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Background Ensuring that a trial is designed so that its participants reflect those who might benefit from the results, or be spared harms, is key to the potential benefits of the trial reaching all they should. This paper describes the process, facilitated by Trial Forge, that was used between July 2019 and October 2020 to develop the INCLUDE Ethnicity Framework, part of the wider INCLUDE initiative from the National Institute for Health Research to improve inclusion of under-served groups in clinical research studies. Methods Development of the Framework was done in seven phases: (1) outline, (2) initial draft, (3) stakeholder meeting, (4) modify draft, (5) Stakeholder feedback, (6) applying the Framework and (7) packaging. Phases 2 and 3 were face-to-face meetings. Consultation with stakeholders was iterative, especially phases 4 to 6. Movement to the next phase was done once all or most stakeholders were comfortable with the results of the current phase. When there was a version of the Framework that could be considered final, the Framework was applied to six trials to create a set of examples (phase 6). Finally, the Framework, guidance and examples were packaged ready for dissemination (phase 7). Results A total of 40 people from stakeholder groups including patient and public partners, clinicians, funders, academics working with various ethnic groups, trial managers and methodologists contributed to the seven phases of development. The Framework comprises two parts. The first part is a list of four key questions: Who should my trial apply to? Are the groups identified likely to respond in different ways? Will my study intervention make it harder for some groups to engage? Will the way I have designed the study make it harder for some groups to engage? The second part is a set of worksheets to help trial teams address these questions. The Framework can be used for any stage of trial, for a healthcare intervention in any disease area. The Framework was launched on 1st October 2020 and is available open access at the Trial Forge website: https://www.trialforge.org/trial-forge-centre/include/ . Conclusion Thinking about the number of people in our trials is not enough: we need to start thinking more carefully about who our participants are.

Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities. This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, examples of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations. We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.

Background Data collection consumes a large proportion of clinical trial resources. Each data item requires time and effort for collection, processing and quality control procedures. In general, more data equals a heavier burden for trial staff and participants. It is also likely to increase costs. Knowing the types of data being collected, and in what proportion, will be helpful to ensure that limited trial resources and participant goodwill are used wisely. Aim The aim of this study is to categorise the types of data collected across a broad range of trials and assess what proportion of collected data each category represents. Methods We developed a standard operating procedure to categorise data into primary outcome, secondary outcome and 15 other categories. We categorised all variables collected on trial data collection forms from 18, mainly publicly funded, randomised superiority trials, including trials of an investigational medicinal product and complex interventions. Categorisation was done independently in pairs: one person having in-depth knowledge of the trial, the other independent of the trial. Disagreement was resolved through reference to the trial protocol and discussion, with the project team being consulted if necessary. Key results Primary outcome data accounted for 5.0% (median)/11.2% (mean) of all data items collected. Secondary outcomes accounted for 39.9% (median)/42.5% (mean) of all data items. Non-outcome data such as participant identifiers and demographic data represented 32.4% (median)/36.5% (mean) of all data items collected. Conclusion A small proportion of the data collected in our sample of 18 trials was related to the primary outcome. Secondary outcomes accounted for eight times the volume of data as the primary outcome. A substantial amount of data collection is not related to trial outcomes. Trialists should work to make sure that the data they collect are only those essential to support the health and treatment decisions of those whom the trial is designed to inform.

Background Dental caries is one of the most prevalent non-communicable disease globally and can have serious health sequelae impacting negatively on quality of life. In the UK most adults experience dental caries during their lifetime and the 2009 Adult Dental Health Survey reported that 85% of adults have at least one dental restoration. Conservative removal of tooth tissue for both primary and secondary caries reduces the risk of failure due to tooth-restoration, complex fracture as well as remaining tooth surfaces being less vulnerable to further caries. However, despite its prevalence there is no consensus on how much caries to remove prior to placing a restoration to achieve optimal outcomes. Evidence for selective compared to complete or near-complete caries removal suggests there may be benefits for selective removal in sustaining tooth vitality, therefore avoiding abscess formation and pain, so eliminating the need for more complex and costly treatment or eventual tooth loss. However, the evidence is of low scientific quality and mainly gleaned from studies in primary teeth. Method This is a pragmatic, multi-centre, two-arm patient randomised controlled clinical trial including an internal pilot set in primary dental care in Scotland and England. Dental health professionals will recruit 623 participants over 12-years of age with deep carious lesions in their permanent posterior teeth. Participants will have a single tooth randomised to either the selective caries removal or complete caries removal treatment arm. Baseline measures and outcome data (during the 3-year follow-up period) will be assessed through clinical examination, patient questionnaires and NHS databases. A mixed-method process evaluation will complement the clinical and economic outcome evaluation and examine implementation, mechanisms of impact and context. The primary outcome at three years is sustained tooth vitality. The primary economic outcome is net benefit modelled over a lifetime horizon. Clinical secondary outcomes include pulp exposure, progession of caries, restoration failure; as well as patient-centred and economic outcomes. Discussion SCRiPT will provide evidence for the most clinically effective and cost-beneficial approach to managing deep carious lesions in permanent posterior teeth in primary care. This will support general dental practitioners, patients and policy makers in decision making. Trial Registration Trial registry: ISRCTN. Trial registration number: ISRCTN76503940. Date of Registration: 30.10.2019. URL of trial registry record: https://www.isrctn.com/ISRCTN76503940?q=ISRCTN76503940%20&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search .

Background/aimsTo evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting.MethodsA patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon.ResultsSD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient’s subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient’s subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%–99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000–£30 000) applied in the UK NHS.ConclusionsEarly treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.

IntroductionSeveral diagnostic tests are often adopted into diagnostic pathways for specific indications without strong evidence to support their use. In this context, real-world prospective cohort studies in combination with decision modelling can generate evidence to support decision-making. The Early Detection of neovascular Age-Related Macular Degeneration (EDNA) study was a prospective cohort designed to assess the diagnostic accuracy and cost-effectiveness of several diagnostic monitoring tests used in routine practice for the detection of neovascular age-related macular degeneration (nAMD) in the second eye of patients being treated for unilateral disease.MethodsFive-hundred and fifty-two participants with newly diagnosed unilateral nAMD were monitored for up to 3 years in 24 UK eye clinics. The diagnostic monitoring performance of five index tests was compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity, fundus assessment by clinical examination or colour photography, and spectral-domain optical coherence tomography (SD-OCT). The reference standard was fundus fluorescein angiography (FFA). A patient-level state transition model was used to simulate the onset of nAMD in the second eye, and assess the impact of different tests on the timing of detection and treatment, and associated costs and quality adjusted life years (QALYs) over a 25-year time-horizon.ResultsOne hundred and forty-five (26.3%) patients developed active nAMD in the study eye, of whom 120 had an FFA at detection. SD-OCT had the highest sensitivity (91.7 percent (95% CI: 85.2-95.6) and provided high specificity (87.8% (95% CI: 83.8-90.9)). It generated more QALYs and lower health and personal social care costs compared to all other monitoring tests. The combination of SD-OCT with fundus-examination provided a marginal increase in sensitivity over OCT alone, but the associated incremental cost-effectiveness ratios was >GBP 100,000 per QALY.ConclusionsThe efficiency of diagnostic pathways for nAMD may be improved by using SD-OCT alone to monitor the second eye of people being treated for unilateral disease. Prospective cohort studies embedded into routine practice offer value for informing decisions surrounding the use of technologies already in routine use.

Background/AimsTo assess the diagnostic performance of retinal nerve fibre layer (RNFL) data of optical coherence tomography (OCT) for detecting glaucoma.MethodsSecondary analyses of a prospective, multicentre diagnostic study (Glaucoma Automated Tests Evaluation (GATE)) referred to hospital eye services in the UK were conducted. We included data from 899 of 966 participants referred to hospital eye services with suspected glaucoma or ocular hypertension. We used both eyes’ data and logistic regression-based receiver operator characteristics analysis to build a set of models to measure the sensitivity and specificity of the average and inferior quadrant RNFL thickness data of OCT. The reference standard was expert clinician examination including automated perimetry. The main outcome measures were sensitivity at 0.95 specificity and specificity at 0.95 sensitivity and the corresponding RNFL thickness thresholds. We explored the possibility of accuracy improvement by adding measures of within-eye and between-eye variation, scan quality, intraocular pressure (IOP) and age.ResultsGlaucoma was diagnosed in at least one eye in 17% of participants. Areas under the curve were between 0.83 and 0.88. When specificity was fixed at 0.95, the sensitivity was between 0.38 and 0.55, and the highest values were reached with models including the inferior quadrant rather than the average RNFL thickness. Fixing sensitivity at 0.95, the specificity was between 0.36 and 0.58. The addition of age, refractive error, IOP or within-subject variation did not improve the accuracy.ConclusionRNFL thickness data of OCT can be used as a diagnostic test, but accuracy estimates remain moderate even in exploratory multivariable modelling of aiming to improve accuracy.

Background Progression of dental caries can result in irreversible pulpal damage. Partial irreversible pulpitis is the initial stage of this damage, confined to the coronal pulp whilst the radicular pulp shows little or no sign of infection. Preserving the pulp with sustained vitality and developing minimally invasive biologically based therapies are key themes within contemporary clinical practice. However, root canal treatment involving complete removal of the pulp is often the only option (other than extraction) given to patients with irreversible pulpitis, with substantial NHS and patient incurred costs. The European Society of Endodontology’s (ESE 2019) recent consensus statement recommends full pulpotomy , where the inflamed coronal pulp is removed with the goal of keeping the radicular pulp vital, as a more minimally invasive technique, potentially avoiding complex root canal treatment. Although this technique may be provided in secondary care, it has not been routinely implemented or evaluated in UK General Dental Practice. Method This feasibility study aims to identify and assess in a primary care setting the training needs of general dental practitioners and clinical fidelity of the full pulpotomy intervention, estimate likely eligible patient pool and develop recruitment materials ahead of the main randomised controlled trial comparing the clinical and cost-effectiveness of full pulpotomy compared to root canal treatment in pre/molar teeth of adults 16 years and older showing signs indicative of irreversible pulpitis. The feasibility study will recruit and train 10 primary care dentists in the full pulpotomy technique. Dentists will recruit and provide full pulpotomy to 40 participants (four per practice) with indications of partial irreversible pulpitis. Discussion The Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP) study will address the lack of high-quality evidence in the treatment of irreversible pulpitis, to aid dental practitioners, patients and policymakers in their decision-making. The PIP feasibility study will inform the main study on the practicality of providing both training and provision of the full pulpotomy technique in general dental practice. Trial registration ISRCTN Registry, ISRCTN17973604 . Registered on 28 January 2021. Protocol version Protocol version: 1; date: 03.02.2021