Emma Bedson

Involving service users in trials: developing a standard operating procedure

BackgroundMany funding bodies require researchers to actively involve service users in research to improve relevance, accountability and quality. Current guidance to researchers mainly discusses general principles. Formal guidance about how to involve service users operationally in the conduct of trials is lacking. We aimed to develop a standard operating procedure (SOP) to support researchers to involve service users in trials and rigorous studies.MethodsResearchers with experience of involving service users and service users who were contributing to trials collaborated with the West Wales Organisation for Rigorous Trials in Health, a registered clinical trials unit, to develop the SOP. Drafts were prepared in a Task and Finish Group, reviewed by all co-authors and amendments made.ResultsWe articulated core principles, which defined equality of service users with all other research team members and collaborative processes underpinning the SOP, plus guidance on how to achieve these. We developed a framework for involving service users in research that defined minimum levels of collaboration plus additional consultation and decision-making opportunities. We recommended service users be involved throughout the life of a trial, including planning and development, data collection, analysis and dissemination, and listed tasks for collaboration. We listed people responsible for involving service users in studies and promoting an inclusive culture. We advocate actively involving service users as early as possible in the research process, with a minimum of two on all formal trial groups and committees. We propose that researchers protect at least 1% of their total research budget as a minimum resource to involve service users and allow enough time to facilitate active involvement.ConclusionsThis SOP provides guidance to researchers to involve service users successfully in developing and conducting clinical trials and creating a culture of actively involving service users in research at all stages. The UK Clinical Research Collaboration should encourage clinical trials units actively to involve service users and research funders should provide sufficient funds and time for this in research grants.

Enhancing rigour in the validation of patient reported outcome measures (PROMs): bridging linguistic and psychometric testing

BackgroundA strong consensus exists for a systematic approach to linguistic validation of patient reported outcome measures (PROMs) and discrete methods for assessing their psychometric properties. Despite the need for robust evidence of the appropriateness of measures, transition from linguistic to psychometric validation is poorly documented or evidenced. This paper demonstrates the importance of linking linguistic and psychometric testing through a purposeful stage which bridges the gap between translation and large-scale validation.FindingsEvidence is drawn from a study to develop a Welsh language version of the Beck Depression Inventory-II (BDI-II) and investigate its psychometric properties. The BDI-II was translated into Welsh then administered to Welsh-speaking university students (n = 115) and patients with depression (n = 37) concurrent with the English BDI-II, and alongside other established depression and quality of life measures. A Welsh version of the BDI-II was produced that, on administration, showed conceptual equivalence with the original measure; high internal consistency reliability (Cronbach’s alpha = 0.90; 0.96); item homogeneity; adequate correlation with the English BDI-II (r = 0.96; 0.94) and additional measures; and a two-factor structure with one overriding dimension. Nevertheless, in the student sample, the Welsh version showed a significantly lower overall mean than the English (p = 0.002); and significant differences in six mean item scores. This prompted a review and refinement of the translated measure.ConclusionsExploring potential sources of bias in translated measures represents a critical step in the translation-validation process, which until now has been largely underutilised. This paper offers important findings that inform advanced methods of cross-cultural validation of PROMs.

Including service users in trials and rigorous studies in health and social care: developing a standard operating procedure for researchers

Background Involving service users in research is encouraged as a way to improve research quality, relevance and accountability and is a pre-requisite for many funding bodies. Existing guidance for researchers on how to do this mainly discusses general principles. Some researchers may question the value, feasibility and impact of including service users and limit the scope of involvement. We defined service users as patients, carers, people eligible for a service or anyone relevant to the trial inclusion criteria.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol

Introduction Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. Methods and analysis The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. Ethics and dissemination This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. Trial Registration Current Controlled Trials ISRCTN05956042.

Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT)

Introduction Despite clinical guidelines recommendations, many relatives of people with psychosis or bipolar disorder do not currently receive the support they need. Online information and support may offer a solution. Methods and analysis This single-blind, parallel, online randomised controlled trial will determine clinical and cost-effectiveness of the Relatives Education And Coping Toolkit (REACT) (including an online resource directory (RD)), compared with RD only, for relatives of people with psychosis or bipolar disorder. Both groups continue to receive treatment as usual. Independent, web-based variable, block, individual randomisation will be used across 666 relatives. Primary outcome is distress at 24 weeks (measured by General Health Questionnaire; GHQ-28) compared between groups using analysis of covariance, adjusting for baseline score. Secondary clinical outcomes are carer well-being and support. Cost-effectiveness analysis will determine cost of a significant unit change (three-point reduction) in the GHQ-28. Costs include offering and supporting the intervention in the REACT arm, relevant healthcare care costs including health professional contacts, medications prescribed and time off (or ability to) work for the relative. Cost utility analysis will be calculated as the marginal cost of changes in quality-adjusted life years, based on EuroQol. We will explore relatives’ beliefs, perceived coping and amount of REACT toolkit use as possible outcome mediators. We have embedded two methodological substudies in the protocol to determine the relative effectiveness of a low-value (£10) versus higher value (£20) incentive, and an unconditional versus conditional incentive, on improving follow-up rates. Ethics and dissemination The trial has ethical approval from Lancaster National Research Ethics Service (NRES)Committee (15/NW/0732) and is overseen by an independent Data Monitoring and Ethics Committee and Trial Steering Committee. Protocol version 1.5 was approved on 9 January 2017. All updates to protocols are uploaded to the National Institute for Health Research (NIHR) Journals Library. A full statistical analysis plan is available at https://figshare.com/account/home#/projects/19975. Publications will be in peer-reviewed journals (open access wherever possible). Requests for access to the data at the end of the study will be reviewed and granted where appropriate by the Trial Management Group. Trial registration number ISRCTN72019945, pre-results.

A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia

Pilot trial to compare prism therapy and visual search training, for homonymous hemianopia, to standard care (information only).

Half-baked? B vitamins and depression

The study by Skarupski et al (1) in this issue of the Journal has made an important contribution to a long-running fascination with the associations between B vitamins and depression. Epidemiologic, observational, and case-control studies dating back to the 1960s have indicated a strong association between functional or absolute folate deficiency and depressive symptoms, symptom severity, and treatment outcomes in adults and the older adult population (2–6). Patients with depression are reported to have lower concentrations of folate than patients with other psychiatric disorders and nonpsychiatric comparison groups. Low folate concentrations are also associated with poor antidepressant response. These findings together with robust evidence of the role of folate in other disease areas, particularly in the prevention of neural tube defects, have prompted large-scale public health interventions, such as folate enrichment of flour in the United States and other countries. Yet, these interventions do not have an entirely benign risk-benefit profile and have led to criticism and concerns that they may be exposing the public to other potential health risks. Given the large-scale and high-profile public health interventions that flow from the interest in the role of B vitamins in mental health and other health areas, it is important to acknowledge that these associations are not clear cut. Up to now there has been less evidence available for the role of other B vitamins in depression. Vitamin B-12 has been shown to be associated with depression, with higher concentrations of vitamin B-12 reported to result in better treatment outcomes (7). Indeed, it has been proposed that vitamin B-12 has a stronger causal relation to depression than does folate (8), although, interestingly, low folate but not low vitamin B-12 significantly delays time to onset of clinical improvement in patients with depression compared with depressed patients with normal folate concentrations (9). There is limited evidence in relation to dietary intake of B vitamins, with much of the research focus placed on supplementation. Higher dietary intakes of folate but not of other B vitamins [including vitamins B-12, B-6, and B-2 (riboflavin)] and higher serum folate concentrations have been shown to be associated with a lower prevalence of depressive symptoms in men (10, 11). However, low folate status (12) and low vitamin B-12 intake (13) have also been associated with depressive symptoms in women. Vitamin B-12 deficiency is reported to increase the risk of severe depression in older women (14), but in one study, B vitamin supplementation had no effect on depression in women (15). Evidence suggests, however, that the older population in particular may benefit from B vitamin supplementation (16) because of the prevalence of disorders that reduce folate and vitamin B-12 and B-6 absorption. The current study by Skarupski et al (1) enhances our existing evidence base by presenting longitudinal findings of the association of B vitamin intake, through both diet and supplementation, with depressive symptoms in older adults. Importantly, the study findings do not support the association of folate intake either by supplementation or diet alone with depressive symptoms in this population. Neither do they report differences between sexes. However, the study provides compelling evidence of the protective effects of dietary intake and supplementation of vitamin B-12 against depression. The study also shows that vitamin B-6 intake through supplementation, but not through diet, may also have this protective effect. This contrasts with the limited available evidence on vitamin B-6 in depression (10, 14, 17). There is still much to be gleaned about the role of these vitamins in the pathogenesis and treatment of depression and indeed more generally in maintaining mental health. First, the role of dietary intake of these vitamins needs further exploration, even though the Skarupski et al study and others (1, 11, 13) come some way to this end. Second, the long-term mental health benefit of supplementation needs further investigation. The Skarupski et al study (1) has provided intriguing insights into this area with the older population, but this type of longitudinal research needs extending to the adult population. Third, the relative benefits of supplementation with naturally occurring vitamins compared with synthetic forms needs to be better understood in relation to depression, with very little evidence currently available in this area. There is still uncertainty as to thresholds to classify deficiency of these vitamins, with observations pointing to large individual differences in the metabolism of vitamins such as folate. There is also uncertainty about the best measurement of these vitamins with, for example, methylmalonic acid and red cell folate reported to be better markers of vitamin B-12 and folate status, respectively, but many studies fail to report these measures. Finally, the extent to which pretreatment folate

A Randomised Controlled Trial of Treatment for Post-Stroke Homonymous Hemianopia: Screening and Recruitment

ABSTRACT The authors report the screening process and recruitment figures for the VISION (Visual Impairment in Stroke; Intervention Or Not) trial. This is a prospective, randomised, single-blinded, three-arm controlled trial in 14 UK acute hospital stroke units. Stroke teams identified stroke survivors suspected as having homonymous hemianopia. Interventions included Fresnel prisms versus visual search training versus standard care (information only). Primary outcome was change in visual field assessment from baseline to 26 weeks. Secondary measures included change in quality-of-life questionnaires. Recruitment opened in May 2011. A total of 1171 patients were screened by the local principal investigators. Of 1171 patients, 178 (15.2%) were eligible for recruitment: 87 patients (7.4%) provided consent and were recruited; 91 patients (7.8%) did not provide consent, and 993 of 1171 patients (84.8%) failed to meet the eligibility criteria. Almost half were excluded due to complete/partial recovery of hemianopia (43.6%; n = 511). The most common ineligibility reason was recovery of hemianopia. When designing future trials in this area, changes in eligibility criteria/outcome selection to allow more patients to be recruited should be considered, e.g., less stringent levels of visual acuity/refractive error. Alternative outcomes measurable in the home environment, rather than requiring hospital attendance for follow-up, could facilitate increased recruitment.

Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT

BACKGROUND The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. OBJECTIVES (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. DESIGN A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. SETTING Fifteen diabetes clinics in hospitals in England and Wales. PARTICIPANTS Patients aged 7 months to 15 years. INTERVENTIONS Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. DATA SOURCES Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. OUTCOMES The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. RESULTS A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs). LIMITATIONS Generalisability beyond 12 months is uncertain. CONCLUSIONS No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. FUTURE WORK Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. TRIAL REGISTRATION Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.