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IntroductionACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence.Methods and analysisPOSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised.Ethics and disseminationProtocol was approved by the National Research Ethics Service Committee East Midlands—Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals.Trial registration numberISRCTN54765244;NCT0240168Cite Now

BackgroundPatients diagnosed with advanced primary open-angle glaucoma are at a high risk of lifetime blindness. Uncertainty exists about whether primary medical management (glaucoma eye drops) or primary surgical treatment (augmented trabeculectomy) provide the best and safest patient outcomes.ObjectivesTo compare primary medical management with primary surgical treatment (augmented trabeculectomy) in patients with primary open-angle glaucoma presenting with advanced disease in terms of health-related quality of life, clinical effectiveness, safety and cost-effectiveness.DesignThis was a two-arm, parallel, multicentre, pragmatic randomised controlled trial.SettingSecondary care eye services.ParticipantsAdult patients presenting with advanced primary open-angle glaucoma in at least one eye, as defined by the Hodapp–Parrish–Anderson classification of severe glaucoma.InterventionPrimary medical treatment – escalating medical management with glaucoma eye drops. Primary trabeculectomy treatment – trabeculectomy augmented with mitomycin C.Main outcome measuresThe primary outcome was health-related quality of life measured with the Visual Function Questionnaire-25 at 2 years post randomisation. Secondary outcomes were mean intraocular pressure; EQ-5D-5L; Health Utilities Index 3; Glaucoma Utility Index; cost and cost-effectiveness; generic, vision-specific and disease-specific health-related quality of life; clinical effectiveness; and safety.ResultsA total of 453 participants were recruited. The mean age of the participants was 67 years (standard deviation 12 years) in the trabeculectomy arm and 68 years (standard deviation 12 years) in the medical management arm. Over 65% of participants were male and more than 80% were white. At 24 months, the mean difference in Visual Function Questionnaire-25 score was 1.06 (95% confidence interval –1.32 to 3.43;p = 0.383). There was no evidence of a difference between arms in the EQ-5D-5L score, the Health Utilities Index or the Glaucoma Utility Index. At 24 months, the mean intraocular pressure was 12.40 mmHg in the trabeculectomy arm and 15.07 mmHg in the medical management arm (mean difference –2.75 mmHg, 95% confidence interval –3.84 to –1.66 mmHg;p p = 0.006) than in the trabeculectomy arm. There was no evidence of difference in safety between the two arms. A discrete choice experiment updated the utility values for the Glaucoma Utility Index. The within-trial economic analysis found a small increase in the mean EQ-5D-5L score (0.04) and that trabeculectomy has a higher probability of being cost-effective than medical management. The incremental cost of trabeculectomy per quality-adjusted life-year was £45,456. Therefore, at 2 years, surgery is unlikely to be considered cost-effective at a threshold of £20,000 per quality-adjusted life-year. When extrapolated over a patient’s lifetime in a model-based analysis, trabeculectomy, compared with medical treatment, was associated with higher costs (average £2687), a larger number of quality-adjusted life-years (average 0.28) and higher incremental cost per quality-adjusted life-year gained (average £9679). The likelihood of trabeculectomy being cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life year gained was 73%.ConclusionsOur results suggested that there was no difference between treatment arms in health-related quality of life, as measured with the Visual Function Questionnaire-25 at 24 months. Intraocular pressure was better controlled in the trabeculectomy arm, and this may reduce visual field progression. Modelling over the patient’s lifetime suggests that trabeculectomy may be cost-effective over the range of values of society’s willingness to pay for a quality-adjusted life-year.Future workFurther follow-up of participants will allow us to estimate the long-term differences of disease progression, patient experience and cost-effectiveness.Trial registrationCurrent Controlled Trials ISRCTN56878850.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 25, No. 72. See the NIHR Journals Library website for further project information.

Fall-related injuries are a significant cause of morbidity and mortality in people with dementia. There is presently little evidence to guide the management of such injuries, and yet there are potentially substantial benefits to be gained if the outcomes of these injuries could be improved. This study aimed to design an appropriate new health-care intervention for people with dementia following a fall and to assess the feasibility of its delivery in the UK NHS.To determine whether or not it is possible to design an intervention to improve outcomes of falls in dementia, to investigate the feasibility and acceptability of the DIFRID (Developing an Intervention for Fall related Injuries in Dementia) intervention and to investigate the feasibility of a future randomised controlled trial and the data collection tools needed to evaluate both the effectiveness and the cost-effectiveness of the DIFRID intervention.This was a mixed-methods feasibility study. A systematic review (using Cochrane methodology) and realist review [using Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) methodology] explored the existing evidence base and developed programme theories. Searches were carried out in November 2015 (updated in January 2018) for effectiveness studies and in August 2016 for economic studies. A prospective observational study identified service use via participant diary completion. Qualitative methods (semistructured interviews, focus groups and observation) were used to explore current practice, stakeholder perspectives of the health and social care needs of people with dementia following a fall, ideas for intervention and barriers to and facilitators of change. Each of the resulting data sets informed intervention development via Delphi consensus methods. Finally, a single-arm feasibility study with embedded process evaluation was conducted.This study was set in the community.The participants were (1) people with dementia presenting with falls necessitating health-care attention in each setting (primary care, the community and secondary care) at three sites and their carers, (2) professionals delivering the intervention, who were responsible for training and supervision and who were members of the intervention team, (3) professionals responsible for approaching and recruiting participants and (4) carers of participants with dementia.This was a complex multidisciplinary therapy intervention. Physiotherapists, occupational therapists and support workers delivered up to 22 sessions of tailored activities in the home or local area of the person with dementia over a period of 12 weeks.(1) Assessment of feasibility of study procedures; (2) assessment of the acceptability, feasibility and fidelity of intervention components; and (3) assessment of the suitability and acceptability of outcome measures for people with dementia and their carers (number of falls, quality of life, fear of falling, activities of daily living, goal-setting, health-care utilisation and carer burden).A multidisciplinary intervention delivered in the homes of people with dementia was designed based on qualitative work, realist review and recommendations of the consensus panel. The intervention was delivered to 11 people with dementia. The study suggested that the intervention is both feasible and acceptable to stakeholders. A number of modifications were recommended to address some of the issues arising during feasibility testing. The measurement of outcome measures was successful.The study has highlighted the feasibility of delivering a creative, tailored, individual approach to intervention for people with dementia following a fall. Although the intervention required greater investment of time than usual practice, many staff valued the opportunity to work more closely with people with dementia and their carers. We conclude that further research is now needed to refine this intervention in the context of a pilot randomised controlled trial.Current Controlled Trials ISRCTN41760734 and PROSPERO CRD42016029565.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inPeople with dementia fall over more often than people who do not have dementia. When they fall over, they are more likely to hurt themselves. They do not get better as easily as people without dementia. After hurting themselves, people with dementia may need a lot more help in looking after themselves. They, and their carer, may not have such a good quality of life after the fall. In this study, we developed and tested a package of care to help people with dementia recover from a fall. In the first part of the study, we looked for papers about clinical trials that have tried to make things better for people with dementia who have had a fall. We found that there were very few previous clinical trials, but we found ideas for ways in which this could be improved. In the second part of the study, we found out what happens to people with dementia who ask for help after an injury due to a fall. We found that very few services were used by people with dementia who fall. We interviewed them and their carers to find out what help they thought they needed after the fall and what they thought we could do better. We also spoke to the staff in existing services to find out how they thought services for people with dementia could be improved. In the third part of the study, we asked a group of experts, people with dementia and their carers to look at the findings of the first two parts of the study. They helped us to design a care package for people with dementia after a fall. In the fourth part of the study, we practised giving the new care package to 11 people with dementia in their own homes. This was very successful and we now recommend that the package is tested further in randomised controlled clinical trials.

Background Falls in people with dementia can result in a number of physical and psychosocial consequences. However, there is limited evidence to inform how best to deliver services to people with dementia following a fall. The aim of the DIFRID study was to determine the feasibility of developing and implementing a new intervention to improve outcomes for people with dementia with fall-related injuries; this encompasses both short-term recovery and reducing the likelihood of future falls. This paper details the development of the DIFRID intervention. Methods The intervention was designed using an integrated, mixed-methods approach. This involved a realist synthesis of the literature and qualitative data gathered through interviews and focus groups with health and social care professionals (n = 81). An effectiveness review and further interviews and observation were also conducted and are reported elsewhere. A modified Delphi panel approach with 24 experts was then used to establish a consensus on how the findings should translate into a new intervention. After feedback from key stakeholders (n = 15) on the proposed model, the intervention was manualised and training developed. Results We identified key components of a new intervention covering three broad areas: • Ensuring that the circumstances of rehabilitation are optimised for people with dementia • Compensating for the reduced ability of people with dementia to self-manage • Equipping the workforce with the necessary skills and information to care for this patient group Consensus was achieved on 54 of 69 statements over two rounds of the Delphi surveys. The statements were used to model the intervention and finalise the accompanying manual and protocol for a feasibility study. Stakeholder feedback was generally positive and the majority of suggested intervention components were approved. The proposed outcome was a 12-week complex multidisciplinary intervention primarily based at the patient’s home. Conclusions A new intervention has been developed to improve outcomes for people with dementia following a fall requiring healthcare attention. The feasibility of this intervention is currently being tested. Trial registration ISRCTN41760734 (16/11/2015). Electronic supplementary material The online version of this article (10.1186/s12877-019-1066-6) contains supplementary material, which is available to authorized users.

ObjectiveTo determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care.DesignEconomic evaluation within a randomised controlled trial.SettingFour National Health Service (NHS) centres in the UK: Queen’s Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust; Northwick Park Hospital, London Northwest Healthcare NHS Trust; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde; and North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust.Participants770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke.InterventionsParticipants randomised to one of three programmes provided over a 12-week period: robot-assisted training plus usual care; the EULT programme plus usual care or usual care.Main economic outcome measuresMean healthcare resource use; costs to the NHS and personal social services in 2018 pounds; utility scores based on EQ-5D-5L responses and quality-adjusted life years (QALYs). Cost-effectiveness reported as incremental cost per QALY and cost-effectiveness acceptability curves.ResultsAt 6 months, on average usual care was the least costly option (£3785) followed by EULT (£4451) with robot-assisted training being the most costly (£5387). The mean difference in total costs between the usual care and robot-assisted training groups (£1601) was statistically significant (pConclusionsThe cost-effectiveness analysis suggested that neither robot-assisted training nor EULT, as delivered in this trial, were likely to be cost-effective at any of the cost per QALY thresholds considered.Trial registration numberISRCTN69371850.

Background: Systematic review of previous randomised controlled trials concluded that the non-antibiotic option of methenamine hippurate may be effective for urinary tract infection (UTI) prevention but outlined the need for further large, well-conducted randomised trials. We aimed to satisfy this requirement by testing its efficacy, compared to the current standard prophylactic treatment of daily low-dose antibiotics. Methods: This randomised, non-inferiority trial recruited from eight UK centres. Women with recurrent UTI, requiring prophylactic treatment, were randomly assigned (1:1), (using permuted blocks of variable length via a web-based system), to receive antibiotic prophylaxis or methenamine hippurate for 12-months. Treatment allocation was not masked and crossover between arms was permitted. The primary outcome was the absolute difference in symptomatic, antibiotic-treated UTI incidence during treatment. The non-inferiority margin was one UTI episode per person-year. Analyses performed in a modified intention-to-treat (mITT) population comprised all participants observed for at least six months. Trial registration was via ISRCTN registry, ISRCTN70219762. Findings: Between June 23, 2016 and June 20, 2018, 240 participants were randomised to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The mITT analysis comprised 205 (85%) participants [102 (85%) antibiotics, 103 (86%) methenamine hippurate]. The incidence of antibiotic-treated UTI during the 12-month treatment period was 0·89 episodes per person-year (95% CI 0·65-1·12) in the antibiotic group and 1·38 (1·05-1·72) in the methenamine hippurate group with an absolute difference of 0·49 (90% CI 0·15-0·84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) and 35/127 (28%) participants receiving antibiotics and methenamine hippurate respectively and the majority were mild. Interpretation: Non-antibiotic prophylactic treatment using methenamine hippurate should now be considered as a first-line option in women with a history of recurrent UTI episodes, given the robust demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. Clinical Trial Registration Details: ISRCTN registry, ISRCTN70219762. Funding Information: National Institute for Health Research Health Technology Assessment Programme. Declaration of Interests: CH, HM, TH,TC , WK, JL, AAb, LV, RF, KW and AAl report grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme pertaining to the reported study. All other authors have nothing to declare. Ethics Approval Statement: The study protocol was approved by North East Tyne and Wear South Research Ethics Committee (15/NE/0381) and has been published. All participants provided written informed consent.

Background A three-arm parallel group, randomised controlled trial set in general dental practices in England, Scotland, and Wales was undertaken to evaluate three strategies to manage dental caries in primary teeth. Children, with at least one primary molar with caries into dentine, were randomised to receive Conventional with best practice prevention (C + P), Biological with best practice prevention (B + P), or best practice Prevention Alone (PA). Methods Data on costs were collected via case report forms completed by clinical staff at every visit. The co-primary outcomes were incidence of, and number of episodes of, dental pain and/or infection avoided. The three strategies were ranked in order of mean cost and a more costly strategy was compared with a less costly strategy in terms of incremental cost-effectiveness. Costs and outcomes were discounted at 3.5%. Results A total of 1144 children were randomised with data on 1058 children (C + P n = 352, B + P n = 352, PA n = 354) used in the analysis. On average, it costs £230 to manage dental caries in primary teeth over a period of up to 36 months. Managing children in PA was, on average, £19 (97.5% CI: -£18 to £55) less costly than managing those in B + P. In terms of effectiveness, on average, there were fewer incidences of, (− 0.06; 97.5% CI: − 0.14 to 0.02) and fewer episodes of dental pain and/or infection (− 0.14; 97.5% CI: − 0.29 to 0.71) in B + P compared to PA. C + P was unlikely to be considered cost-effective, as it was more costly and less effective than B + P. Conclusions The mean cost of a child avoiding any dental pain and/or infection (incidence) was £330 and the mean cost per episode of dental pain and/or infection avoided was £130. At these thresholds B + P has the highest probability of being considered cost-effective. Over the willingness to pay thresholds considered, the probability of B + P being considered cost-effective never exceeded 75%. Trial registration The trial was prospectively registered with the ISRCTN (reference number ISRCTN77044005) on the 26th January 2009 and East of Scotland Research Ethics Committee provided ethical approved (REC reference: 12/ES/0047).

BackgroundHistorically, lack of evidence for effective management of decay in primary teeth has caused uncertainty, but there is emerging evidence to support alternative strategies to conventional fillings, which are minimally invasive and prevention orientated.ObjectivesThe objectives were (1) to assess the clinical effectiveness and cost-effectiveness of three strategies for managing caries in primary teeth and (2) to assess quality of life, dental anxiety, the acceptability and experiences of children, parents and dental professionals, and caries development and/or progression.DesignThis was a multicentre, three-arm parallel-group, participant-randomised controlled trial. Allocation concealment was achieved by use of a centralised web-based randomisation facility hosted by Newcastle Clinical Trials Unit.SettingThis trial was set in primary dental care in Scotland, England and Wales.ParticipantsParticipants were NHS patients aged 3–7 years who were at a high risk of tooth decay and had at least one primary molar tooth with decay into dentine, but no pain/sepsis.InterventionsThree interventions were employed: (1) conventional with best-practice prevention (local anaesthetic, carious tissue removal, filling placement), (2) biological with best-practice prevention (sealing-in decay, selective carious tissue removal and fissure sealants) and (3) best-practice prevention alone (dietary and toothbrushing advice, topical fluoride and fissure sealing of permanent teeth).Main outcome measuresThe clinical effectiveness outcomes were the proportion of children with at least one episode (incidence) and the number of episodes, for each child, of dental pain or dental sepsis or both over the follow-up period. The cost-effectiveness outcomes were the cost per incidence of, and cost per episode of, dental pain and/or dental sepsis avoided over the follow-up period.ResultsA total of 72 dental practices were recruited and 1144 participants were randomised (conventional arm,n = 386; biological arm,n = 381; prevention alone arm,n = 377). Of these, 1058 were included in an intention-to-treat analysis (conventional arm,n = 352; biological arm,n = 352; prevention alone arm,n = 354). The median follow-up time was 33.8 months (interquartile range 23.8–36.7 months). The proportion of children with at least one episode of pain or sepsis or both was 42% (conventional arm), 40% (biological arm) and 45% (prevention alone arm). There was no evidence of a difference in incidence or episodes of pain/sepsis between arms. When comparing the biological arm with the conventional arm, the risk difference was –0.02 (97.5% confidence interval –0.10 to 0.06), which indicates, on average, a 2% reduced risk of dental pain and/or dental sepsis in the biological arm compared with the conventional arm. Comparing the prevention alone arm with the conventional arm, the risk difference was 0.04 (97.5% confidence interval –0.04 to 0.12), which indicates, on average, a 4% increased risk of dental pain and/or dental sepsis in the prevention alone arm compared with the conventional arm. Compared with the conventional arm, there was no evidence of a difference in episodes of pain/sepsis among children in the biological arm (incident rate ratio 0.95, 97.5% confidence interval 0.75 to 1.21, which indicates that there were slightly fewer episodes, on average, in the biological arm than the conventional arm) or in the prevention alone arm (incident rate ratio 1.18, 97.5% confidence interval 0.94 to 1.48, which indicates that there were slightly more episodes in the prevention alone arm than the conventional arm). Over the willingness-to-pay values considered, the probability of the biological treatment approach being considered cost-effective was approximately no higher than 60% to avoid an incidence of dental pain and/or dental sepsis and no higher than 70% to avoid an episode of pain/sepsis.ConclusionsThere was no evidence of an overall difference between the three treatment approaches for experience of, or number of episodes of, dental pain or dental sepsis or both over the follow-up period.Future workRecommendations for future work include exploring barriers to the use of conventional techniques for carious lesion detection and diagnosis (e.g. radiographs) and developing and evaluating suitable techniques and strategies for use in young children in primary care.Trial registrationCurrent Controlled Trials ISRCTN77044005.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 1. See the NIHR Journals Library website for further project information.

This multicenter 3-arm, parallel-group, patient-randomized controlled trial compared clinical effectiveness of 3 treatment strategies over 3 y for managing dental caries in primary teeth in UK primary dental care. Participants aged 3 to 7 y with at least 1 primary molar with dentinal carious lesion were randomized across 3 arms (1:1:1 via centrally administered system with variable-length random permuted blocks): C+P, conventional carious lesion management (complete carious tooth tissue removal and restoration placement) with prevention; B+P, biological management (sealing in carious tooth tissue restoratively) with prevention; and PA, prevention alone (diet, plaque removal, fluorides, and fissure sealants). Parents, children, and dentists were not blind to allocated arm. Co–primary outcomes were 1) the proportion of participants with at least 1 episode of dental pain and/or infection and 2) the number of episodes of dental pain and/or infection during follow-up (minimum, 23 mo). In sum, 1,144 participants were randomized (C+P, n = 386; B+P, n = 381; PA, n = 377) by 72 general dental practitioners, of whom 1,058 (C+P, n = 352; B+P, n = 352; PA, n = 354) attended at least 1 study visit and were included in the primary analysis. The median follow-up was 33.8 mo (interquartile range, 23.8 to 36.7). Proportions of participants with at least 1 episode of dental pain and/or infection were as follows: C+P, 42%; B+P, 40%; PA, 45%. There was no evidence of a difference in incidence of dental pain and/or infection when B+P (adjusted risk difference [97.5% CI]: −2% [−10% to 6%]) or PA (4% [−4% to 12%]) was compared with C+P. The mean (SD) number of episodes of dental pain and/or infection were as follows: C+P, 0.62 (0.95); B+P, 0.58 (0.87); and PA, 0.72 (0.98). Superiority could not be concluded for number of episodes between B+P (adjusted incident rate ratio (97.5% CI): 0.95 [0.75 to 1.21]) or PA (1.18 [0.94 to 1.48]) and C+P. In conclusion, there was no evidence of a difference among the 3 treatment approaches for incidence or number of episodes of dental pain and/or infection experienced by these participants with high caries risk and established disease (trial registration: ISRCTN77044005).

TPS600 Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary nodes in 40% to 70% of patients. This raises questions about the benefit of further axillary treatment in those patients with no evidence of residual nodal disease (ypN0) after NACT. Methods: Design: ATNEC is a phase 3, randomised (1:1), multi-centre trial, with embedded economic evaluation, comparing standard axillary treatment (axillary lymph node dissection [ALND] or axillary radiotherapy [ART]) with no further axillary treatment in T1-3N1M0 breast cancer patients with needle biopsy proven axillary nodal metastases, who after NACT have no residual nodal disease (ypN0) on dual tracer sentinel node biopsy (SNB) and removal of at least 3 nodes (sentinel nodes and marked involved node). Stratification: Institution, type of surgery (breast conserving surgery vs mastectomy), receptor status (triple negative vs HER2 positive vs ER positive and/or PR positive and HER2 negative). Inclusion criteria are: Age ≥ 18, Male or female, T1-3N1M0 breast cancer at diagnosis (pre-NACT), FNA or core biopsy confirmed axillary nodal metastases at presentation, ER and HER2 status evaluated on primary tumour, received standard NACT as per local guidelines, ultrasound of the axilla at completion of NACT, dual tracer SNB after NACT and at least 3 nodes removed (sentinel nodes and marked node), no evidence of nodal metastases post NACT (ypN0). Exclusion criteria are: bilateral invasive breast cancer, SNB prior to NACT, marked node not removed except where at least one node removed shows evidence of down-staging with complete pathological response e.g. fibrosis/scarring and at least 3 nodes removed, previous ipsilateral axillary surgery, previous cancer within last 5 years or concomitant malignancy except basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ or stage 1 melanoma, contra- or ipsilateral in situ breast cancer. Aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy - who after NACT have no residual nodal disease on SNB (ypN0) - is non-inferior to axillary treatment in terms of disease free survival, and reduces the risk of lymphoedema at 5 years. Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Radiotherapy quality assurance: Study has in-built radiotherapy QA programme that will be co-ordinated by National Radiotherapy Trials QA (RTTQA) group. Target accrual: 1900. Trial status: Recruiting. Number of sites: 100. Clinical trial information: NCT04109079.

Background: Neoadjuvant chemotherapy (NACT) results in eradication of cancer in the axillary lymph nodes in 40% to 70% of patients. This has raised questions about the benefit of further axillary treatment in these patients with no evidence of residual disease in the lymph nodes. Trial design: A multi-centre phase III randomised controlled trial with embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study participants: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: Participants in the experimental group will not receive further axillary treatment (axillary lymph node dissection [ALND] or axillary radiotherapy [ART]), after NACT and surgery. Participants in the control group will receive further axillary treatment (ALND or ART) after NACT and surgery, as per local guidelines. Stratification: Institution, type of breast surgery (breast conserving surgery (BCS) vs mastectomy), receptor status (triple negative vs HER2 positive vs ER status positive and/or PR status positive and HER2 negative) Eligible participants will be/should have:•Age ≥ 18•Male or female •T1-3N1M0 breast cancer at diagnosis (prior to NACT) •FNA or core biopsy confirmed axillary nodal metastases at presentation •Oestrogen receptor and HER2 status evaluated on primary tumour •Received standard NACT as per local guidelines (Patients undergoing neoadjuvant endocrine therapy as part of another clinical trial are eligible) •Ultrasound of the axilla at completion of NACT •Undergo dual tracer sentinel node biopsy after NACT and at least 3 nodes removed (sentinel nodes and marked node). If axillary node sampling is performed following failed localisation of sentinel nodes, patient will be eligible if at least 3 nodes removed (including the marked node) •No evidence of nodal metastases post NACT (isolated tumour cells, micro or macro metastasis) Participants will be excluded if they have any one of the following:•Bilateral invasive breast cancer•Sentinel node biopsy prior to NACT•Marked node not removed except where at least one node removed showsoevidence of down-staging with complete pathological response e.g. fibrosis or scarring and at least 3 nodes removed•Previous axillary surgery on the same body side as the scheduled targeted sampling•Any previous cancer within last 5 years or concomitant malignancy except basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix oin situ or stage 1 melanoma, contra- or ipsilateral in situ breast cancer Specific aims: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS), and reduces the risk of lymphoedema at 5 years.Statistical methods: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Target accrual: 1900, Number of sites: ~100 ClinicalTrials.gov: NCT04109079 Contact information: atnec@warwick.ac.uk Disclaimer: This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (Reference - HTA NIHR128311). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Citation Format: Amit Goyal, Sophie Cramp, Duncan Wheatley, Andrea Marshall, Shama Puri, Tara Homer, Luke Vale, Romaana Mir, Zohal Nabi, Janice Rose, Helen Teresa Edwards, Samreen Ahmed, Abeer Shaaban, Beatrix Elsberger, Julie Bruce, Sophie Gasson, Valerie Speirs, Jacqui Shaw, Helen Higgins, Janet Dunn. Axillary management in T1-3N1M0 breast cancer patients with needle biopsy proven nodal metastases at presentation after neoadjuvant chemotherapy - ATNEC (ClinicalTrials.gov NCT04109079) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-04-01.

Background People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed-methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED, facilitated discharge services, rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life–Alzheimer’s Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL-AD Proxy and a Health Utilisation Questionnaire (HUQ). The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration International Standard Randomised Controlled Trial Registry. Registration number: ISRCTN41760734. Date of registration: 16/11/2015. Electronic supplementary material The online version of this article (10.1186/s40814-018-0364-7) contains supplementary material, which is available to authorized users.

Background INVESTIGATE-I (INVasive Evaluation before Surgical Treatment of Incontinence Gives Added Therapeutic Effect?) was a mixed methods study to assess the feasibility of a future randomised controlled trial of invasive urodynamic testing (IUT) prior to surgery for stress urinary incontinence (SUI) in women. Here we report one of the study’s five components, with the specific objectives of (i) exploring the cost-effectiveness of IUT compared with clinical assessment plus non-invasive tests (henceforth described as ‘IUT’ and ‘no IUT’ respectively) in women with SUI or stress-predominant mixed urinary incontinence (MUI) prior to surgery, and (ii) determining the expected net gain (ENG) from additional research. Methods Study participants were women with SUI or stress-predominant MUI who had failed to respond to conservative treatments recruited from seven UK urogynaecology and female urology units. They were randomised to receive either ‘IUT’ or ‘no IUT’ before undergoing further treatment. Data from 218 women were used in the economic analysis. Cost utility, net benefit and value of information (VoI) analyses were performed within a randomised controlled pilot trial. Costs and quality-adjusted life years (QALYs) were estimated over 6 months to determine the incremental cost per QALY of ‘IUT’ compared to ‘no IUT’. Net monetary benefit informed the VoI analysis. The VoI estimated the ENG and optimal sample size for a future definitive trial. Results At 6 months, the mean difference in total average cost was £138 (p = 0.071) in favour of ‘IUT’; there was no difference in QALYs estimated from the SF-12 (difference 0.004; p = 0.425) and EQ-5D-3L (difference − 0.004; p = 0.725); therefore, the probability of IUT being cost-effective remains uncertain. The estimated ENG was positive for further research to address this uncertainty with an optimal sample size of 404 women. Conclusions This is the largest economic evaluation of IUT. On average, up to 6 months after treatment, ‘IUT’ may be cost-saving compared to ‘no IUT’ because of the reduction in surgery following invasive investigation. However, uncertainty remains over the probability of ‘IUT’ being considered cost-effective, especially in the longer term. The VoI analysis indicated that further research would be of value. Trial registration ISRCTN. ISRCTN71327395. Registered 7 June 2010. Electronic supplementary material The online version of this article (10.1186/s40814-018-0255-y) contains supplementary material, which is available to authorized users.

The management of carious primary teeth is a challenge for patients, parents and clinicians. Most evidence supporting different management strategies originates from a specialist setting and therefore its relevance to the primary care setting is questionable. The UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) has commissioned the FiCTION (Filling Children's Teeth: Indicated Or Not?) trial; a multi-centre primary dental care randomised controlled trial (RCT) to determine the most clinically and cost-effective approach to managing caries in the primary dentition in the UK. This large trial began in 2012, is due to be completed in late 2017 and involves 72 practices and 1,124 children initially aged three to seven years with dentine caries, following randomisation to one of three caries management strategies. Clinical, radiographic, quality of life, treatment acceptability and health economics data are collected during the three-year follow up period. This article provides an overview of the development and conduct of FiCTION and discusses some approaches adopted to manage challenges and achieve the patient recruitment target.

BackgroundThe position of invasive urodynamic testing in the diagnostic pathway for urinary incontinence (UI) is unclear. Systematic reviews have called for further trials evaluating clinical utility, although a preliminary feasibility study was considered appropriate.ObjectivesTo inform the decision whether or not to proceed to a definitive randomised trial of invasive urodynamic testing compared with clinical assessment with non-invasive tests, prior to surgery in women with stress UI (SUI) or stress predominant mixed UI (MUI).DesignA mixed-methods study comprising a pragmatic multicentre randomised pilot trial; economic evaluation; survey of clinicians’ views about invasive urodynamic testing; qualitative interviews with clinicians and trial participants.SettingUrogynaecology, female urology and general gynaecology units in Newcastle, Leicester, Swansea, Sheffield, Northumberland, Gateshead and South Tees.ParticipantsTrial recruits were women with SUI or stress predominant MUI who were considering surgery after unsuccessful conservative treatment. Relevant clinicians completed two online surveys. Subsets of survey respondents and trial participants took part in separate qualitative interview studies.InterventionsPilot trial participants were randomised to undergo clinical assessment with non-invasive tests (control arm); or assessment as controls, plus invasive urodynamic testing (intervention arm).Main outcome measuresConfirmation that units can identify and recruit eligible women; acceptability of investigation strategies and data collection tools; acquisition of outcome data to determine the sample size for a definitive trial. The proposed primary outcome for the definitive trial was International Consultation on Incontinence Modular Questionnaire (ICIQ) Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) (total score) 6 months after surgery or the start of non-surgical treatment; secondary outcomes included: ICIQ-FLUTS (subscales); ICIQ Urinary Incontinence Short Form; ICIQ Lower Urinary Tract Symptoms Quality of Life; Urogenital Distress Inventory; EuroQol-5D; costs, quality-adjusted life-years (QALYs) and incremental cost per QALY, Short Form 12; 3-day bladder diary.ResultsOf 284 eligible women, 222 (78%) were recruited; 165/219 (75%) returned questionnaires at baseline and 125/200 (63%) who were sent questionnaires at follow-up. There were few missing data items in returned questionnaires, with individual outcome scales calculable for 81%–94%. Most women underwent surgery; management plans were changed in 19 (19%) participants following invasive urodynamic testing. Participant Costs Questionnaires were returned by 53% 6 months after treatment; complete data to undertake cost–utility analysis were available in 27% (intervention) and 47% (control). While insufficient to recommend changes in practice, the results suggest further research would be valuable. All clinicians responding to the survey had access to invasive urodynamic testing, and most saw it as essential prior to surgery in women with SUI with or without other symptoms; nevertheless, 70% considered the research question underlying INVESTIGATE important and most were willing to randomise patients in a definitive trial. Participants interviewed were positive about the trial and associated documentation; the desire of some women to avoid invasive urodynamic testing contrasted with opinions expressed by clinicians through both survey and interview responses.ConclusionsAll elements of a definitive trial and economic evaluation were rehearsed; several areas for protocol modification were identified. Such a trial would require to 400–900 participants, depending on the difference in primary outcome sought.Future workA definitive trial of invasive urodynamic testing versus clinical assessment prior to surgery for SUI or stress predominant MUI should be undertaken.Trial registrationCurrent Controlled Trials ISRCTN71327395.FundingThe National Institute for Health Research Health Technology Assessment programme.

SummaryCirrhosis has a long natural history with considerable symptomatic impacts, particularly in advancing disease. Measuring health related quality of life (HRQOL) in liver disease provides detail about the nature and extent of its effects on individuals. Understanding the drivers of impaired HRQOL can help identify targets for improvement through new treatments or health systems service delivery. Evaluation of novel therapies which target symptomatic improvement, should be done with suitable outcome measures, including HRQOL assessment. In this article, we provide an overview of HRQOL in advanced liver disease for the clinician. A clear description of the important HRQOL tools is given alongside a discussion of the factors, which are known to contribute to impaired HRQOL in advanced liver disease.

BackgroundAlcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit.ObjectivesThe aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX.DesignThe trial was a randomised, double-blind, 2 × 2 factorial, multicentre design.SettingSixty-five gastroenterology and hepatology inpatient units across the UK.ParticipantsPatients with a clinical diagnosis of AH who had a Maddrey’s discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis.InterventionsThose allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days.OutcomesThe primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed.ResultsAt 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40;p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01;p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91;p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year.ConclusionsWe conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection.Trial registrationThis trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.

Our base case analysis used the EQ-5D 3L as the primary outcome measure. The results suggest that, on average, the ‘IUT’ arm was £154 less costly than ‘no IUT’ (95% bootstrapped, CI: -315 to 24) but had a lower utility score. The ‘IUT’ was deemed to be cost-effective up to a £30,000 willingness to pay threshold. The EVSI analysis confirmed that additional research was needed to prove that ‘no IUT’ was the most cost-effective option. The ENG of this additional research is £91m and 105 additional complete cases in each arm are needed to achieve this. Cost-utility results: EVSI Analysis

Introduction Cirrhosis is associated with impaired Health-Related Quality of Life (HRQoL) and considerable resource use. The association between healthcare utilisation and HRQoL in cirrhosis has not been previously studied. Methods Four HRQoL tools (SF-36v2, CLDQ, PBC-40 and PROMIS-HAQ) and a healthcare utilisation tool were completed by patients with cirrhosis. Associations between resource utilisation and HRQoL were explored; means were compared using unpaired t tests. Results 108 patients have been recruited to the study to date with completed tools received from 73. Regular care was required by 29 (40%) with 15 (21%) requiring help with personal care, 12 (16%) with medical care, 18 (25%) with meal preparation and 21 (29%) with housework. All types of care were associated with significantly impaired HRQoL across all domains of all measures tested (p Conclusion The need for any type of regular care and more frequent consultations with healthcare professionals are associated with poorer HRQoL in cirrhosis. Disclosure of Interest None Declared.