National Institute For Health Research Health Technology Assessment Programme Research Articles

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT

Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. A total of 44 English general practices. Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed 'dose-by-age' amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. Immediate 'dose-by-age' oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated 'no' or 'very slight' problem (without need for analgesia). Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4-9), 4 (3-7) and 4 (3-6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. The over-riding weakness was the failure to recruit enough children. We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Modelling of hypothetical SARS-CoV-2 point of care tests for routine testing in residential care homes: rapid cost-effectiveness analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), which at the time of writing (January 2021) was responsible for more than 2.25 million deaths worldwide and over 100,000 deaths in the UK. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in residential care homes. The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests in the setting of a hypothetical care home facility for elderly residents. The perspective was that of the NHS in 2020. The setting was a hypothetical care home facility for elderly residents. Care homes with en suite rooms and with shared facilities were modelled separately. A discrete event simulation model was constructed to model individual residents and simulate the spread of SARS-CoV-2 once it had entered the residential care facility. The numbers of COVID-19-related deaths and critical cases were recorded in addition to the number of days spent in isolation. Thirteen strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests and for hospital-based SARS-CoV-2 tests were modelled. Scenario analyses modelled early release from isolation based on receipt of a negative SARS-CoV-2 test result and the impact of vaccination. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits. Cost-effectiveness results depended on the proportion of residential care facilities penetrated by SARS-CoV-2. SARS-CoV-2 point-of-care tests with desirable target product profiles appear to have high net monetary benefit values. In contrast, SARS-CoV-2 point-of-care tests with acceptable target product profiles had low net monetary benefit values because of unnecessary isolations. The benefit of allowing early release from isolation depended on whether or not the facility had en suite rooms. The greater the assumed efficacy of vaccination, the lower the net monetary benefit values associated with SARS-CoV-2 point-of-care tests, when assuming that a vaccine lowers the risk of contracting SARS-CoV-2. There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. Some degree of Monte Carlo sampling error persists because of the timelines of the project. The example care home simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly the cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. SARS-CoV-2 point-of-care tests have considerable potential for benefit for use in residential care facilities, but whether or not this materialises depends on the diagnostic accuracy and costs of forthcoming SARS-CoV-2 point-of-care tests. More accurate results would be obtained when there is more certainty on the diagnostic accuracy of and the reduction in time to test result associated with SARS-CoV-2 point-of-care tests when used in the context of residential care facilities, the proportion of care home penetrated by SARS-CoV-2 and the levels of immunity once vaccination is administered. These parameters are currently uncertain. This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 39. See the NIHR Journals Library website for further project information.

Modelling of hypothetical SARS-CoV-2 point-of-care tests on admission to hospital from A&E: rapid cost-effectiveness analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019. At the time of writing (October 2020), the number of cases of COVID-19 had been approaching 38 million and more than 1 million deaths were attributable to it. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in hospital wards. The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests. A further objective was to assess occupancy levels in hospital areas, such as waiting bays, before allocation to an appropriate bay. The perspective was that of the UK NHS in 2020. The setting was a hypothetical hospital with an accident and emergency department. An individual patient model was constructed that simulated the spread of disease and mortality within the hospital and recorded occupancy levels. Thirty-two strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests were modelled. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits, and key patient outcomes, such as death and intensive care unit care, caused directly by COVID-19 were recorded. A SARS-CoV-2 point-of-care test with a desirable target product profile appears to have a relatively small number of infections, a low occupancy level within the waiting bays, and a high net monetary benefit. However, if hospital laboratory testing can produce results in 6 hours, then the benefits of point-of-care tests may be reduced. The acceptable target product profiles performed less well and had lower net monetary benefits than both a laboratory-based test with a 24-hour turnaround time and strategies using data from currently available SARS-CoV-2 point-of-care tests. The desirable and acceptable point-of-care test target product profiles had lower requirement for patients to be in waiting bays before being allocated to an appropriate bay than laboratory-based tests, which may be of high importance in some hospitals. Tests that appeared more cost-effective also had better patient outcomes. There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. The example hospital simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. Should a SARS-CoV-2 point-of-care test with a desirable target product profile become available, this appears promising, particularly when the reduction on the requirements for waiting bays before allocation to a SARS-CoV-2-infected bay, or a non-SARS-CoV-2-infected bay, is considered. The results produced should be informative to decision-makers who can identify the results most pertinent to their specific circumstances. More accurate results could be obtained when there is more certainty on the diagnostic accuracy of, and the reduction in time to test result associated with, SARS-CoV-2 point-of-care tests, and on the impact of these tests on occupancy of waiting bays and isolation bays. These parameters are currently uncertain. This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 21. See the NIHR Journals Library website for further project information.

Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation. Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms. A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study. Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands. Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation. Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol. Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study. In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial. Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks. Current Controlled Trials ISRCTN52040363. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 21. See the NIHR Journals Library website for further project information.

Role of feasibility and pilot studies in randomised controlled trials: a cross-sectional study

ObjectivesTo assess the value of pilot and feasibility studies to randomised controlled trials (RCTs) funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. To explore...

National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme research funding and UK burden of disease

BackgroundHTA Programme funding is governed by the need for evidence and scientific quality, reflecting funding of the National Institute for Health Research (NIHR) by the NHS. The need criterion incorporates covering the spectrum of diseases, but also taking account of research supported by other funders. This study compared the NIHR HTA Programme portfolio of research with the UK burden of disease as measured by Disability-adjusted Life Years (DALYs).MethodsA retrospective cross-sectional study using a cohort of all funded primary research and evidence syntheses projects received by the HTA Programme from April 2011 to March 2016 (n = 363); to determine the proportion of spend by disease compared with burden of disease in the UK calculated using 2015 UK DALY data.ResultsThe programme costing just under £44 million broadly reflected UK DALY burden by disease. Spend was lower than disease burden for cancer, cardiovascular and musculoskeletal diseases, which may reflect the importance of other funders, notably medical charities, which concentrate on these diseases.ConclusionThe HTA Programme spend, adjusted for other relevant funders, broadly matches disease burden in the UK; no diseases are being neglected.

Therapy interventions for children with neurodisabilities: a qualitative scoping study.

Therapy interventions emerged four times in the top 10 research priorities in a James Lind Alliance research prioritisation exercise for children with neurodisabilities (Morris C, Simkiss D, Busk M, Morris M, Allard A, Denness J, et al. Setting research priorities to improve the health of children and young people with neurodisability: a British Academy of Childhood Disability-James Lind Alliance Research Priority Setting Partnership. BMJ Open 2015;5:e006233). The National Institute for Health Research (NIHR) commissioned this study as part of an information-gathering exercise in response to this. The objectives were to (1) describe the current practice, approaches and schools of thought in relation to physiotherapy, occupational therapy and speech and language therapy for children with neurodisability; (2) explore clinical decision-making; (3) investigate views on outcomes and their measurement, particularly participation as an outcome, that is, the child's ability to have the opportunity to be involved in life situations and activities (e.g. communication, mobility, interpersonal interactions, self-care, learning and applying knowledge); (4) seek views on the aspects of therapy interventions that have an impact on outcomes; and (5) elicit stakeholder views on research needs and priorities. More than 70 professionals (therapists, service leads, paediatricians and education staff) and 25 parents participated in a qualitative interview (either individually or as part of a focus group). Professional thinking and models of service delivery are in a state of flux and development. There is a move towards goals-focused, family-centred approaches. Work tends to be highly individualised, with few protocols. Parents are certain of the value of therapies, although they may experience difficulties with provision and may seek (additional) private provision. Therapy interventions are conceived as three components: the therapist, the procedures/equipment, etc., and the wider therapeutic environment. They are believed to be highly complex and poorly understood. Although participation is widely endorsed as a core intervention objective of therapy interventions, its suitability, or appropriateness, as an outcome measure was questioned. Other child and/or parent outcomes were identified as more or equally important. Notions of intermediate outcomes - in terms of body structure/function, and the achievement of activities - were regarded as important and not counter to participation-focused approaches. Among therapists, research on intervention effectiveness was (cautiously) welcomed. A number of methodological challenges were identified. A portfolio of study designs - quantitative and qualitative, experimental and observational - was called for, and which included economic evaluation and clear pathways to impact. The study was not successful in recruiting children and young people. Further work is required to elucidate the views of this key stakeholder group. Therapy interventions are poorly understood. There was strong support, tempered a little by concerns among some about the feasibility of demonstrating impact, for investment in research. The identification of research priorities was a core study objective, and a wide-ranging research agenda was identified. It included 'foundational' research into neurodisability, the active components of therapy interventions and the concept of participation. Three areas of evaluation were identified: overall approaches to therapy, service organisation and delivery issues, and the evaluation of specific techniques. Parents regarded evaluations of approaches to therapy (e.g. goals-focused; supporting family-self management) as priorities, along with evaluations of models of service provision. Professionals' views were broadly similar, with an additional emphasis on methodological research. In terms of specific techniques, there was no shared agreement regarding priorities, with views informed by personal interests and experiences. The NIHR Health Technology Assessment programme.

Self-management toolkit and delivery strategy for end-of-life pain: the mixed-methods feasibility study.

Pain affects most people approaching the end of life and can be severe for some. Opioid analgesia is effective, but evidence is needed about how best to support patients in managing these medicines. To develop a self-management support toolkit (SMST) and delivery strategy and to test the feasibility of evaluating this intervention in a future definitive trial. Phase I - evidence synthesis and qualitative interviews with patients and carers. Phase II - qualitative semistructured focus groups and interviews with patients, carers and specialist palliative care health professionals. Phase III - multicentre mixed-methods single-arm pre-post observational feasibility study. Phase I - six patients and carers. Phase II - 15 patients, four carers and 19 professionals. Phase III - 19 patients recruited to intervention that experienced pain, living at home and were treated with strong opioid analgesia. Process evaluation interviews with 13 patients, seven carers and 11 study nurses. Self-Management of Analgesia and Related Treatments at the end of life (SMART) intervention comprising a SMST and a four-step educational delivery approach by clinical nurse specialists in palliative care over 6 weeks. Recruitment rate, treatment fidelity, treatment acceptability, patient-reported outcomes (such as scores on the Brief Pain Inventory, Self-Efficacy for Managing Chronic Disease Scale, Edmonton Symptom Assessment Scale, EuroQol-5 Dimensions, Satisfaction with Information about Medicines Scale, and feasibility of collecting data on health-care resource use for economic evaluation). Phase I - key themes on supported self-management were identified from evidence synthesis and qualitative interviews. Phase II - the SMST was developed and refined. The delivery approach was nested within a nurse-patient consultation. Phase III - intervention was delivered to 17 (89%) patients, follow-up data at 6 weeks were available on 15 patients. Overall, the intervention was viewed as acceptable and valued. Descriptive analysis of patient-reported outcomes suggested that interference from pain and self-efficacy were likely to be candidates for primary outcomes in a future trial. No adverse events related to the intervention were reported. The health economic analysis suggested that SMART could be cost-effective. We identified key limitations and considerations for a future trial: improve recruitment through widening eligibility criteria, refine the SMST resources content, enhance fidelity of intervention delivery, secure research nurse support at recruiting sites, refine trial procedures (including withdrawal process and data collection frequency), and consider a cluster randomised design with nurse as cluster unit. (1) The recruitment rate was lower than anticipated. (2) The content of the intervention was focused on strong opioids only. (3) The fidelity of intervention delivery was limited by the need for ongoing training and support. (4) Recruitment sites where clinical research nurse support was not secured had lower recruitment rates. (5) The process for recording withdrawal was not sufficiently detailed. (6) The number of follow-up visits was considered burdensome for some participants. (7) The feasibility trial did not have a control arm or assess randomisation processes. A future randomised controlled trial is feasible and acceptable. This study is registered as PROSPERO CRD42014013572; Current Controlled Trials ISRCTN35327119; and National Institute for Health Research (NIHR) Portfolio registration 162114. The NIHR Health Technology Assessment programme.

Managing diabetes in people with dementia: a realist review.

Dementia and diabetes mellitus are common long-term conditions that coexist in a large number of older people. People living with dementia and diabetes may be at increased risk of complications such as hypoglycaemic episodes because they are less able to manage their diabetes. To identify the key features or mechanisms of programmes that aim to improve the management of diabetes in people with dementia and to identify areas needing further research. Realist review, using an iterative, stakeholder-driven, four-stage approach. This involved scoping the literature and conducting stakeholder interviews to develop initial programme theories, systematic searches of the evidence to test and develop the theories, and the validation of programme theories with a purposive sample of stakeholders. Twenty-six stakeholders (user/patient representatives, dementia care providers, clinicians specialising in dementia or diabetes and researchers) took part in interviews and 24 participated in a consensus conference. The following databases were searched from 1990 to March 2016: MEDLINE (PubMed), Cumulative Index to Nursing and Allied Health Literature, Scopus, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Database of Abstracts of Reviews of Effects, the Health Technology Assessment (HTA) database, NHS Economic Evaluation Database, AgeInfo (Centre for Policy on Ageing - UK), Social Care Online, the National Institute for Health Research (NIHR) portfolio database, NHS Evidence, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (Google Inc., Mountain View, CA, USA). We included 89 papers. Ten papers focused directly on people living with dementia and diabetes, and the rest related to people with dementia or diabetes or other long-term conditions. We identified six context-mechanism-outcome (CMO) configurations that provide an explanatory account of how interventions might work to improve the management of diabetes in people living with dementia. This includes embedding positive attitudes towards people living with dementia, person-centred approaches to care planning, developing skills to provide tailored and flexible care, regular contact, family engagement and usability of assistive devices. A general metamechanism that emerges concerns the synergy between an intervention strategy, the dementia trajectory and social and environmental factors, especially family involvement. A flexible service model for people with dementia and diabetes would enable this synergy in a way that would lead to the improved management of diabetes in people living with dementia. There is little evidence relating to the management of diabetes in people living with dementia, although including a wider literature provided opportunities for transferable learning. The outcomes in our CMOs are largely experiential rather than clinical. This reflects the evidence available. Outcomes such as increased engagement in self-management are potential surrogates for better clinical management of diabetes, but this is not proven. This review suggests that there is a need to prioritise quality of life, independence and patient and carer priorities over a more biomedical, target-driven approach. Much current research, particularly that specific to people living with dementia and diabetes, identifies deficiencies in, and problems with, current systems. Although we have highlighted the need for personalised care, continuity and family-centred approaches, there is much evidence to suggest that this is not currently happening. Future research on the management of diabetes in older people with complex health needs, including those with dementia, needs to look at how organisational structures and workforce development can be better aligned to the needs of people living with dementia and diabetes. This study is registered as PROSPERO CRD42015020625. The NIHR HTA programme.

International multicentre randomised controlled trial of improvisational music therapy for children with autism spectrum disorder: TIME-A study

Preliminary studies have indicated that music therapy may benefit children with autism spectrum disorders (ASD). To examine the effects of improvisational music therapy (IMT) on social affect and responsiveness of children with ASD. International, multicentre, three-arm, single-masked randomised controlled trial, including a National Institute for Health Research (NIHR)-funded centre that recruited in London and the east of England. Randomisation was via a remote service using permuted blocks, stratified by study site. Schools and private, voluntary and state-funded health-care services. Children aged between 4 and 7 years with a confirmed diagnosis of ASD and a parent or guardian who provided written informed consent. We excluded children with serious sensory disorder and those who had received music therapy within the past 12 months. All parents and children received enhanced standard care (ESC), which involved three 60-minute sessions of advice and support in addition to treatment as usual. In addition, they were randomised to either one (low-frequency) or three (high-frequency) sessions of IMT per week, or to ESC alone, over 5 months in a ratio of 1 : 1 : 2. The primary outcome was measured using the social affect score derived from the Autism Diagnostic Observation Schedule (ADOS) at 5 months: higher scores indicated greater impairment. Secondary outcomes included social affect at 12 months and parent-rated social responsiveness at 5 and 12 months (higher scores indicated greater impairment). A total of 364 participants were randomised between 2011 and 2015. A total of 182 children were allocated to IMT (90 to high-frequency sessions and 92 to low-frequency sessions), and 182 were allocated to ESC alone. A total of 314 (86.3%) of the total sample were followed up at 5 months [165 (90.7%) in the intervention group and 149 (81.9%) in the control group]. Among those randomised to IMT, 171 (94.0%) received it. From baseline to 5 months, mean scores of ADOS social affect decreased from 14.1 to 13.3 in music therapy and from 13.5 to 12.4 in standard care [mean difference: music therapy vs. standard care = 0.06, 95% confidence interval (CI) -0.70 to 0.81], with no significant difference in improvement. There were also no differences in the parent-rated social responsiveness score, which decreased from 96.0 to 89.2 in the music therapy group and from 96.1 to 93.3 in the standard care group over this period (mean difference: music therapy vs. standard care = -3.32, 95% CI -7.56 to 0.91). There were seven admissions to hospital that were unrelated to the study interventions in the two IMT arms compared with 10 unrelated admissions in the ESC group. Adding IMT to the treatment received by children with ASD did not improve social affect or parent-assessed social responsiveness. Other methods for delivering music-focused interventions for children with ASD should be explored. Current Controlled Trials ISRCTN78923965. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 59. See the NIHR Journals Library website for further project information.

ImmunoCAP® ISAC and Microtest for multiplex allergen testing in people with difficult to manage allergic disease: a systematic review and cost analysis.

Allergy is a form of immune-mediated exaggerated sensitivity (hypersensitivity) to a substance that is either inhaled, swallowed, injected or comes into contact with the skin. Foreign substances that provoke allergies are called allergens. It has been claimed that multiplex allergen testing may help in diagnosing the cause of symptoms in patients with an unclear cause of allergy or who are allergic to more than one substance. To evaluate multiplex allergen testing [devices that can measure the presence of multiple immunoglobulin E (IgE) antibodies in a patient's blood at the same time], by assessing (1) clinical effectiveness (allergy symptoms, incidence of acute exacerbations, mortality, adverse events of testing and treatment, health-care presentations or admissions, health-related quality of life); (2) effects on treatment (diet, immunotherapy medications, other potential testing); (3) any additional diagnostic information provided by multiplex allergen testing; and (4) cost-effectiveness (cost of different assessment strategies). Fifteen databases were searched from 2005 to April 2015, including MEDLINE (via OvidSp), MEDLINE In-Process Citations, MEDLINE Daily Update, PubMed (National Library of Medicine), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Science Citation Index (SCI), Conference Proceedings Citation Index-Science (CPCI-S), BIOSIS Previews, Latin American and Caribbean Health Sciences Literature (LILACS), National Institute for Health Research (NIHR) HTA programme, and the US Food and Drug Administration (FDA); supplementary searches of conference proceedings and trials registries were performed. Review methods followed published guidance from the Cochrane Collaboration and the Centre for Reviews and Dissemination, University of York, UK. The methodological quality of included studies was assessed using appropriate published tools or a review-specific tool designed by the project team. Studies were summarised in a narrative synthesis. Owing to a lack of data on the clinical effectiveness of multiplex allergen testing, no long-term cost-effectiveness model was developed. A conceptual model structure was developed and cost analyses were performed to examine the short-term costs of various possible diagnostic pathways. Fifteen studies were included in the review. The very limited available data indicated that the addition of multiplex allergen testing [ImmunoCAP(®) Immuno Solid-phase Allergen Chip (ISAC), Thermo Fisher Scientific/Phadia AB, Uppsala, Sweden] to standard diagnostic work-up can change the clinicians' views on the diagnosis, management and treatment of patients. There was some indication that the use of ImmunoCAP ISAC testing may be useful to guide decisions on the discontinuation of restrictive diets, the content of allergen-specific immunotherapy (SIT) prescriptions, and whether or not patients should receive SIT. However, none of the studies that we identified reported any information on clinical outcomes subsequent to changes in treatment or management. There was some evidence that ImmunoCAP ISAC may be useful for discriminating allergens that are structurally similar and are recognised by the same IgE antibody (cross-immunoreactive). No data were available for Microtest (Microtest Matrices Ltd, London, UK). Detailed cost analyses suggested that multiplex allergen testing would have to result in a substantial reduction of the proportions of patients receiving single IgE testing and oral food challenge tests in order to be cost-saving in the short term. No recommendations for service provision can be made based on the analyses included in this report. It is suggested that a consensus-based protocol for the use of multiplex allergen testing be developed. The clinical effectiveness and cost-effectiveness of the proposed protocol should then be assessed by comparing long-term clinical and quality of life outcomes and resource use in patients managed using the protocol with those managed using a standard diagnostic pathway. This study is registered as PROSPERO CRD42015019739. This project was a Diagnostic Assessment Report commissioned by the NIHR HTA programme on behalf of the National Institute for Health and Care Excellence.

Breast pumps as an incentive for breastfeeding: a mixed methods study of acceptability.

Increasing breastfeeding rates would improve maternal and child health, but multiple barriers to breastfeeding persist. Breast pump provision has been used as an incentive for breastfeeding, although effectiveness is unclear. Women's use of breast pumps is increasing and a high proportion of mothers express breastmilk. No research has yet reported women's and health professionals' perspectives on breast pumps as an incentive for breastfeeding. In the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study, mixed methods research explored women's and professionals' views of breast pumps as an incentive for breastfeeding. A survey of health professionals across Scotland and North West England measured agreement with ‘a breast pump costing around £40 provided for free on the NHS’ as an incentive strategy. Qualitative interviews and focus groups were conducted in two UK regions with a total of 68 participants (pregnant women, new mothers, and their significant others and health professionals) and thematic analysis undertaken. The survey of 497 health professionals found net agreement of 67.8% (337/497) with the breast pump incentive strategy, with no predictors of agreement shown by a multiple ordered logistic regression model. Qualitative research found interrelated themes of the ‘appeal and value of breast pumps’, ‘sharing the load’, ‘perceived benefits’, ‘perceived risks’ and issues related to ‘timing’. Qualitative participants expressed mixed views on the acceptability of breast pumps as an incentive for breastfeeding. Understanding the mechanisms of action for pump type, timing and additional support required for effectiveness is required to underpin trials of breast pump provision as an incentive for improving breastfeeding outcomes. © 2016 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.

Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis.

Patients with substantive bleeding usually require transfusion and/or (re-)operation. Red blood cell (RBC) transfusion is independently associated with a greater risk of infection, morbidity, increased hospital stay and mortality. ROTEM (ROTEM® Delta, TEM International GmbH, Munich, Germany; www.rotem.de), TEG (TEG® 5000 analyser, Haemonetics Corporation, Niles, IL, USA; www.haemonetics.com) and Sonoclot (Sonoclot® coagulation and platelet function analyser, Sienco Inc., Arvada, CO) are point-of-care viscoelastic (VE) devices that use thromboelastometry to test for haemostasis in whole blood. They have a number of proposed advantages over standard laboratory tests (SLTs): they provide a result much quicker, are able to identify what part of the clotting process is disrupted, and provide information on clot formation over time and fibrinolysis. This assessment aimed to assess the clinical effectiveness and cost-effectiveness of VE devices to assist with the diagnosis, management and monitoring of haemostasis disorders during and after cardiac surgery, trauma-induced coagulopathy and post-partum haemorrhage (PPH). Sixteen databases were searched to December 2013: MEDLINE (OvidSP), MEDLINE In-Process and Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE (OvidSP), BIOSIS Previews (Web of Knowledge), Science Citation Index (SCI) (Web of Science), Conference Proceedings Citation Index (CPCI-S) (Web of Science), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Latin American and Caribbean Health Sciences Literature (LILACS), International Network of Agencies for Health Technology Assessment (INAHTA), National Institute for Health Research (NIHR) HTA programme, Aggressive Research Intelligence Facility (ARIF), Medion, and the International Prospective Register of Systematic Reviews (PROSPERO). Randomised controlled trials (RCTs) were assessed for quality using the Cochrane Risk of Bias tool. Prediction studies were assessed using QUADAS-2. For RCTs, summary relative risks (RRs) were estimated using random-effects models. Continuous data were summarised narratively. For prediction studies, the odds ratio (OR) was selected as the primary effect estimate. The health-economic analysis considered the costs and quality-adjusted life-years of ROTEM, TEG and Sonoclot compared with SLTs in cardiac surgery and trauma patients. A decision tree was used to take into account short-term complications and longer-term side effects from transfusion. The model assumed a 1-year time horizon. Thirty-one studies (39 publications) were included in the clinical effectiveness review. Eleven RCTs (n=1089) assessed VE devices in patients undergoing cardiac surgery; six assessed thromboelastography (TEG) and five assessed ROTEM. There was a significant reduction in RBC transfusion [RR 0.88, 95% confidence interval (CI) 0.80 to 0.96; six studies], platelet transfusion (RR 0.72, 95% CI 0.58 to 0.89; six studies) and fresh frozen plasma to transfusion (RR 0.47, 95% CI 0.35 to 0.65; five studies) in VE testing groups compared with control. There were no significant differences between groups in terms of other blood products transfused. Continuous data on blood product use supported these findings. Clinical outcomes did not differ significantly between groups. There were no apparent differences between ROTEM or TEG; none of the RCTs evaluated Sonoclot. There were no data on the clinical effectiveness of VE devices in trauma patients or women with PPH. VE testing was cost-saving and more effective than SLTs. For the cardiac surgery model, the cost-saving was £43 for ROTEM, £79 for TEG and £132 for Sonoclot. For the trauma population, the cost-savings owing to VE testing were more substantial, amounting to per-patient savings of £688 for ROTEM compared with SLTs, £721 for TEG, and £818 for Sonoclot. This finding was entirely dependent on material costs, which are slightly higher for ROTEM. VE testing remained cost-saving following various scenario analyses. VE testing is cost-saving and more effective than SLTs, in both patients undergoing cardiac surgery and trauma patients. However, there were no data on the clinical effectiveness of Sonoclot or of VE devices in trauma patients. This study is registered as PROSPERO CRD42013005623. The NIHR Health Technology Assessment programme.

The impact of Cochrane Reviews: a mixed-methods evaluation of outputs from Cochrane Review Groups supported by the National Institute for Health Research.

The last few decades have seen a growing emphasis on evidence-informed decision-making in health care. Systematic reviews, such as those produced by Cochrane, have been a key component of this movement. The National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs) in the UK and it is important that this funding represents value for money. The overall aim was to identify the impacts and likely impacts on health care, patient outcomes and value for money of Cochrane Reviews published by 20 NIHR-funded CRGs during the years 2007-11. We sent questionnaires to CRGs and review authors, undertook interviews with guideline developers (GDs) and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane Reviews. The evaluation was guided by a framework with four categories (knowledge production, research targeting, informing policy development and impact on practice/services). A total of 3187 new and updated reviews were published on the Cochrane Database of Systematic Reviews between 2007 and 2011, 1502 (47%) of which were produced by the 20 CRGs funded by the NIHR. We found 40 examples where reviews appeared to have influenced primary research and reviews had contributed to the creation of new knowledge and stimulated debate. Twenty-seven of the 60 reviews had 100 or more citations in Google Scholar™ (Google, CA, USA). Overall, 483 systematic reviews had been cited in 247 sets of guidance. This included 62 sets of international guidance, 175 sets of national guidance (87 from the UK) and 10 examples of local guidance. Evidence from the interviews suggested that Cochrane Reviews often play an instrumental role in informing guidance, although reviews being a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and GDs were barriers to their use. Cochrane Reviews appeared to have led to a number of benefits to the health service including safer or more appropriate use of medication or other health technologies or the identification of new effective drugs or treatments. However, whether or not these changes were directly as a result of the Cochrane Review and not the result of subsequent clinical guidance was difficult to judge. Potential benefits of Cochrane Reviews included economic benefits through budget savings or the release of funds, improvements in clinical quality, the reduction in the use of unproven or unnecessary procedures and improvements in patient and carer experiences. This study identified a number of impacts and likely impacts of Cochrane Reviews. The clearest impacts of Cochrane Reviews are on research targeting and health-care policy, with less evidence of a direct impact on clinical practice and the organisation and delivery of NHS services. Although it is important for researchers to consider how they might increase the influence of their work, such impacts are difficult to measure. More work is required to develop suitable methods for defining and quantifying the impact of research. The NIHR Health Technology Assessment programme.

Smoking Cessation Intervention for severe Mental Ill Health Trial (SCIMITAR): a pilot randomised control trial of the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation service.

There is a high prevalence of smoking among people who experience severe mental ill health (SMI). Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health, increase longevity and also reduce health inequalities. Around half of people with SMI who smoke express an interest in cutting down or quitting smoking. There is limited evidence that smoking cessation can be achieved for people with SMI. Those with SMI rarely access routine NHS smoking cessation services. This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI. The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment, randomisation and follow-up. We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness. The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual general practitioner (GP) care for people with SMI. A pilot pragmatic two-arm individually randomised controlled trial (RCT). Simple randomisation was used following a computer-generated random number sequence. Participants and practitioners were not blinded to allocation. Primary care and secondary care mental health services in England. Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking. A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual GP care. The primary outcome was carbon monoxide-verified smoking cessation at 12 months. Smoking-related secondary outcomes were reduction of number of cigarettes smoked, Fagerstrom test of nicotine dependence and motivation to quit (MTQ). Other secondary outcomes were Patient Health Questionnaire-9 items and Short Form Questionnaire-12 items to assess whether there were improvements or deterioration in mental health and quality of life. We also measured body mass index to assess whether or not smoking cessation was associated with weight gain. These were measured at 1, 6 and 12 months post randomisation. The trial recruited 97 people aged 19-73 years who smoked between 5 and 60 cigarettes per day (mean 25 cigarettes). Participants were recruited from four mental health trusts and 45 GP surgeries. Forty-six people were randomised to the BSC intervention and 51 people were randomised to usual GP care. The odds of quitting at 12 months was higher in the BSC intervention (36% vs. 23%) but did not reach statistical significance (odds ratio 2.9; 95% confidence interval 0.8% to 10.5%). At 3 and 6 months there was no evidence of difference in self-reported smoking cessation. There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence. MTQ and number of quit attempts all increased in the BSC group compared with usual care. There was no difference in terms of quality of life at any time point, but there was evidence of an increase in depression scores at 12 months for the BSC group. There were no serious adverse events thought likely to be related to the trial interventions. The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis. It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication. The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants. A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research (NIHR) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness. Current Controlled Trials ISRCTN79497236. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 19, No. 25. See the NIHR Journals Library website for further project information.

Systematic evaluation of the patient-reported outcome (PRO) content of clinical trial protocols.

BackgroundQualitative evidence suggests patient-reported outcome (PRO) information is frequently absent from clinical trial protocols, potentially leading to inconsistent PRO data collection and risking bias. Direct evidence regarding PRO trial protocol content is lacking. The aim of this study was to systematically evaluate the PRO-specific content of UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme trial protocols.Methods and FindingsWe conducted an electronic search of the NIHR HTA programme database (inception to August 2013) for protocols describing a randomised controlled trial including a primary/secondary PRO. Two investigators independently reviewed the content of each protocol, using a specially constructed PRO-specific protocol checklist, alongside the ‘Standard Protocol Items: Recommendations for Interventional Trials’ (SPIRIT) checklist. Disagreements were resolved through discussion with a third investigator. 75 trial protocols were included in the analysis. Protocols included a mean of 32/51 (63%) SPIRIT recommendations (range 16–41, SD 5.62) and 11/33 (33%) PRO-specific items (range 4–18, SD 3.56). Over half (61%) of the PRO items were incomplete. Protocols containing a primary PRO included slightly more PRO checklist items (mean 14/33 (43%)). PRO protocol content was not associated with general protocol completeness; thus, protocols judged as relatively ‘complete’ using SPIRIT were still likely to have omitted a large proportion of PRO checklist items.ConclusionsThe PRO components of HTA clinical trial protocols require improvement. Information on the PRO rationale/hypothesis, data collection methods, training and management was often absent. This low compliance is unsurprising; evidence shows existing PRO guidance for protocol developers remains difficult to access and lacks consistency. Study findings suggest there are a number of PRO protocol checklist items that are not fully addressed by the current SPIRIT statement. We therefore advocate the development of consensus-based supplementary guidelines, aimed at improving the completeness and quality of PRO content in clinical trial protocols.

The clinical relevance and newsworthiness of NIHR HTA-funded research: a cohort study

ObjectiveTo assess the clinical relevance and newsworthiness of the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme funded reports.Study designRetrospective cohort study.SettingThe cohort included 311 NIHR...

Time to publication for NIHR HTA programme-funded research: a cohort study

ObjectiveTo assess the time to publication of primary research and evidence syntheses funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme published as a monograph...