Search

Background: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5-7 days during an upper respiratory tract infection reduces the risk of relapse., Objectives: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none., Design: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis., Setting: A total of 122 UK paediatric departments, of which 91 recruited patients., Participants: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively)., Interventions: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m 2 ) or an equivalent dose of placebo., Main Outcome Measures: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years., Results: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference -0.024, 95% confidence interval -0.14 to 0.09; p  = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis., Limitations: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial., Conclusions: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse., Future Work: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome., Trial Registration: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39., 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. 26, No. 3. See the NIHR Journals Library website for further project information.

Background: Pregnancy is a high-risk time for excessive weight gain. The rising prevalence of obesity in women, combined with excess weight gain during pregnancy, means that there are more women with obesity in the postnatal period. This can have adverse health consequences for women in later life and increases the health risks during subsequent pregnancies., Objective: The primary aim was to produce evidence of whether or not a Phase III trial of a brief weight management intervention, in which postnatal women are encouraged by practice nurses as part of the national child immunisation programme to self-monitor their weight and use an online weight management programme, is feasible and acceptable., Design: The research involved a cluster randomised controlled feasibility trial and two semistructured interview studies with intervention participants and practice nurses who delivered the intervention. Trial data were collected at baseline and 3 months later. The interview studies took place after trial follow-up., Setting: The trial took place in Birmingham, UK., Participants: Twenty-eight postnatal women who were overweight/obese were recruited via Birmingham Women's Hospital or general practices. Nine intervention participants and seven nurses were interviewed., Interventions: The intervention was delivered in the context of the national child immunisation programme. The intervention group were offered brief support that encouraged self-management of weight when they attended their practice to have their child immunised at 2, 3 and 4 months of age. The intervention involved the provision of motivation and support by nurses to encourage participants to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme. The role of the nurse was to provide regular external accountability for weight loss. Women were asked to weigh themselves weekly and record this on a record card in their child's health record ('red book') or using the online programme. The behavioural goal was for women to lose 0.5-1 kg per week. The usual-care group received a healthy lifestyle leaflet., Main Outcome Measures: The primary outcome was the feasibility of a Phase III trial to test the effectiveness of the intervention, as assessed against three traffic-light stop-go criteria (recruitment, adherence to regular self-weighing and registration with an online weight management programme)., Results: The traffic-light criteria results were red for recruitment (28/80, 35% of target), amber for registration with the online weight loss programme (9/16, 56%) and green for adherence to weekly self-weighing (10/16, 63%). Nurses delivered the intervention with high fidelity. In the qualitative studies, participants indicated that the intervention was acceptable to them and they welcomed receiving support to lose weight at their child immunisation appointments. Although nurses raised some caveats to implementation, they felt that the intervention was easy to deliver and that it would motivate postnatal women to lose weight., Limitations: Fewer participants were recruited than planned., Conclusions: Although women and practice nurses responded well to the intervention and adherence to self-weighing was high, recruitment was challenging and there is scope to improve engagement with the intervention., Future Work: Future research should focus on investigating other methods of recruitment and, thereafter, testing the effectiveness of the intervention., Trial Registration: Current Controlled Trials ISRCTN12209332., 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. 25, No. 49. See the NIHR Journals Library website for further project information.

Background: Excess weight in children is a continuing health issue. Community-based children's weight management programmes have had some effect in promoting weight loss. Families from minority ethnic communities are less likely to complete these programmes but, to date, no programmes have been culturally adapted to address this., Objectives: We aimed to (1) culturally adapt an existing weight management programme for children aged 4-11 years and their families to make it more suited to Pakistani and Bangladeshi communities but inclusive of all families and (2) evaluate the adapted programme to assess its feasibility and acceptability, as well as the feasibility of methods, for a future full-scale trial., Design: In phase I, a cultural adaptation of a programme that was informed by formative research and guided by two theoretical frameworks was undertaken and in phase II this adapted programme was delivered in a cluster-randomised feasibility study (for which the clusters were the standard and adapted children's weight management programmes)., Setting: Birmingham: a large, ethnically diverse UK city., Participants: In phase I, Pakistani and Bangladeshi parents of children with excess weight, and, in phase II, children aged 4-11 years who have excess weight and their families., Interventions: A culturally adapted children's weight management programme, comprising six sessions, which was delivered to children and parents, targeting diet and physical activity and incorporating behaviour change techniques, was developed in phase I and delivered in the intervention arm to 16 groups in phase II. The eight groups in the comparator arm received the standard (unadapted) children's weight management programme., Main Outcome Measures: The primary outcome was the proportion of Pakistani and Bangladeshi families completing (attending ≥ 60% of) the adapted programme. Secondary outcomes included the proportion of all families completing the adapted programme, the feasibility of delivery of the programme, the programme's acceptability to participants, the feasibility of trial processes and the feasibility of collection of outcome and cost data., Results: The proportion of Pakistani and Bangladeshi families and all families completing the adapted programme was 78.8% [95% confidence interval (CI) 64.8% to 88.2%] and 76.3% (95% CI 67.0% to 83.6%), respectively. The programme was feasible to deliver with some refinements and was well received. Ninety-two families participated in outcome data collection. Data collection was mostly feasible, but participant burden was high. Data collection on the cost of programme delivery was feasible, but costs to families were more challenging to capture. There was high attrition over the 6-month follow-up period (35%) and differential attrition in the two study arms (29% and 52% in the intervention and comparator arms, respectively)., Limitations: The study was not designed to address the issue of low participant uptake of children's weight management programmes. The design of a future trial may include individual randomisation and a 'minimal intervention' arm, the acceptability of which has not been evaluated in this study., Conclusions: The theoretically informed, culturally adapted children's weight management programme was highly acceptable to children and families of all ethnicities. Consideration should be given to a future trial to evaluate clinical effectiveness and cost-effectiveness of the adapted programme, but the design of a future trial would need to address the logistics of data collection, participant burden and study attrition., Trial Registration: Current Controlled Trials ISRCTN81798055., 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. 33. See the NIHR Journals Library website for further project information. Kate Jolly is part-funded by the Collaboration for Leadership in Applied Health Research and Care West Midlands., Competing Interests: Eleanor McGee was the manager of the First Steps children’s weight management programme (the programme on which this study is based). Peymane Adab is a member of the National Institute for Health Research (NIHR) Public Health Research Funding Board. Jayne Parry undertakes committee work for the NIHR that attracts a small stipend, which is paid directly to the University of Birmingham where she is employed full-time.

Background: The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS)., Objectives: The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs., Design: Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis., Setting: One hundred and twenty-five UK paediatric departments., Participants: Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years)., Interventions: The control group ( n  = 118) received standard course (SC) prednisolone therapy: 60 mg/m 2 /day of prednisolone in weeks 1-4, 40 mg/m 2 of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m 2 ). The intervention group ( n  = 119) received extended course (EC) prednisolone therapy: 60 mg/m 2 /day of prednisolone in weeks 1-4; started at 60 mg/m 2 of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m 2 every 2 weeks (total 3150 mg/m 2 )., Main Outcome Measures: The primary outcome measure was time to first relapse [Albustix ® (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months., Results: There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank p  = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p  = 0.7), SDNS (44% vs. 42%; p  = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p  = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg ( p  = 0.07). SAE rates were not significantly different (25% vs. 17%; p  = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696)., Limitations: Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating., Conclusions: This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit., Future Work: Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted., Trial Registration: Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29., 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. 26. See the NIHR Journals Library website for further project information., Competing Interests: Nicholas JA Webb has served on advisory boards within the past 5 years for AbbVie Inc. (North Chicago, IL, USA), Alexion Pharmaceuticals (New Haven, CT, USA), AMAG Pharmaceuticals Inc. (Waltham, MA, USA), Astellas Pharma Inc. (Tokyo, Japan), Raptor Pharmaceuticals (Novato, CA, USA), Takeda Pharmaceutical Company (Osaka, Japan) and UCB (Union Chimique Belge) (Brussels, Belgium). These have related to the design and conduct of early-phase trials in childhood kidney disease. None has been related to the treatment of corticosteroid-sensitive nephrotic syndrome. Since August 2018, Nicholas JA Webb has been Translational Medicine Discovery Director, Renal and Transplantation, at Novartis Institutes for BioMedical Research. Carole Cummins has received grants from Kidney Research UK and Kids Kidney Research.

Background: Systematic reviews suggest that school-based interventions can be effective in preventing childhood obesity, but better-designed trials are needed that consider costs, process, equity, potential harms and longer-term outcomes., Objective: To assess the clinical effectiveness and cost-effectiveness of the WAVES (West Midlands ActiVe lifestyle and healthy Eating in School children) study intervention, compared with usual practice, in preventing obesity among primary school children., Design: A cluster randomised controlled trial, split across two groups, which were randomised using a blocked balancing algorithm. Schools/participants could not be blinded to trial arm. Measurement staff were blind to allocation arm as far as possible., Setting: Primary schools, West Midlands, UK., Participants: Schools within a 35-mile radius of the study centre and all year 1 pupils (aged 5-6 years) were eligible. Schools with a higher proportion of pupils from minority ethnic populations were oversampled to enable subgroup analyses., Interventions: The 12-month intervention encouraged healthy eating/physical activity (PA) by (1) helping teachers to provide 30 minutes of additional daily PA, (2) promoting 'Villa Vitality' (interactive healthy lifestyles learning, in an inspirational setting), (3) running school-based healthy cooking skills/education workshops for parents and children and (4) highlighting information to families with regard to local PA opportunities., Main Outcome Measures: The primary outcomes were the difference in body mass index z-scores (BMI-zs) between arms (adjusted for baseline body mass index) at 3 and 18 months post intervention (clinical outcome), and cost per quality-adjusted life-year (QALY) (cost-effectiveness outcome). The secondary outcomes were further anthropometric, dietary, PA and psychological measurements, and the difference in BMI-z between arms at 27 months post intervention in a subset of schools., Results: Two groups of schools were randomised: 27 in 2011 ( n  = 650 pupils) [group 1 (G1)] and another 27 in 2012 ( n  = 817 pupils) [group 2 (G2)]. Primary outcome data were available at first follow-up ( n  = 1249 pupils) and second follow-up ( n  = 1145 pupils) from 53 schools. The mean difference (MD) in BMI-z between the control and intervention arms was -0.075 [95% confidence interval (CI) -0.183 to 0.033] and -0.027 (95% CI -0.137 to 0.083) at 3 and 18 months post intervention, respectively. The main analyses showed no evidence of between-arm differences for any secondary outcomes. Third follow-up included data on 467 pupils from 27 G1 schools, and showed a statistically significant difference in BMI-z (MD -0.20, 95% CI -0.40 to -0.01). The mean cost of the intervention was £266.35 per consented child (£155.53 per child receiving the intervention). The incremental cost-effectiveness ratio associated with the base case was £46,083 per QALY (best case £26,804 per QALY), suggesting that the intervention was not cost-effective., Limitations: The presence of baseline primary outcome imbalance between the arms, and interschool variation in fidelity of intervention delivery., Conclusions: The primary analyses show no evidence of clinical effectiveness or cost-effectiveness of the WAVES study intervention. A post hoc analysis, driven by findings at third follow-up, suggests a possible intervention effect, which could have been attenuated by baseline imbalances. There was no evidence of an intervention effect on measures of diet or PA and no evidence of harm., Future Work: A realist evidence synthesis could provide insights into contextual factors and strategies for future interventions. School-based interventions need to be integrated within a wider societal framework and supported by upstream interventions., Trial Registration: Current Controlled Trials ISRCTN97000586., 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. 8. See the NIHR Journals Library website for further project information.

Objectives: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated., Data Sources: Major electronic databases were searched from inception to November 2006., Review Methods: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed., Results: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population., Conclusions: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.

Objectives: To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals., Data Sources: Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed., Review Methods: The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective., Results: Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses., Conclusions: Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.

Objectives: To investigate the clinical effectiveness and cost-effectiveness of naltrexone for relapse prevention in detoxified formerly opioid-dependent individuals compared with any strategy that does not use naltrexone, including treatment with placebo, other pharmacological treatments, psychosocial interventions or no treatment., Data Sources: Major electronic databases were searched from inception to September 2005., Review Methods: Selected studies were screened and quality assessed. Meta-analyses were carried out as appropriate. A decision-analytic model using Monte Carlo simulation was developed that compared naltrexone as an adjunctive therapy to no naltrexone. It assumed compliance rates that were not enhanced by contingent management rewards (because this is current UK practice). Utility values could not be identified from the literature and so were obtained by research specially commissioned from the Value of Health Panel., Results: The methodological quality of the 26 randomised controlled trials (RCTs) that met the inclusion criteria was poor to moderate. The results suggest that naltrexone as maintenance therapy may be better than placebo in terms of retention in treatment, but this was not statistically significant. A meta-analysis of seven included RCTs gave the relative risk (RR) of loss of retention in treatment in the naltrexone arm as 0.94. The pooled hazard ratio (HR) reported in five of the RCTs for retention in treatment data followed up to 35 weeks was calculated as 0.90 in favour of naltrexone and also did not reach statistical significance. The risk of drug abuse in naltrexone versus placebo, with or without psychological support given in both arms, gave a pooled RR of 0.72, which was a statistically significant difference in favour of naltrexone. The pooled HR from three RCTs for opioid relapse-free rates was significantly different from placebo in favour of naltrexone 0.53; however, this fell off over time and may be of limited clinical significance. The RR of reimprisonment while on naltrexone therapy showed results in favour of naltrexone in the combined two studies of parolees or people on probation, but the number of participants was small. One study of 52 participants found that the difference in improvement score for risky sexual behaviour in the naltrexone group compared with the placebo group was not statistically significant. The adverse events data reported showed no significant difference between the naltrexone and placebo arms. The quality of the nine RCTs of interventions designed to increase retention with naltrexone was poor to moderate; however, all three different modalities of enhanced care showed some evidence of effectiveness. All of the contingency management programmes used incentive vouchers; the mean duration of treatment retention was 7.4 weeks for the contingency management intervention compared with 2.3-5.6 weeks for the naltrexone treatment alone. The mean length of time for which patients stayed on naltrexone was 84-103 days with additional psychosocial therapy compared with 43-64 days for the control group. In trials with added pharmacological agents the RRs of stopping treatment were 1.63 at 6 months and 1.31 at 12 months (in favour of naltrexone plus fluoxetine). It became statistically significant at 6 months, but not at 12 months. A meta-analysis of the RR of stopping treatment at week 12 (the minimum follow-up period) was carried out using six of the nine studies. The pooled RR of stopping treatment was 0.81. The results indicated that overall the intervention groups had 19% fewer patients who stopped treatment compared with the control group, but there was only a small number of studies and their quality was relatively poor. No existing economic evaluations were identified. The point estimate for the cost-effectiveness of naltrexone was pound42,500 per quality-adjusted life-year (QALY). Sensitivity analysis was carried out and the incremental cost-effectiveness ratio varied between pound34,600 and pound42,500 per QALY gained., Conclusions: Following successful withdrawal from opioids, naltrexone may be administered on a chronic basis to block any future effects of opioids. Naltrexone appears to have some limited benefit in helping formerly opioid-dependent individuals to remain abstinent, although the quality of the evidence is relatively poor and heterogeneous. The limited quality and extent of the studies precluded an analysis of subgroups likely to benefit from naltrexone prescribing. Oral naltrexone is used infrequently in current UK practice, and this review suggests that this is appropriate as there is little evidence to support its wider implementation. There is an important deficit in information about the quality of life of people who use illicit opioids and this would perhaps be a worthwhile area of research in informing policy questions about the cost-effectiveness of different programmes and interventions.

Objectives: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease., Data Sources: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004., Review Methods: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case., Results: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY., Conclusions: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

Objectives: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1)., Data Sources: Electronic databases from inception up to mid-2004. Contact with clinical experts., Review Methods: Relevant studies were identified and assessed using recommended quality criteria., Results: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless., Conclusions: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.

Objectives: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin., Data Sources: Electronic databases. Drug company submissions., Review Methods: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model., Results: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective., Conclusions: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

Objectives: To assess the clinical and cost-effectiveness of parent training programmes for the treatment of children with conduct disorder (CD) up to the age of 18 years., Data Sources: Electronic databases., Review Methods: For the effectiveness review, relevant studies were identified and evaluated. A quantitative synthesis of behavioural outcomes across trials was also undertaken using two approaches: vote counting and meta-analysis. The economic analysis consisted of reviewing previous economic/cost evaluations of parent training/education programmes and the economic information within sponsor's submissions; carrying out a detailed exploration of costs of parent training/education programmes; and a de novo modelling assessment of the cost-effectiveness of parent training/education programmes. The potential budget impact to the health service of implementing such programmes was also considered., Results: Many of the 37 randomised controlled trials that met the review inclusion and exclusion criteria were assessed as being of poor methodological quality. Studies were clinically heterogeneous in terms of the population, type of parent training/education programme and content, setting, delivery, length and child behaviour outcomes used. Both vote counting and meta-analysis revealed a consistent trend across all studies towards short-term effectiveness (up to 4 months) of parent training/education programmes (compared with control) as measured by a change in child behaviour. Pooled estimates showed a statistically significant improvement on the Eyberg Child Behaviour Inventory frequency and intensity scales, the Dyadic Parent-Child Interaction Coding System and the Child Behaviour Checklist. No studies reported a statistically significant result favouring control over parent training/education programmes. There were few statistically significant differences between different parent training/education programmes, although there was a trend towards more intensive interventions (e.g. longer contact hours, additional child involvement) being more effective. The cost of treating CD is high, with costs incurred by many agencies. A recent study suggested that by age 28, costs for individuals with CD were around 10 times higher than for those with no problems, with a mean cost of 70,019 pounds sterling. Criminality incurs the greatest cost, followed by educational provision, foster and residential care and state benefits. Only a small proportion of these costs fall on health services. Using a 'bottom-up' costing approach, the costs per family of providing parent training/education programmes range from 629 pounds sterling to 3839 pounds sterling depending on the type and style of delivery. Using the conservative assumption that there are no cost savings from treatment, a total lifetime quality of life gain of 0.1 would give a cost per quality-adjusted life-year of between 38,393 pounds sterling and 6288 pounds sterling depending on the type of programme delivery and setting., Conclusions: Parent training/education programmes appear to be an effective and potentially cost-effective therapy for children with CD. However, the relative effectiveness and cost-effectiveness of different models (such as therapy intensity and setting) require further investigation. Further research is required on the impact of parent training/education programmes on the quality of life of children with CD and their parents/carers, as well as on longer term child outcomes.