Septoplasty (surgery to straighten a deviation in the nasal septum) is a frequently performed operation worldwide, with approximately 250,000 performed annually in the US and 22,000 in the UK. Most ...septoplasties aim to improve diurnal and nocturnal nasal obstruction. The evidence base for septoplasty clinical effectiveness is hitherto very limited.
To establish, and inform guidance for, the best management strategy for individuals with nasal obstruction associated with a deviated septum.
A multicentre, mixed-methods, open label, randomised controlled trial of septoplasty versus medical management for adults with a deviated septum and a reduced nasal airway. Eligible patients will have septal deflection visible at nasendoscopy and a nasal symptom score ≥ 30 on the NOSE questionnaire. Surgical treatment comprises septoplasty with or without reduction of the inferior nasal turbinate on the anatomically wider side of the nose. Medical management comprises a nasal saline spray followed by a fluorinated steroid spray daily for six months. The recruitment target is 378 patients, recruited from up to 17 sites across Scotland, England and Wales. Randomisation will be on a 1:1 basis, stratified by gender and severity (NOSE score). Participants will be followed up for 12 months post randomisation. The primary outcome measure is the total SNOT-22 score at 6 months. Clinical and economic outcomes will be modelled against baseline severity (NOSE scale) to inform clinical decision-making. The study includes a recruitment enhancement process, and an economic evaluation.
The NAIROS trial will evaluate the clinical effectiveness and cost-effectiveness of septoplasty versus medical management for adults with a deviated septum and symptoms of nasal blockage. Identifying those individuals most likely to benefit from surgery should enable more efficient and effective clinical decision-making, and avoid unnecessary operations where there is low likelihood of patient benefit.
EudraCT: 2017-000893-12, ISRCTN: 16168569. Registered on 24 March 2017.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background
Critically unwell babies in intensive care units may develop acute renal failure. Options for renal replacement therapy are limited by their small size and available technology.
...Objectives
To determine the clinical efficacy, outcomes and safety profile of the NIDUS
®
(a novel infant haemodialysis device) for babies under 8 kg, compared with current renal replacement therapy.
Design
A clinical investigation using a non-blinded cluster stepped wedge design with paediatric intensive care units randomised to sequences.
Setting
Paediatric intensive care units in six UK hospitals.
Participants
Children under 8 kg who required renal replacement therapy for fluid overload or biochemical disturbance.
Interventions
Continuous renal replacement therapy was provided by the usual methods: peritoneal dialysis and continuous haemofiltration (during control periods) and by the NIDUS (during intervention periods), a novel device designed for babies with a smaller circuit and filter and volumetric control of ultrafiltration.
Main outcome measures
Primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances, accuracy of reported ultrafiltration and mortality.
Data sources
Bedside study data collected by weighing bags of fluid entering and leaving the device were entered into the study database along with case descriptors. Some secondary outcome data was collected via the Paediatric Intensive Care Audit Network.
Results
Ninety-seven participants were recruited by study closure, 62 to control and 35 to intervention. The primary outcome was obtained from 62 control but only 21 intervention patients, largely because of technical difficulties using NIDUS. The analysis comparing the available primary outcomes showed that ultrafiltration with NIDUS was closer to that prescribed than with control: standard deviations controls 18.75, intervention 2.95 (ml/hour), adjusted ratio 0.13, 95% confidence interval (0.03 to 0.71);
p
= 0.018.
The mean clearances for creatinine, urea and phosphate were lower on peritoneal dialysis than NIDUS, which were in turn lower than continuous veno-venous haemofiltration. The variability in the clearances was in the same order.
Of the 62 control patients, 10 died (2/62 on peritoneal dialysis; 7/13 on continuous haemofiltration) before discharge from paediatric intensive care unit (16%), compared with 12 out of 35 (34%) in the NIDUS group:
p
= 0.04, 95% confidence interval for difference (0 to 36%).
Harms
No important adverse events occurred and the NIDUS has an acceptable safety profile compared with other renal replacement therapies in this critically ill population with multi-organ failure. Mortality was lowest for Peritoneal Dialysis, highest for continuous haemofiltration, with the NIDUS in-between. Only one serious adverse device event which was reported to the Medicines and Healthcare products Regulatory Agency.
Conclusions
NIDUS works effectively, delivering appropriate blood clearances and accurate, controllable fluid removal (ultrafiltration), indicating that it has an important place alongside other dialysis modalities for infant renal replacement therapy.
Future work
Findings from this study indicate some modifications are required to NIDUS to improve usability. Further studies on use of the NIDUS device in other populations of babies for example those with chronic renal failure, and long-term outcomes are required.
Trial registration
This trial is registered as ISRCTN 13787486.
Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/23/26) and is published in full in
Efficacy and Mechanism Evaluation
; Vol. 11, No. 1. See the NIHR Funding and Awards website for further award information.
Effective weight loss interventions are widely available but, after weight loss, most individuals regain weight. This article describes the protocol for the NULevel trial evaluating the effectiveness ...and cost-effectiveness of a systematically developed, inexpensive, scalable, technology-assisted, behavioural intervention for weight loss maintenance (WLM) in obese adults after initial weight loss.
A 12-month single-centre, two-armed parallel group, participant randomised controlled superiority trial is underway, recruiting a total of 288 previously obese adults after weight loss of ≥5 % within the previous 12 months. Participants are randomly assigned to intervention or control arms, with a 1:1 allocation, stratified by sex and percentage of body weight lost (<10 % vs ≥10 %). Change in weight (kg) from baseline to 12 months is the primary outcome. Weight, other anthropometric variables and 7-day physical activity (assessed via accelerometer) measures are taken at 0 and 12 months. Questionnaires at 0, 6 and 12 months assess psychological process variables, health service use and participant costs. Participants in the intervention arm initially attend an individual face-to-face WLM consultation with an intervention facilitator and then use a mobile internet platform to self-monitor and report their diet, daily activity (via pedometer) and weight through daily weighing on wirelessly connected scales. Automated feedback via mobile phone, tailored to participants' weight regain and goal progress is provided. Participants in the control arm receive quarterly newsletters (via links embedded in text messages) and wirelessly connected scales. Qualitative process evaluation interviews are conducted with a subsample of up to 40 randomly chosen participants. Acceptability and feasibility of procedures, cost-effectiveness, and relationships among socioeconomic variables and WLM will also be assessed.
It is hypothesised that participants allocated to the intervention arm will show significantly lower levels of weight regain from baseline than those in the control arm. To date, this is the first WLM trial using remote real-time weight monitoring and mobile internet platforms to deliver a flexible, efficient and scalable intervention, tailored to the individual. This trial addresses a key research need and has the potential to make a vital contribution to the evidence base to inform future WLM policy and provision.
http://www.isrctn.com/ISRCTN14657176 (registration date 20 March 2014).
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Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Aneurysmal subarachnoid haemorrhage is a major cause of haemorrhagic stroke. The incidence is ≈ 80 per million population per year; it peaks in the 40–60 years age range and often has a ...poor prognosis with the outcome linked to severity of the initial haemorrhage. Aneurysmal subarachnoid haemorrhage accounts for 5% of strokes, but 20% of quality-adjusted life-years are lost to stroke and much of that loss is concentrated in World Federation of Neurosurgical Societies grade 4–5 (or poor-grade) aneurysmal subarachnoid haemorrhage patients. Before endovascular coiling was available, the conventional management strategy for poor-grade aneurysmal subarachnoid haemorrhage patients was to treat the ruptured aneurysm on neurological improvement. That incurs a risk of aneurysm rebleeding, which is highest soon after the first bleed; if rebleed occurs prior to aneurysm treatment, prognosis is dismal. Reducing rebleeding with early treatment might improve outcome. Therefore, an early coiling strategy in grade 4–5 patients is appealing, but not robustly evidenced. Early treatment in all grade 4–5 patients might prevent death from rebleeding but possibly at the expense of creating severely disabled survivors, with attendant societal costs. Many neuroclinicians have expressed genuine uncertainty regarding whether or not to treat all grade 4–5 aneurysmal subarachnoid haemorrhage patients emergently (as soon as possible regardless of neurological status). A pilot trial, the treatment of poor-grade subarachnoid haemorrhage trial 1 (TOPSAT1), indicated that recruitment to a randomised trial to address this uncertainty was feasible.
Methods
We investigated a management policy in aneurysmal subarachnoid haemorrhage World Federation of Neurosurgical Societies grades 4 or 5 of securing the ruptured aneurysm emergently (within 24 hours of randomisation) compared with the strategy to treat the aneurysm on neurological improvement (to World Federation of Neurosurgical Societies grades 1–3), irrespective of when that improvement occurred. The treatment of poor-grade subarachnoid haemorrhage trial 2 (TOPSAT2) was a pragmatic, randomised, open-blinded, end-point design trial aiming to recruit 346 adult patients (aged 18–80 years) in 30 UK and European neuroscience centres. Randomisation was web based, with minimisation criteria relating to age, grade, presence of hydrocephalus and UK location (vs. non-UK). Fifteen sites were opened to recruitment, 12 of which were in the UK. Standard institutional procedures for securing aneurysms were followed. An exploratory magnetic resonance biomarker substudy of 100 UK participants was planned but not opened. The primary end point was functional outcome at 12 months, determined by analysis of the modified Rankin Scale score. The secondary end points relating to safety were assessed.
Results
Of the 305 World Federation of Neurosurgical Societies grade 4–5 patients screened, 23 were randomised: 11 to the emergent treatment arm and 12 to the treatment on neurological improvement (control) arm. Trial recruitment was suspended when it was judged to have failed a feasibility assessment. The median time from ictus to treatment (where aneurysm was treated) was 26 hours in the emergent treatment arm and 163 hours in the treatment on neurological improvement arm. There were no statistically significant differences between arms in mortality (
p
= 0.4) or functional outcome at 365 days modified Rankin Scale score 0–3 vs. 4–6 (
p
= 0.32). Sensitivity analysis was performed to examine the effect of missing data but differences remained non-significant.
Limitations
A limitation was the failure to recruit to time/target.
Conclusions
The randomised trial approach to investigating whether poor-grade aneurysmal subarachnoid haemorrhage patients should receive emergent treatment or be treated on neurological improvement proved unfeasible. No statistically significant differences were identified between the trial arms in mortality or functional outcome, but the small number of patients enrolled limits drawing firm conclusions.
Future work
No future work is currently planned.
Trial registration
Current Controlled Trials ISRCTN15960635.
Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 8, No. 8. See the NIHR Journals Library website for further project information.
Background
Primary biliary cirrhosis (PBC) is an autoimmune liver disease, and 50% of patients with this disease experience fatigue. This is a debilitating symptom affecting quality of life and ...resulting in social isolation, which is highlighted by patients as a research priority. PBC is characterised immunologically by the presence of high-titre autoantibodies that are directed at the pyruvate dehydrogenase complex (PDC) and are highly effective at blocking its energy generation function. We hypothesised that if anti-PDC antibodies were a driver of fatigue through bioenergetic dysfunction, then the B-cell-targeting biological agent rituximab (MabThera
®
, Roche Products Ltd, Welwyn Garden City, UK) might be a therapeutic option.
Objective
To assess whether or not rituximab safely improved moderate or severe fatigue in PBC patients.
Design
A Phase II, double-blind, randomised controlled trial comparing rituximab with placebo in fatigued PBC patients. Randomisation was conducted using a web-based system. Participants received two infusions on days 1 and 15 and were followed up at 3, 6, 9 and 12 months.
Setting
A single-centre UK study in Newcastle upon Tyne Hospitals NHS Foundation Trust.
Participants
Seventy-one participants aged ≥ 18 years with PBC and moderate or severe fatigue (score of > 33 on the PBC-40 fatigue domain) were screened. The PBC-40 questionnaire is a fully validated disease-specific health-related quality-of-life measure for use in patients with PBC. Fatigue, with a maximum score of 55, is one of its six domains. Fifty-seven participants were randomised to the trial, 55 of whom reached the primary end-point assessment.
Intervention
Participants were randomised in a 1 : 1 ratio to receive either rituximab (1000 mg) or a saline intravenous infusion (placebo) on days 1 and 15. The infusions were delivered in a double-blind manner using the same protocol.
Main outcome measures
The primary outcome measure was the PBC-40 fatigue domain at 3 months, assessed on an intention-to-treat basis. Secondary outcome measures included markers of bioenergetics function (anaerobic threshold and post-exercise muscle pH assessed using magnetic resonance imaging) and physical activity levels. Impact on biochemical markers of liver disease severity was assessed as an experimental outcome.
Results
Rituximab therapy was safe, with no serious adverse events linked to the drug. There was no statistically significant difference in fatigue score at 3 months between the rituximab and placebo arms adjusted mean difference –0.9, 95% confidence interval (CI) –4.6 to 3.1. However, improvement in fatigue was observed in both arms {mean score decreasing from 41.2 standard deviation (SD) 5.5 to 36.2 (SD 8.4) in the rituximab arm and from 43.0 (SD 5.9) to 38.1 (SD 8.7) in the placebo arm}. There was little difference in any of the secondary outcomes between arms. However, anaerobic threshold improved significantly in the rituximab arm (adjusted mean difference at 3 months 1.41, 95% CI 0.03 to 2.80). No change in muscle bioenergetics characteristics was seen. A suggestive improvement in liver biochemistry was observed.
Limitations
Recruitment was lower than the original target, leading to a reduction in study power. A clinically significant placebo effect on PBC-40 fatigue scores was seen.
Conclusions
Rituximab is ineffective for the treatment of fatigue in unselected PBC patients despite metabolic modulation through improvement of anaerobic threshold.
Future work
Results from the trial demonstrate that metabolic effect of rituximab is not translated into clinical benefit. This will help to guide us to design future trials and when looking at completely different targets.
Trial registration
Current Controlled Trials ISRCTN03978701, ClinicalTrials.gov identifier NCT02376335 and EudraCT number 2012-000145-12.
Funding
This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 5, No. 2. See the NIHR Journals Library website for further project information. Additional funding was received from the Medical Research Council and a Department of Health and Social Care subvention.
Abstract
Background: Doxorubicin is a key component of a number of treatment regimens used in paediatric oncology despite the very limited pharmacology data on which current dosing regimens are ...based. In recognition of this, doxorubicin was included on the EMA priority list for paediatric off-patent medicines for which more information was required, particularly on pharmacokinetics.
Methods: The EPOC consortium, with collaborators in the UK, France, Germany and Italy, performs paediatric oncology pharmacology clinical trials. This study is a multicentre, multinational phase II pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. All patients are being treated according to a tumour-specific national or European therapeutic trial. The aim was to recruit 100 patients, with a particular focus on children less than 3 years. The plasma levels of markers such as troponin T, are being measured to evaluate their use as clinical markers for cardiotoxicity. Data is being analysed using a population pharmacokinetic approach and the impact of pharmacogenetics is being investigated.
Results: The study has been open to recruitment in 20 clinical centres across the four participating countries. The target 100 patients have been recruited from all the contributing study protocols, with 26 patients less than 3 years. Of these 26 patients, 5 patients are less than 1 year. An interim pharmacokinetic analysis has been performed on the data from the first 31 patients. The results of the analysis are consistent with the primary aims of the overall study.
Conclusion: The data generated during this study should provide comparative data on the age-dependent pharmacokinetics and pharmacogenetics of doxorubicin. The results will contribute to optimising the safe use of doxorubicin in children with cancer.
Acknowledgements: Study funded under the seventh framework programme of the European Commission (FP7)
Citation Format: Alan V. Boddy, Alison J. Steel, Joachim Boos, Miriam Krischke, Nicolas Andre, Gianni Bisogno, Georg Hempel, Gerlind Bode, Maurizio D'Incalci, Nina Kontny. The European Paediatric Oncology off-patent medicines Consortium (EPOC) pharmacokinetic/pharmacodynamic study of doxorubicin. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2013-2219
Unlike gastro-oesophageal reflux, extra-oesophageal reflux (EOR) is not necessarily associated with heartburn. The potential prevalence of EOR in general practice in the UK using the Reflux Symptom ...Index (RSI) questionnaire was determined. A total of 1152 patients attending a GP surgery for routine conditions completed the RSI questionnaire: 26.5% had an RSI score >10, regarded as a clinically significant score for EOR; 29% of patients with a significant RSI score rated the impact of heartburn in the previous month as zero. Significant numbers of patients presenting to GPs have high RSI scores suggesting significant reflux. Many patients likely to have EOR do not experience classical heartburn. This might explain why some GPs may not attribute common symptoms affecting the throat to gastric reflux.
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