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Background: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. Objective To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. Design This was a Phase IV, multicentre, parallel-group, randomised controlled trial. Setting Seventy UK and two Italian cystic fibrosis centres. Participants Participants were individuals with cystic fibrosis aged> 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. Interventions Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1:1 ratio using simple block randomisation with random variable block length. Main outcome measures The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. Results Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to-£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. Limitations Only 15 out of the 286 participants recruited were adults-partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. Conclusions Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. Future work Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. Trial registration Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10.

Additional file 1: S1. Example parent topic guide. S2. Draft Participant Information Sheet sent prior to interview. S3. Staff focus group topic guide. S4 Table 1. Approach to qualitative data analysis

Additional file 1.

Background Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. Methods/design This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. Discussion This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting. Trial registration ISRCTN identifier, ISRCTN22567894 . Registered on 27 August 2015 EudraCT identifier, 2014-002188-13 . Registered on 21 May 2014 NIHR HTA Grant: 12/127/134

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus.

Background Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. Objective To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. Design This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost–utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. Setting The setting was tertiary care centres throughout the UK. Participants Patients aged 2–18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). Interventions All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing Main outcome measures Primary outcome – time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome – incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. Results A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p Conclusions Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is Future work A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. Trial registration Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. 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. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

Site initiation visit (SIV) questionnaire. (DOCX 647 kb)

Example telephone interviews and focus group topic guide questions related to site visit training. (DOCX 18 kb)

Statistical analysis plan (PDF 607Â kb)

SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOCX 60 kb)

Background: Despite optimal therapy, many children with Crohn’s disease (CD) experience growth retardation.\ud The objectives of the study are to assess the feasibility of a randomised control trial (RCT) of injectable forms of\ud growth-promoting therapy and to survey the attitudes of children with CD and their parents to it.\ud Methods: A feasibility study was carried out to determine study arms, sample size and numbers of eligible patients.\ud A face-to-face questionnaire surveyed willingness to consent to future participation in the RCT. Eligibility to the\ud survey was any child under 18 (with their parent/guardian) with CD whose height standard deviation score (HtSDS)\ud was ≤+1. Of 118 questionnaires, 94 (80%) were returned (48 by children and 46 by parents).\ud Results: The median age of the patients in the survey was 14.3 years (range 7.0 to 17.7), and 35 (73%) were male.\ud Their median HtSDS was −1.2 (−3.01, 0.23), and it was lower than the median mid-parental HtSDS of −0.6 (−3.1, 1.4).\ud We analysed the willingness of the children whose HtSDS

PPI Planning for Clinical Trials â Guidance for Chief Investigators. (PDF 213 kb)

PPI Remit TSC Public Contributor. (PDF 807 kb)

List of Tools. (PDF 303 kb)

PPI Remit TMG Public Contributor. (PDF 711 kb)

Participant Information Review Question Bank. (PDF 441 kb)

PPI Planning Tool. (PDF 202 kb)

Participant Information Review - Guidance for Public Contributors. (PDF 523 kb)

While recently imposed targets are reducing the time taken for R&D departments to approve valid applications, the time taken to open UK research sites remains excessive and must be reduced. At present significant public funds are being used inefficiently in order to navigate NHS systems, challenging the resolve of trial teams and the competitiveness of the UK.

Objective: To inform the design of a randomised controlled trial (called EcLiPSE) to improve the treatment of children with convulsive status epilepticus (CSE). EcLiPSE requires the use of a controversial deferred consent process. Design: Qualitative interview and focus group study. Setting: 8 UK support groups for parents of children who have chronic or acute health conditions and experience of paediatric emergency care. Participants: 17 parents, of whom 11 participated in telephone interviews (10 mothers, 1 father) and 6 in a focus group (5 mothers, 1 father). 6 parents (35%) were bereaved and 7 (41%) had children who had experienced seizures, including CSE. Results: Most parents had not heard of deferred consent, yet they supported its use to enable the progress of emergency care research providing a child's safety was not compromised by the research. Parents were reassured by tailored explanation, which focused their attention on aspects of EcLiPSE that addressed their priorities and concerns. These aspects included the safety of the interventions under investigation and how both EcLiPSE interventions are used in routine clinical practice. Parents made recommendations about the appropriate timing of a recruitment discussion, the need to individualise approaches to recruiting bereaved parents and the use of clear written information. Conclusions: Our study provided information to help ensure that a challenging trial was patient centred in its design. We will use our findings to help EcLiPSE practitioners to: discuss potentially threatening trial safety information with parents, use open-ended questions and prompts to identify their priorities and concerns and clarify related aspects of written trial information to assist understanding and decisionmaking.