Flexor Injury Rehabilitation Splint Trial (FIRST): protocol for a pragmatic randomised controlled trial comparing three splints for finger flexor tendon repairs.

BACKGROUND: Without surgical repair, flexor tendon injuries do not heal and patients' ability to bend fingers and grip objects is impaired. However, flexor tendon repair surgery also requires optimal rehabilitation. There are currently three custom-made splints used in the rehabilitation of zone I/II flexor tendon repairs, each with different assumed harm/benefit profiles: the dorsal forearm and hand-based splint (long), the Manchester short splint (short), and the relative motion flexion splint (mini). There is, however, no robust evidence as to which splint, if any, is most clinical or cost effective. The Flexor Injury Rehabilitation Splint Trial (FIRST) was designed to address this evidence gap. METHODS: FIRST is a parallel group, superiority, analyst-blind, multi-centre, individual participant-randomised controlled trial. Participants will be assigned 1:1:1 to receive either the long, short, or mini splint. We aim to recruit 429 participants undergoing rehabilitation following zone I/II flexor tendon repair surgery. Potential participants will initially be identified prior to surgery, in NHS hand clinics across the UK, and consented and randomised at their splint fitting appointment post-surgery. The primary outcome will be the mean post-randomisation score on the patient-reported wrist and hand evaluation measure (PRWHE), assessed at 6, 12, 26, and 52 weeks post randomisation. Secondary outcome measures include blinded grip strength and active range of movement (AROM) assessments, adverse events, adherence to the splinting protocol (measured via temperature sensors inserted into the splints), quality of life assessment, and further patient-reported outcomes. An economic evaluation will assess the cost-effectiveness of each splint, and a qualitative sub-study will evaluate participants' preferences for, and experiences of wearing, the splints. Furthermore, a mediation analysis will determine the relationship between patient preferences, splint adherence, and splint effectiveness. DISCUSSION: FIRST will compare the three splints with respect to clinical efficacy, complications, quality of life and cost-effectiveness. FIRST is a pragmatic trial which will recruit from 26 NHS sites to allow findings to be generalisable to current clinical practice in the UK. It will also provide significant insights into patient experiences of splint wear and how adherence to splinting may impact outcomes. TRIAL REGISTRATION: ISRCTN: 10236011.

Personalised versus standard text message prompts for increasing trial participant response to telephone follow-up: an embedded randomised controlled retention trial.

BACKGROUND: Improving retention within randomised controlled trials is important. The effectiveness of different strategies can be assessed using a Study Within A Trial (SWAT). Previous research has shown personalised text message reminders improve clinic attendance rates; however, the results are mixed on improving postal questionnaire return. This SWAT aims to assess whether personalised text message reminders improve completion rates for scheduled telephone follow-ups. METHODS: This SWAT is a two-arm, multi-centre randomised controlled trial with equal allocation. The host trial was the Melatonin for Anxiety prior to General anaesthesia In Children trial (ISRCTN 18296119), where the child's caregiver was to answer a scheduled telephone follow-up 14 days post-surgery; participants for the SWAT were therefore the caregiver. Text messages were sent 24-48 h before the scheduled call and the personalised version contained the first name of the caregiver which was omitted in the non-personalised version. The primary outcome was questionnaire completion rate, defined as the proportion of caregivers successfully contacted, and completed any of the questionnaires, over the telephone within the follow-up window (day 14 + 7 days). RESULTS: The SWAT included 100 of the 110 (91%) participants randomised into the host trial. Randomisation within the SWAT was equal between non-personalised (n = 50) and personalised (n = 50) interventions. The overall questionnaire response rate was 73% with a difference between the two interventions of 68% in the non-personalised text message arm and 78% in the personalised text message arm. The adjusted absolute risk difference was 7.1% (95% confidence interval = -10.2%, 24.4%). There was no difference in either the time to response or the number of contact attempts between the two interventions. CONCLUSIONS: There is some evidence that personalised text messages could be effective at increasing response rates when data is collected via telephone and in a population of caregivers for paediatric trial participants. However, similar SWATs have shown mixed results. Given the low-cost and low risks associated with personalising text message reminders, this SWAT could be implemented easily in other RCTs scheduling telephone follow-up appointments. TRIAL REGISTRATION: ISRCTN 18296119 , SWAT 35 (MRC Northern Ireland Network for Trials Methodology Network).

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

The Journeying through Dementia psychosocial intervention versus usual care study: a single-blind, parallel group, phase 3 trial.

BACKGROUND: There is an urgent clinical need for evidence-based psychosocial interventions for people with mild dementia. We aimed to determine the clinical benefits and cost-effectiveness of Journeying through Dementia (JtD), an intervention designed to promote wellbeing and independence in people with mild dementia. METHODS: We did a single-blind, parallel group, individually randomised, phase 3 trial at 13 National Health Service sites across England. People with mild dementia (Mini-Mental State Examination score of ≥18) who lived in the community were eligible for inclusion. Patients were centrally randomly assigned (1:1) to receive the JtD intervention plus standard care (JtD group) or standard care only (standard care group). Randomisation was stratified by study site. The JtD intervention included 12 group and four one-to-one sessions, delivered in the community at each site. The primary endpoint was Dementia Related Quality of Life (DEMQOL) 8 months after randomisation, assessed according to the intention-to-treat principle. Only outcome assessors were masked to group assignment. A cost-effectiveness analysis reported cost per quality-adjusted life-year (QALY) from a UK NHS and social care perspective. The study is registered with ISRCTN, ISRCTN17993825. FINDINGS: Between Nov 30, 2016, and Aug 31, 2018, 1183 patients were screened for inclusion, of whom 480 (41%) participants were randomly assigned: 241 (50%) to the JtD group and 239 (50%) to the standard care group. Intervention adherence was very good: 165 (68%) of 241 participants in the JtD group attended at least ten of the 16 sessions. Mean DEMQOL scores at 8 months were 93·3 (SD 13·0) for the JtD group and 91·9 (SD 14·6) for the control group. Difference in means was 0·9 (95% CI -1·2 to 3·0; p=0·38) after adjustment for covariates, lower than that identified as clinically meaningful. Incremental cost per QALY ranged from £88 000 to -£205 000, suggesting that JtD was not cost-effective. Unrelated serious adverse events were reported by 40 (17%) patients in the JtD group and 35 (15%) patients in the standard care group. INTERPRETATION: In common with other studies, the JtD intervention was not proven effective. However, this complex trial successfully recruited and retained people with dementia without necessarily involving carers. Additionally, people with dementia were actively involved as participants and study advisers throughout. More research into methods of measuring small, meaningful changes in this population is needed. Questions remain regarding how services can match the complex, diverse, and individual needs of people with mild dementia, and how interventions to meet such needs can be delivered at scale. FUNDING: UK National Institute of Health Research Health Technology Assessment Programme.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

An intervention to promote self-management, independence and self-efficacy in people with early-stage dementia: the Journeying through Dementia RCT.

BACKGROUND: There are few effective interventions for dementia. AIM: To determine the clinical effectiveness and cost-effectiveness of an intervention to promote self-management, independence and self-efficacy in people with early-stage dementia. OBJECTIVES: To undertake a randomised controlled trial of the Journeying through Dementia intervention compared with usual care, conduct an internal pilot testing feasibility, assess intervention delivery fidelity and undertake a qualitative exploration of participants' experiences. DESIGN: A pragmatic two-arm individually randomised trial analysed by intention to treat. PARTICIPANTS: A total of 480 people diagnosed with mild dementia, with capacity to make informed decisions, living in the community and not participating in other studies, and 350 supporters whom they identified, from 13 locations in England, took part. INTERVENTION: Those randomised to the Journeying through Dementia intervention (n = 241) were invited to take part in 12 weekly facilitated groups and four one-to-one sessions delivered in the community by secondary care staff, in addition to their usual care. The control group (n = 239) received usual care. Usual care included drug treatment, needs assessment and referral to appropriate services. Usual care at each site was recorded. MAIN OUTCOME MEASURES: The primary outcome was Dementia-Related Quality of Life score at 8 months post randomisation, with higher scores representing higher quality of life. Secondary outcomes included resource use, psychological well-being, self-management, instrumental activities of daily living and health-related quality of life. RANDOMISATION AND BLINDING: Participants were randomised in a 1 : 1 ratio. Staff conducting outcome assessments were blinded. DATA SOURCES: Outcome measures were administered in participants' homes at baseline and at 8 and 12 months post randomisation. Interviews were conducted with participants, participating carers and interventionalists. RESULTS: The mean Dementia-Related Quality of Life score at 8 months was 93.3 (standard deviation 13.0) in the intervention arm (n = 191) and 91.9 (standard deviation 14.6) in the control arm (n = 197), with a difference in means of 0.9 (95% confidence interval -1.2 to 3.0; p = 0.380) after adjustment for covariates. This effect size (0.9) was less than the 4 points defined as clinically meaningful. For other outcomes, a difference was found only for Diener's Flourishing Scale (adjusted mean difference 1.2, 95% confidence interval 0.1 to 2.3), in favour of the intervention (i.e. in a positive direction). The Journeying through Dementia intervention cost £608 more than usual care (95% confidence interval £105 to £1179) and had negligible difference in quality-adjusted life-years (-0.003, 95% confidence interval -0.044 to 0.038). Therefore, the Journeying through Dementia intervention had a mean incremental cost per quality-adjusted life-year of -£202,857 (95% confidence interval -£534,733 to £483,739); however, there is considerable uncertainty around this. Assessed fidelity was good. Interviewed participants described receiving some benefit and a minority benefited greatly. However, negative aspects were also raised by a minority. Seventeen per cent of participants in the intervention arm and 15% of participants in the control arm experienced at least one serious adverse event. None of the serious adverse events were classified as related to the intervention. LIMITATIONS: Study limitations include recruitment of an active population, delivery challenges and limitations of existing outcome measures. CONCLUSIONS: The Journeying through Dementia programme is not clinically effective, is unlikely to be cost-effective and cannot be recommended in its existing format. FUTURE WORK: Research should focus on the creation of new outcome measures to assess well-being in dementia and on using elements of the intervention, such as enabling enactment in the community. TRIAL REGISTRATION: This trial is registered as ISRCTN17993825. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 24. See the NIHR Journals Library website for further project information.

There are few services proven effective for people with mild dementia. We therefore explored the potential benefit of a programme called Journeying through Dementia. The content, devised in partnership with people living with dementia, aims to help affected individuals to live well and participate in life. The programme involves meeting in groups of about eight every week for 12 weeks. Each person also has four face-to-face meetings with a staff member. Carers are invited to 3 of the 12 group meetings to all individual meetings if the participant wanted this involvement. A total of 480 people with dementia and 350 carers from 13 locations in England took part. Just over half of the participants were randomly allocated to the new programme, whereas the others were not. This allowed us to compare the groups. We were interested in whether or not attending the Journeying through Dementia programme improved participants' quality of life. The results showed that it did not. We also measured participants' mood, self-management skills, positive attitudes and ability with daily living skills. Only one measure of positive psychology suggested even a small benefit. There was no difference between groups in the remaining measures. Although some individual participants described being more confident, enjoying social contact, trying new activities, feeling valued and having increased independence, overall, the programme is unlikely to be worth implementing. Certain aspects of the programme are worth implementing.

Prognostic accuracy of emergency department triage tools for adults with suspected COVID-19: the PRIEST observational cohort study.

BACKGROUND: The WHO and National Institute for Health and Care Excellence recommend various triage tools to assist decision-making for patients with suspected COVID-19. We aimed to compare the accuracy of triage tools for predicting severe illness in adults presenting to the ED with suspected COVID-19. METHODS: We undertook a mixed prospective and retrospective observational cohort study in 70 EDs across the UK. We collected data from people attending with suspected COVID-19 and used presenting data to determine the results of assessment with the WHO algorithm, National Early Warning Score version 2 (NEWS2), CURB-65, CRB-65, Pandemic Modified Early Warning Score (PMEWS) and the swine flu adult hospital pathway (SFAHP). We used 30-day outcome data (death or receipt of respiratory, cardiovascular or renal support) to determine prognostic accuracy for adverse outcome. RESULTS: We analysed data from 20 891 adults, of whom 4611 (22.1%) died or received organ support (primary outcome), with 2058 (9.9%) receiving organ support and 2553 (12.2%) dying without organ support (secondary outcomes). C-statistics for the primary outcome were: CURB-65 0.75; CRB-65 0.70; PMEWS 0.77; NEWS2 (score) 0.77; NEWS2 (rule) 0.69; SFAHP (6-point rule) 0.70; SFAHP (7-point rule) 0.68; WHO algorithm 0.61. All triage tools showed worse prediction for receipt of organ support and better prediction for death without organ support. At the recommended threshold, PMEWS and the WHO criteria showed good sensitivity (0.97 and 0.95, respectively) at the expense of specificity (0.30 and 0.27, respectively). The NEWS2 score showed similar sensitivity (0.96) and specificity (0.28) when a lower threshold than recommended was used. CONCLUSION: CURB-65, PMEWS and the NEWS2 score provide good but not excellent prediction for adverse outcome in suspected COVID-19, and predicted death without organ support better than receipt of organ support. PMEWS, the WHO criteria and NEWS2 (using a lower threshold than usually recommended) provide good sensitivity at the expense of specificity. TRIAL REGISTRATION NUMBER: ISRCTN56149622.

Derivation and validation of a clinical severity score for acutely ill adults with suspected COVID-19: The PRIEST observational cohort study.

OBJECTIVES: We aimed to derive and validate a triage tool, based on clinical assessment alone, for predicting adverse outcome in acutely ill adults with suspected COVID-19 infection. METHODS: We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. The primary outcome was death or organ support (respiratory, cardiovascular, or renal) by record review at 30 days. We split the cohort into derivation and validation sets, developed a clinical score based on the coefficients from multivariable analysis using the derivation set, and the estimated discriminant performance using the validation set. RESULTS: We analysed 11773 derivation and 9118 validation cases. Multivariable analysis identified that age, sex, respiratory rate, systolic blood pressure, oxygen saturation/inspired oxygen ratio, performance status, consciousness, history of renal impairment, and respiratory distress were retained in analyses restricted to the ten or fewer predictors. We used findings from multivariable analysis and clinical judgement to develop a score based on the NEWS2 score, age, sex, and performance status. This had a c-statistic of 0.80 (95% confidence interval 0.79-0.81) in the validation cohort and predicted adverse outcome with sensitivity 0.98 (0.97-0.98) and specificity 0.34 (0.34-0.35) for scores above four points. CONCLUSION: A clinical score based on NEWS2, age, sex, and performance status predicts adverse outcome with good discrimination in adults with suspected COVID-19 and can be used to support decision-making in emergency care. REGISTRATION: ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533.

Post-exertion oxygen saturation as a prognostic factor for adverse outcome in patients attending the emergency department with suspected COVID-19: a substudy of the PRIEST observational cohort study.

BACKGROUND: Measurement of post-exertion oxygen saturation has been proposed to assess illness severity in suspected COVID-19 infection. We aimed to determine the accuracy of post-exertional oxygen saturation for predicting adverse outcome in suspected COVID-19. METHODS: We undertook a substudy of an observational cohort study across 70 emergency departments during the first wave of the COVID-19 pandemic in the UK. We collected data prospectively, using a standardised assessment form, and retrospectively, using hospital records, from patients with suspected COVID-19, and reviewed hospital records at 30 days for adverse outcome (death or receiving organ support). Patients with post-exertion oxygen saturation recorded were selected for this analysis. We constructed receiver-operating characteristic curves, calculated diagnostic parameters, and developed a multivariable model for predicting adverse outcome. RESULTS: We analysed data from 817 patients with post-exertion oxygen saturation recorded after excluding 54 in whom measurement appeared unfeasible. The c-statistic for post-exertion change in oxygen saturation was 0.589 (95% CI 0.465 to 0.713), and the positive and negative likelihood ratios of a 3% or more desaturation were, respectively, 1.78 (1.25 to 2.53) and 0.67 (0.46 to 0.98). Multivariable analysis showed that post-exertion oxygen saturation was not a significant predictor of adverse outcome when baseline clinical assessment was taken into account (p=0.368). Secondary analysis excluding patients in whom post-exertion measurement appeared inappropriate resulted in a c-statistic of 0.699 (0.581 to 0.817), likelihood ratios of 1.98 (1.26 to 3.10) and 0.61 (0.35 to 1.07), and some evidence of additional prognostic value on multivariable analysis (p=0.019). CONCLUSIONS: Post-exertion oxygen saturation provides modest prognostic information in the assessment of selected patients attending the emergency department with suspected COVID-19. TRIAL REGISTRATION NUMBER: ISRCTN Registry (ISRCTN56149622) http://www.isrctn.com/ISRCTN28342533.

Characterisation of 22445 patients attending UK emergency departments with suspected COVID-19 infection: Observational cohort study.

BACKGROUND: Hospital emergency departments play a crucial role in the initial assessment and management of suspected COVID-19 infection. This needs to be guided by studies of people presenting with suspected COVID-19, including those admitted and discharged, and those who do not ultimately have COVID-19 confirmed. We aimed to characterise patients attending emergency departments with suspected COVID-19, including subgroups based on sex, ethnicity and COVID-19 test results. METHODS AND FINDINGS: We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. Outcomes were admission to hospital, COVID-19 result, organ support (respiratory, cardiovascular or renal), and death, by record review at 30 days. Mean age was 58.4 years, 11200 (50.4%) were female and 11034 (49.6%) male. Adults (age >16 years) were acutely unwell (median NEWS2 score of 4), frequently had limited performance status (46.9%) and had high rates of admission (67.1%), COVID-19 positivity (31.2%), organ support (9.8%) and death (15.5%). Children had much lower rates of admission (27.4%), COVID-19 positivity (1.2%), organ support (1.4%) and death (0.3%). Similar numbers of men and women presented to the ED, but men were more likely to be admitted (72.9% v 61.4%), require organ support (12.2% v 7.7%) and die (18.2% v 13.0%). Black or Asian adults tended to be younger than White adults (median age 54, 50 and 67 years), were less likely to have impaired performance status (43.1%, 26.8% and 51.6%), be admitted to hospital (60.8%, 57.3%, 69.6%) or die (11.6%, 11.2%, 16.4%), but were more likely to require organ support (15.9%, 14.3%, 8.9%) or have a positive COVID-19 test (40.8%, 42.1%, 30.0%). Adults admitted with suspected and confirmed COVID-19 had similar age, performance status and comorbidities (except chronic lung disease) to those who did not have COVID-19 confirmed, but were much more likely to need organ support (22.2% v 8.9%) or die (32.1% v 15.5%). CONCLUSIONS: Important differences exist between patient groups presenting to the emergency department with suspected COVID-19. Adults and children differ markedly and require different approaches to emergency triage. Admission and adverse outcome rates among adults suggest that policies to avoid unnecessary ED attendance achieved their aim. Subsequent COVID-19 confirmation confers a worse prognosis and greater need for organ support. REGISTRATION: ISRCTN registry, ISRCTN56149622, http://www.isrctn.com/ISRCTN28342533.

Study protocol for a randomised controlled trial assessing the clinical and cost-effectiveness of the Journeying through Dementia (JtD) intervention compared to usual care.

INTRODUCTION: Services are being encouraged to provide postdiagnostic treatment to those with dementia but the availability of evidence-based interventions following diagnosis has not kept pace with increase in demand. To address this need, the Journeying through Dementia (JtD) intervention was created. A randomised controlled trial (RCT), based on a pilot study, is in progress. METHODS AND ANALYSIS: The RCT is a pragmatic, two-arm, parallel group trial designed to test the clinical and cost-effectiveness of JtD compared with usual care. Recruitment will be through NHS services, third sector organisations and Join Dementia Research. The sample size is 486 randomised (243 to usual care and 243 to the intervention usual care). Participants can choose to ask a friend or relative (supporter) to become involved in the study. The primary outcome measure for participants is Dementia-Related Quality of Life (DEMQOL), collected at baseline and at 8 months' postrandomisation. Secondary outcome measures will be collected from participants and supporters at those visits. Participants will also be followed up at 12 months' postrandomisation with a reduced set of measures. A process evaluation will be conducted through qualitative and fidelity substudies. Analyses will compare the two arms of the trial on an intention to treat as allocated basis. The primary analyses will compare the mean DEMQOL scores of the participants at 8 months between the two study arms. A cost-effectiveness analysis will consider the incremental cost per Quality Adjusted Life Years of the intervention compared with usual care. Qualitative and fidelity substudies will be analysed through framework analysis and fidelity assessment tools respectively. ETHICS AND DISSEMINATION: REC and HRA approval were obtained. A Data Monitoring and Ethics Committee has been constituted. Dissemination will be via publications, conferences and social media. Intervention materials will be made open access. TRIAL REGISTRATION NUMBER: ISRCTN17993825.

Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial.

BACKGROUND: The number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP. METHODS/DESIGN: A multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway. DISCUSSION: The study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment. TRIAL REGISTRATION: ISRCTN17545443 . Registered on 12 September 2016.

The association between long-term conditions and uptake of population-based screening for colorectal cancer: results from two English cohort studies.

INTRODUCTION: Uptake of screening for colorectal cancer (CRC) can reduce mortality, and population-based screening is offered in England. To date, there is little evidence on the association between having a long-term condition (LTC) and CRC screening uptake. The objective of this study was to examine the association between having an LTC and uptake of CRC screening in England with the guaiac fecal occult blood test, with a particular focus on common mental disorders. METHODS: The study was a preregistered secondary analysis of two cohorts: first, a linked data set between the regional Yorkshire Health Study (YHS) and the National Health Service National Bowel Cancer Screening Program (BCSP, years 2006-2014); second, the national English Longitudinal Study of Ageing (ELSA, years 2014-2015). Individuals eligible for BCSP screening who participated in either the YHS (7,142) or ELSA Wave 7 (4,099) were included. Study registration: ClinicalTrials.gov, number NCT02503969. RESULTS: In both the cohorts, diabetes was associated with lower uptake (YHS odds ratio [OR] for non-uptake 1.35, 95% CI 1.03-1.78; ELSA 1.33, 1.03-1.72) and osteoarthritis was associated with increased uptake (YHS 0.75, 0.57-0.99; ELSA 0.76, 0.62-0.93). After controlling for broader determinants of health, there was no evidence of significantly different uptake for individuals with common mental disorders. CONCLUSION: Two large independent cohorts provided evidence that uptake of CRC screening is lower among individuals with diabetes and higher among individuals with osteoarthritis. Further work should compare barriers and facilitators to screening among individuals with either of these conditions. This study also demonstrates the benefits of data linkage for improving clinical decision-making.

A randomized trial found online questionnaires supplemented by postal reminders generated a cost-effective and generalizable sample but don't forget the reminders.

OBJECTIVES: The objective of this study was to compare the response rates, data completeness, and representativeness of survey data produced by online and postal surveys. STUDY DESIGN AND SETTING: A randomized trial nested within a cohort study in Yorkshire, United Kingdom. Participants were randomized to receive either an electronic (online) survey questionnaire with paper reminder (N = 2,982) or paper questionnaire with electronic reminder (N = 2,855). RESULTS: Response rates were similar for electronic contact and postal contacts (50.9% vs. 49.7%, difference = 1.2%, 95% confidence interval: -1.3% to 3.8%). The characteristics of those responding to the two groups were similar. Participants nevertheless demonstrated an overwhelming preference for postal questionnaires, with the majority responding by post in both groups. CONCLUSION: Online survey questionnaire systems need to be supplemented with a postal reminder to achieve acceptable uptake, but doing so provides a similar response rate and case mix when compared to postal questionnaires alone. For large surveys, online survey systems may be cost saving.

PLEASANT: Preventing and Lessening Exacerbations of Asthma in School-age children Associated with a New Term - a cluster randomised controlled trial and economic evaluation.

BACKGROUND: Asthma episodes and deaths are known to be seasonal. A number of reports have shown peaks in asthma episodes in school-aged children associated with the return to school following the summer vacation. A fall in prescription collection in the month of August has been observed, and was associated with an increase in the number of unscheduled contacts after the return to school in September. OBJECTIVE: The primary objective of the study was to assess whether or not a NHS-delivered public health intervention reduces the September peak in unscheduled medical contacts. DESIGN: Cluster randomised trial, with the unit of randomisation being 142 NHS general practices, and trial-based economic evaluation. SETTING: Primary care. INTERVENTION: A letter sent (n = 70 practices) in July from their general practitioner (GP) to parents/carers of school-aged children with asthma to remind them of the importance of taking their medication, and to ensure that they have sufficient medication prior to the start of the new school year in September. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of children aged 5-16 years who had an unscheduled medical contact in September 2013. Supporting end points included the proportion of children who collected prescriptions in August 2013 and unscheduled contacts through the following 12 months. Economic end points were quality-adjusted life-years (QALYs) gained and costs from an NHS and Personal Social Services perspective. RESULTS: There is no evidence of effect in terms of unscheduled contacts in September. Among children aged 5-16 years, the odds ratio (OR) was 1.09 [95% confidence interval (CI) 0.96 to 1.25] against the intervention. The intervention did increase the proportion of children collecting a prescription in August (OR 1.43, 95% CI 1.24 to 1.64) as well as scheduled contacts in the same month (OR 1.13, 95% CI 0.84 to 1.52). For the wider time intervals (September-December 2013 and September-August 2014), there is weak evidence of the intervention reducing unscheduled contacts. The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children collecting prescriptions in August as well as having scheduled contacts in the same month. These unscheduled contacts in September could be a result of the intervention, as GPs may have wanted to see patients before issuing a prescription. The economic analysis estimated a high probability that the intervention was cost-saving, for baseline-adjusted costs, across both base-case and sensitivity analyses. There was no increase in QALYs. LIMITATION: The use of routine data led to uncertainty in the coding of medical contacts. The uncertainty was mitigated by advice from a GP adjudication panel. CONCLUSIONS: The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children both collecting prescriptions and having scheduled contacts in August. After September there is weak evidence in favour of the intervention. The intervention had a favourable impact on costs but did not demonstrate any impact on QALYs. The results of the trial indicate that further work is required on assessing and understanding adherence, both in terms of using routine data to make quantitative assessments, and through additional qualitative interviews with key stakeholders such as practice nurses, GPs and a wider group of children with asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03000938. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 93. See the HTA programme website for further project information.

Cohort Profile: The Yorkshire Health Study.

The Yorkshire Health Study is a longitudinal observational regional health study collecting health information on the residents from the Yorkshire and Humberside region in England. The second wave of data collection is currently under way. The study aims to inform National Health Service (NHS) and local authority health-related decision making in Yorkshire, with wider implications from findings as well. The first wave contains records for 27 806 individuals (2010-12), aged between 16 and 85, from one part of Yorkshire (South Yorkshire), with the second wave expanding data collection to the whole of the Yorkshire and Humberside region. Data were collected on current and long-standing health, health care usage and health-related behaviours, with a particular focus on weight and weight management. The majority of individuals have also given consent for record linkage with routine clinical data, allowing the linking to disease diagnosis, medication use and health care usage. The study encourages researchers to utilize the sample through the embedding of randomized controlled trials, other controlled trials and qualitative studies. To access the anonymized data or use the sample to recruit participants to studies, researchers should contact Clare Relton (c.relton@sheffield.ac.uk).

South Yorkshire Cohort: a 'cohort trials facility' study of health and weight - protocol for the recruitment phase.

BACKGROUND: Growing levels of both obesity and chronic disease in the general population pose a major public health problem. In the UK, an innovative 'health and weight' cohort trials facility, the 'South Yorkshire Cohort', is being built in order to provide robust evidence to inform policy, commissioning and clinical decisions in this field. This protocol reports the design of the facility and outlines the recruitment phase methods. METHOD/DESIGN: The South Yorkshire Cohort health and weight study uses the cohort multiple randomised controlled trial design. This design recruits a large observational cohort of patients with the condition(s) of interest which then provides a facility for multiple randomised controlled trials (with large representative samples of participants, long term outcomes as standard, increased comparability between each trial conducted within the cohort and increased efficiency particularly for trials of expensive interventions) as well as ongoing information as to the natural history of the condition and treatment as usual.This study aims to recruit 20,000 participants to the population based South Yorkshire Cohort health and weight research trials facility. Participants are recruited by invitation letters from their General Practitioners. Data is collected using postal and/or online patient self completed Health Questionnaires. NHS numbers will be used to facilitate record linkage and access to routine data. Participants are eligible if they are: aged 16 - 85 years, registered with one of 40 practices in South Yorkshire, provide consent for further contact from the researchers and to have their information used to look at the benefit of health treatments. The first wave of data is being collected during 2010/12 and further waves are planned at 2 - 5 year intervals for the planned 20 year duration of the facility. DISCUSSION: The South Yorkshire Cohort combines the strengths of the standard observational, longitudinal cohort study design with a population based cohort facility for multiple randomised controlled trials in a range of long term health and weight related conditions (including obesity). This infrastructure will allow the rapid and cheap identification and recruitment of patients, and facilitate the provision of robust evidence to inform the management and self-management of health and weight.

"Booster" interventions to sustain increases in physical activity in middle-aged adults in deprived urban neighbourhoods: internal pilot and feasibility study.

BACKGROUND: Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. A randomised controlled trial is needed to assess whether providing motivational interviewing, three months after giving initial advice, sustains physical activity levels in those who recently became physically active. This paper reports the results of an internal pilot study designed to test the feasibility of the study in terms of recruitment, per protocol delivery of the intervention and retention at three months. METHODS: Participants were: aged 40-64 years; resident in deprived areas of Sheffield, UK; and, had recently become physically active as a result of using a brief intervention following an invitation from a mass mail out. INTERVENTIONS: Motivational Interviewing 'boosters' aimed at sustaining change in physical activity status delivered face-to-face or over the telephone compared with no further intervention. Outcomes of the feasibility study: recruitment of 60 participants from mail out of 3,300; retention of 45 participants with 3-month follow-up accelerometry measurements; 70% of those randomised to boosters receiving intervention per protocol. Sample size and power were recalculated using the accelerometry data collected. RESULTS: Forty-seven participants were randomised (78% of the feasibility target); 37 participants were retained at three months, 29 with at least four days of accelerometry data (64% of the feasibility target); 79% of those allocated boosters received them per protocol (surpassing the feasibility target). The proposed sample size of 600 was confirmed as appropriate and power is expected to be sufficient to detect a difference between groups. CONCLUSIONS: The main study will continue with the original recruitment target of 600 participants but to ensure feasibility, it is necessary to increase recruitment and improve the numbers of those followed-up who have evaluable data. Strategies will include increasing the number of initial invitations sent out and improving the training of research assistants and participants in the positioning of the accelerometer.