An automated feeding system for the African killifish reveals the impact of diet on lifespan and allows scalable assessment of associative learning.

The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof of concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.

Use of routinely collected data in a UK cohort of publicly funded randomised clinical trials.

Routinely collected data about health in medical records, registries and hospital activity statistics is now routinely collected in an electronic form. The extent to which such sources of data are now being routinely accessed to deliver efficient clinical trials, is unclear. The aim of this study was to ascertain current practice amongst a United Kingdom (UK) cohort of recently funded and ongoing randomised controlled trials (RCTs) in relation to sources and use of routinely collected outcome data. Recently funded and ongoing RCTs were identified for inclusion by searching the National Institute for Health Research journals library. Trials that have a protocol available were assessed for inclusion and those that use or plan to use routinely collected health data (RCHD) for at least one outcome were included. RCHD sources and outcome information were extracted. Of 216 RCTs, 102 (47%) planned to use RCHD. A RCHD source was the sole source of outcome data for at least one outcome in 46 (45%) of those 102 trials. The most frequent sources are Hospital Episode Statistics (HES) and Office for National Statistics (ONS), with the most common outcome data to be extracted being on mortality, hospital admission, and health service resource use. Our study has found that around half of publicly funded trials in a UK cohort (NIHR HTA funded trials that had a protocol available) plan to collect outcome data from routinely collected data sources.

The Association Between Wait Times for Colorectal Cancer Treatment and Health Care Costs: A Population-Based Analysis.

BACKGROUND: Health care costs and wait times for colorectal cancer treatment are increasing in Canada, but the association between the 2 remains unclear. OBJECTIVE: This study aimed to determine the association between wait times and health care costs and utilization. DESIGN: This is a population-based retrospective cohort study. SETTING: This study was conducted in Manitoba, Canada. PATIENTS: Patients diagnosed with colorectal cancer between 2004 and 2014 were sorted and ranked into quintiles based on the time from index contact for a colorectal cancer-related symptom to first treatment. MAIN OUTCOME MEASURES: The primary outcome is risk-adjusted health care costs, and the secondary outcomes include health care utilization and overall mortality. RESULTS: We included a total of 6936 patients. Total wait times ranged between 0 and 762 days. In comparison with very short wait times, longer wait times were associated with significantly increased costs (short: mean cost ratio 1.21; 95% CI, 1.10-1.32; moderate: mean cost ratio 1.30; 95% CI, 1.19-1.43; long: mean cost ratio 1.48; 95% CI, 1.33-1.64; and very long: mean cost ratio 1.39; 95% CI, 1.26-1.54). Compared with very short wait times, longer wait times were associated with significantly lower risk of mortality (short: HR, 0.78; 95% CI, 0.71-0.86; moderate: HR, 0.72; 95% CI, 0.65-0.80; long: HR, 0.73; 95% CI, 0.66-0.82; very long: HR, 0.76; 95% CI, 0.68-0.85). The median number of pretreatment radiological and endoscopic investigations and surgeon clinic visits increased over the study period across all wait time categories. LIMITATIONS: This is a nonrandomized, retrospective cohort study with potentially limited generalizability. CONCLUSION: Patients with very short and short wait times are likely those diagnosed with life-threatening complications of colorectal cancer. Outside this window, patients with longer wait times experience increased health care costs and utilization with similar overall mortality. Improved care coordination and patient navigation may help contain the increasing wait times and associated increasing health care costs and utilization. See Video Abstract at http://links.lww.com/DCR/B81. ASOCIACIÓN ENTRE LOS TIEMPOS DE ESPERA PARA EL TRATAMIENTO DE UN CÁNCER COLORRECTAL Y LOS COSTOS DE ATENCIÓN MÉDICA: UN ANÁLISIS DE POBLACIÓN: los costos de atención médica y los tiempos de espera para el tratamiento del cáncer colorrectal están aumentando en Canadá, pero la asociación entre los dos sigue sin estar clara.determinar la asociación entre los tiempos de espera y los costos y la utilización de la atención médicaun estudio de cohorte retrospectivo basado en la población.Manitoba, Canadálos pacientes diagnosticados con cáncer colorrectal entre 2004-2014 se clasificaron y sub-clasificaron en quintiles según el tiempo desde el primer contacto índice de síntomas relacionados con cáncer colorrectal hasta el primer tratamiento.El resultado primario son los costos de atención médica ajustados al riesgo, y los resultados secundarios incluyen la utilización de la atención médica y la mortalidad general.Incluimos un total de 6,936 pacientes. Los tiempos de espera totales oscilaron entre 0-762 días. En comparación con los tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con costos significativamente mayores (Corto: relación de costo promedio 1.21, intervalo de confianza del 95% 1.10-1.32; Moderado: relación de costo promedio 1.30, intervalo de confianza del 95% 1.19-1.43; Largo: media relación de costo 1.48, intervalo de confianza del 95% 1.33-1.64; Muy largo: relación de costo promedio 1.39, intervalo de confianza del 95% 1.26-1.54). En comparación con tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con un riesgo de mortalidad significativamente menor (Corto: razón de riesgo 0.78, intervalo de confianza del 95% 0.71-0.86; Moderado: razón de riesgo 0.72, intervalo de confianza del 95% 0.65-0.80; Largo: peligro cociente 0.73, intervalo de confianza del 95% 0.66-0.82; Muy largo: cociente de riesgos 0.76, intervalo de confianza del 95% 0.68-0.85). La mediana del número de investigaciones radiológicas y endoscópicas previas al tratamiento y las visitas al cirujano aumentaron durante el período de estudio en todas las categorías de tiempo de espera.estudio de cohortes retrospectivo, no aleatorio con generalización potencialmente limitadalos pacientes con tiempos de espera « muy cortos ¼ y « cortos ¼ son probablemente aquellos diagnosticados con complicaciones potencialmente mortales del cáncer colorrectal. Fuera de esta ventana, los pacientes con tiempos de espera más largos experimentan mayores costos de atención médica y utilización con una mortalidad general similar. La coordinación mejorada de la atención y la navegación del paciente pueden ayudar a contener el aumento de los tiempos de espera y el aumento de los costos y la utilización de la atención médica. Consulte Video Resumen en http://links.lww.com/DCR/B81. (Traducción-Dr. Edgar Xavier Delgadillo).

Timing of Palliative Care in Colorectal Cancer Patients: Does It Matter?

BACKGROUND: Palliative care can improve end-of-life care and reduce health care expenditures, but the optimal timing for initiation remains unclear. We sought to characterize the association between timing of palliative care, in-hospital deaths, and health care costs. METHODS: This is a retrospective cohort study including all patients who were diagnosed and died of colorectal cancer between 2004 and 2012 in Manitoba, Canada. The primary exposure was timing of palliative care, defined as no involvement, late involvement (less than 14 d before death), early involvement (14 to 60 d before death), and very early involvement (>60 d before death). The primary outcome was in-hospital deaths and end-of-life health care costs. RESULTS: A total of 1607 patients were included; 315 (20%) received palliative care and 162 (10%) died in hospital. Compared to those who did not receive palliative care, patients with early and very early involvement experienced significantly decreased odds of dying in hospital (OR 0.21 95% CI 0.06-0.69 P = 0.01 and OR 0.11 95% CI 0.01-0.78 P = 0.03, respectively) and significantly lower health care costs. There were no significant differences in in-hospital deaths and health care costs between patients without palliative care and those who received late palliative care. CONCLUSIONS: Early palliative care involvement is associated with decreased odds of dying in hospital and lower health care utilization and costs in patients with colorectal cancer. These findings provide real-world evidence supporting early integration of palliative care, although the optimal timing (early versus very early) remains a matter of debate.

Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation.

OBJECTIVE: To compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people. DESIGN: Pragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation. SETTING: 15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017. PARTICIPANTS: Patients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible. INTERVENTIONS: Participants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice. MAIN OUTCOME MEASURES: Primary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), paediatric quality of life inventory score, and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective. RESULTS: 294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol v 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants v 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)). CONCLUSION: During the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25.

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT.

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 < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. 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 < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. CONCLUSIONS: Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. 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.

Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children and young people, who are at risk of developing inflammation in an area of the eye called the uvea (called uveitis). The purpose of the study was to look at how effective the use of adalimumab in combination with methotrexate (MTX) is compared with using MTX alone to treat JIA-associated uveitis. A total of 90 children (aged 2­18 years) taking MTX with JIA-associated uveitis took part in the study. If the inflammation in a patient's eye or eyes was not getting better during the 18 months, the patient was told to stop taking the study drug. It was found that those patients who were taking placebo and MTX in the trial stopped taking the study drug sooner than those who were taking adalimumab and MTX. This means that adalimumab and MTX was better at treating uveitis than MTX alone. It was found that more patients taking adalimumab and MTX together either reduced or stopped taking topical steroids than the patients taking placebo and MTX. It was found that patients taking adalimumab and MTX together experienced more side effects than those taking placebo with MTX. However, these were expected based on what was already known about adalimumab's side effects. An economic evaluation was conducted to estimate whether or not adalimumab would represent value for money for the NHS for this condition. This included long-term effects based on information about patients' clarity of vision. The analysis showed that adalimumab may not be cost-effective, as the additional costs of treatment may not be justified by the benefits. The final results show that although adalimumab used in combination with MTX does help to treat patients with JIA and uveitis, it may not represent good value for the NHS.

Cost-Effectiveness Analysis of Adalimumab for the Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: A cost-utility analysis based on a clinical trial and decision analytic model. PARTICIPANTS: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. METHODS: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. MAIN OUTCOME MEASURES: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. RESULTS: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. CONCLUSIONS: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT.

BACKGROUND: The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. OBJECTIVES: (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. DESIGN: A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. SETTING: Fifteen diabetes clinics in hospitals in England and Wales. PARTICIPANTS: Patients aged 7 months to 15 years. INTERVENTIONS: Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. DATA SOURCES: Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. OUTCOMES: The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs). LIMITATIONS: Generalisability beyond 12 months is uncertain. CONCLUSIONS: No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. FUTURE WORK: Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. 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. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis.

BACKGROUND: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS: The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]). CONCLUSIONS: Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).

Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study.

BACKGROUND: Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful. OBJECTIVE: Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam. DESIGN: Multicentre, double-blind, randomised equivalence trial. SETTING: Ten UK PICUs. PARTICIPANTS: Children (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours. INTERVENTIONS: Clonidine (3 µg/kg loading then 0-3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0-200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine. MAIN OUTCOME MEASURES: Primary end point Adequate sedation defined by COMFORT score of 17-26 for ≥ 80% of the time with a ± 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data. RESULTS: The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61). CONCLUSIONS: Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02639863. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information.

A cost-utility analysis of treatments for malignant liver tumours: a pilot project.

BACKGROUND: Hepatic resection is the standard treatment for colorectal liver metastases when feasible. Techniques such as radiofrequency ablation (RFA) have been the subject of ongoing research in hopes of achieving a similar survival to that achieved with hepatic resection, but with less morbidity and better quality of life (QOL). The aim was to to generate a hypothesis concerning the cost-utility of various treatments that may be further tested with randomized trials in the future. PATIENTS AND METHODS: This was a prospective, non-randomized pilot study comparing the cost-utility of hepatic resection, RFA, systemic chemotherapy, and symptom control alone for colorectal liver metastases. All patients with newly diagnosed liver malignancies were eligible. QOL was measured serially with the Health Utilities Index. Costs, in 2001 Canadian dollars, were captured from the viewpoint of society in general. RESULTS: In all, 40 patients were enrolled in the study: 7 underwent hepatic resection, 7 underwent RFA (sometimes in combination with resection), 20 received systemic chemotherapy, and 6 received symptom control alone. Liver resection appeared to be the most effective approach, with an average benefit of 2.58 QALYs (quality-adjusted life years) compared with 1.95 QALYs for RFA, 1.18 QALYs for chemotherapy, and 0.82 QALYs for symptom control alone, resulting in cost-utility ratios of $7792, $8056, $12,571, and $4788 per QALY, respectively. DISCUSSION: The cost-utility of hepatic resection and RFA appeared similar even though patients receiving RFA had more advanced disease. The role of RFA is still being defined; however, if long-term survival proves to be promising, then this study lends support to the conduct of randomized controlled trials in the future.