidence of respiratory tract infections, marked socio-economic differences in consultation rates, the results from the National Prospective Tonsillectomy Audit and the Government's waiting list initiatives.