Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment.

PURPOSE: To develop an agreed upon set of outcomes known as a "core outcome set" (COS) for noninfectious uveitis of the posterior segment (NIU-PS) clinical trials. DESIGN: Mixed-methods study design comprising a systematic review and qualitative study followed by a 2-round Delphi exercise and face-to-face consensus meeting. PARTICIPANTS: Key stakeholders including patients diagnosed with NIU-PS, their caregivers, and healthcare professionals involved in decision-making for patients with NIU-PS, including ophthalmologists, nurse practitioners, and policymakers/commissioners. METHODS: A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a 2-round Delphi exercise of stakeholders rating the importance of outcomes on a 9-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of "include," "exclude," or "for discussion" that were taken to a face-to-face consensus meeting of key stakeholders at which they agreed on the final COS. MAIN OUTCOME MEASURE: Items recommended for inclusion in the COS for NIU-PS. RESULTS: A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting, of which 7 of 15 were agreed on for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, health-related quality of life, treatment side effects, and disease control. CONCLUSIONS: This study builds on international work across the clinical trials community and our qualitative research to construct the world's first COS for NIU-PS. The COS provides a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce noninformative research. Some of the outcomes identified do not yet have internationally agreed upon methods for measurement and should be the subject of future international consensus development.

Outcomes important to patients with non-infectious posterior segment-involving uveitis: a qualitative study.

OBJECTIVE: Uveitis, a group of disorders characterised by intraocular inflammation, causes 10%-15% of total blindness in the developed world. The most sight-threatening forms of non-infectious uveitis are those affecting the posterior segment of the eye, collectively known as posterior segment-involving uveitis (PSIU). Numerous different clinical outcomes have been used in trials evaluating treatments for PSIU, but these may not represent patients' and carers' concerns. Therefore, the aims of this study were to understand the impact of PSIU on adult patients' and carers' lives and to explore what outcomes of treatment are important to them. METHODS AND ANALYSIS: Four focus group discussions were undertaken to understand the perspectives of adult patients (=18) and carers (10) with PSIU. Participants were grouped according to whether or not their uveitis was complicated by the sight-threatening condition uveitic macular oedema. Discussions were audio-recorded, transcribed and analysed using the framework analytical approach. Outcomes were identified and grouped into outcome domains. RESULTS: Eleven core domains were identified as important to patients and carers undergoing treatment for PSIU, comprising (1) visual function, (2) symptoms, (3) functional ability, (4) impact on relationships, (5) financial impact, (6) psychological morbidity and emotional well-being, (7) psychosocial adjustment to uveitis, (8) doctor/patient/interprofessional relationships and access to healthcare, (9) treatment burden, (10) treatment side effects, and (11) disease control. CONCLUSION: The domains identified represent patients' and carers' experience and perspectives and can be used to reflect on outcomes assessed in PSIU. They will directly inform the development of a core outcome set for PSIU clinical trials.

Three wound-dressing strategies to reduce surgical site infection after abdominal surgery: the Bluebelle feasibility study and pilot RCT.

BACKGROUND: Surgical site infection (SSI) affects up to 20% of people with a primary closed wound after surgery. Wound dressings may reduce SSI. OBJECTIVE: To assess the feasibility of a multicentre randomised controlled trial (RCT) to evaluate the effectiveness and cost-effectiveness of dressing types or no dressing to reduce SSI in primary surgical wounds. DESIGN: Phase A - semistructured interviews, outcome measure development, practice survey, literature reviews and value-of-information analysis. Phase B - pilot RCT with qualitative research and questionnaire validation. Patients and the public were involved. SETTING: Usual NHS care. PARTICIPANTS: Patients undergoing elective/non-elective abdominal surgery, including caesarean section. INTERVENTIONS: Phase A - none. Phase B - simple dressing, glue-as-a-dressing (tissue adhesive) or 'no dressing'. MAIN OUTCOME MEASURES: Phase A - pilot RCT design; SSI, patient experience and wound management questionnaires; dressing practices; and value-of-information of a RCT. Phase B - participants screened, proportions consented/randomised; acceptability of interventions; adherence; retention; validity and reliability of SSI measure; and cost drivers. DATA SOURCES: Phase A - interviews with patients and health-care professionals (HCPs), narrative data from published RCTs and data about dressing practices. Phase B - participants and HCPs in five hospitals. RESULTS: Phase A - we interviewed 102 participants. HCPs interpreted 'dressing' variably and reported using available products. HCPs suggested practical/clinical reasons for dressing use, acknowledged the weak evidence base and felt that a RCT including a 'no dressing' group was acceptable. A survey showed that 68% of 1769 wounds (727 participants) had simple dressings and 27% had glue-as-a-dressing. Dressings were used similarly in elective and non-elective surgery. The SSI questionnaire was developed from a content analysis of existing SSI tools and interviews, yielding 19 domains and 16 items. A main RCT would be valuable to the NHS at a willingness to pay of £20,000 per quality-adjusted life-year. Phase B - from 4 March 2016 to 30 November 2016, we approached 862 patients for the pilot RCT; 81.1% were eligible, 59.4% consented and 394 were randomised (simple, n = 133; glue, n = 129; no dressing, n = 132); non-adherence was 3 out of 133, 8 out of 129 and 20 out of 132, respectively. SSI occurred in 51 out of 281 participants. We interviewed 55 participants. All dressing strategies were acceptable to stakeholders, with no indication that adherence was problematic. Adherence aids and patients' understanding of their allocated dressing appeared to be key. The SSI questionnaire response rate overall was 67.2%. Items in the SSI questionnaire fitted a single scale, which had good reliability (test-retest and Cronbach's alpha of > 0.7) and diagnostic accuracy (c-statistic = 0.906). The key cost drivers were hospital appointments, dressings and redressings, use of new medicines and primary care appointments. LIMITATIONS: Multiple activities, often in parallel, were challenging to co-ordinate. An amendment took 4 months, restricting recruitment to the pilot RCT. Only 67% of participants completed the SSI questionnaire. We could not implement photography in theatres. CONCLUSIONS: A main RCT of dressing strategies is feasible and would be valuable to the NHS. The SSI questionnaire is sufficiently accurate to be used as the primary outcome. A main trial with three groups (as in the pilot) would be valuable to the NHS, using a primary outcome of SSI at discharge and patient-reported SSI symptoms at 4-8 weeks. TRIAL REGISTRATION: Phase A - Current Controlled Trials ISRCTN06792113; Phase B - Current Controlled Trials ISRCTN49328913. 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. 23, No. 39. See the NIHR Journals Library website for further project information. Funding was also provided by the Medical Research Council ConDuCT-II Hub (reference number MR/K025643/1).

Wound infections are common after surgery. Some are cured with simple treatment, but others may lead to serious problems. Reducing the risk of a wound infection is important. We do not know if the type of dressing, or not using a dressing, influences the risk of infection. A study that allocated patients to receive different dressings (or no dressing) would answer this question. We did preliminary research to explore whether or not such a study is possible. We interviewed doctors, nurses and patients about their views on dressings and a future study. We also described dressings currently being used in the NHS and found that simple dressings and tissue adhesive (glue) 'as-a-dressing' are used most frequently. We studied existing evidence and interviewed experts to develop a questionnaire, completed by patients, to identify wound infections after patients leave hospital and tested its accuracy. We also explored taking photographs of wounds. We investigated whether or not a major study would be worth the cost and designed a pilot study to test its feasibility. The pilot study recruited 394 patients undergoing abdominal operations in five NHS hospitals. These patients were allocated to have a simple dressing, glue-as-a-dressing or no dressing, and 92% received the allocated dressing method. Patients and their doctors and nurses found the dressing methods to be acceptable. We showed that the new patient questionnaire accurately identified infections. Patients or their carers also found it acceptable to photograph their wounds. Our research suggests that a future large study would be worth the investment and is possible.

Anti-tumour necrosis factor biological therapies for the treatment of uveitic macular oedema (UMO) for non-infectious uveitis.

BACKGROUND: Non-infectious uveitis describes a heterogenous group of ocular disorders characterised by intraocular inflammation in the absence of infection. Uveitis is a leading cause of visual loss, most commonly due to uveitic macular oedema (UMO). Treatment is aimed at reducing disease activity by suppression of the intraocular inflammatory response. In the case of macular oedema, the aim is to restore macular architecture as quickly as possible, in order to prevent irreversible photoreceptor damage in this area. Acute exacerbations are typically managed with corticosteroids, which may be administered topically, locally or systemically. Whilst these are often rapidly effective in achieving disease control, long-term use is associated with significant local and systemic side effects, and 'steroid sparing agents' are typically used to achieve prolonged control in severe or recalcitrant disease. Anti-tumour necrosis factor (TNF) drugs block a critical cytokine in the inflammatory signalling process, and have emerged as effective steroid-sparing immunomodulatory agents in a wide range of non-ocular conditions. There is mechanistic data to suggest that they may provide a more targeted approach to disease control in UMO than other agents, but to date, these agents have predominantly been used 'off label' as the majority are not licensed for ocular use. This review aims to summarise the available literature reporting the use of anti-TNF therapy in UMO, thus developing the evidence-base on which to make future treatment decisions and develop clinical guidelines in this area. OBJECTIVES: To assess the efficacy of anti-TNF therapy in treatment of UMO. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; LILACS; Web of Science Conference Proceedings Citation Index- Science (CPCI-S); System for Information on Grey Literature in Europe (OpenGrey); the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 29 March 2018. SELECTION CRITERIA: We planned to include all relevant randomised controlled trials assessing the use of anti-TNF agents in treatment of UMO. No limits were applied to participant age, gender or ethnicity. The primary comparisons of this review were: anti-TNF versus no treatment or placebo; anti-TNF versus another pharmacological agent; comparison of different anti-TNF drugs; comparison of different doses and routes of administration of the same anti-TNF drug. The primary outcome measure that we assessed for this review was best-corrected visual acuity (BCVA) in the treated eye. Secondary outcome measures were anatomical macular change, clinical estimation of vitreous haze and health-related quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts retrieved through the database searches. We retrieved full-text reports of studies categorised as 'unsure' or 'include' after we had reviewed the abstracts. Two review authors independently reviewed each full-text report for eligibility. We resolved discrepancies through discussion. MAIN RESULTS: We identified no completed or ongoing trial that was eligible for this Cochrane Review. AUTHORS' CONCLUSIONS: Our review did not identify any evidence from randomised controlled trials for or against the role of anti-TNF agents in the management of UMO. Although there are a number of high-quality randomised controlled trials that demonstrate the efficacy of anti-TNF agents in preventing recurrence of inflammation in uveitis, the reported study outcomes do not include changes in UMO. As a result, there were insufficient data to conclude whether there was a significant treatment effect specifically for UMO. Future trials should be designed to include quantitative measures of UMO as primary study outcomes, for example by reporting the presence or absence of UMO, or by measuring central macular thickness for study participants. Furthermore, whilst UMO is an important complication of uveitis, we acknowledge that uveitis is associated with many significant structural and functional complications. It is not possible to determine treatment efficacy based on a single outcome measure. We recommend that future reviews of therapeutic interventions in uveitis should use composite measures of treatment response comprising a range of potential complications of disease.

COSUMO: study protocol for the development of a core outcome set for efficacy and effectiveness trials in posterior segment-involving uveitis.

BACKGROUND: Uveitis, a group of disorders characterised by intraocular inflammation, causes 10-15% of total blindness in the developed world. The most sight-threatening uveitis affects the posterior segment of the eye (posterior-segment involving uveitis (PSIU)). Numerous different outcomes have been used in clinical trials evaluating alternative treatments for uveitis, limiting inter-trial comparison and aggregation of data. We aim to develop a core outcome set (COS) that would provide a standardised set of outcomes to be measured and reported in all effectiveness trials for PSIU. METHODS: A three-phase design will be used informed by recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Phase 1: a comprehensive list of outcomes will be identified through both a systematic review of effectiveness trials of PSIU and qualitative research with stakeholders. The qualitative study will comprise focus groups with patients and their carers in parallel with one-to-one telephone interviews with health professionals and policy-makers. In the focus groups, patients will be grouped according to whether or not their uveitis is complicated by the sight-threatening condition uveitic macular oedema (UMO) since it is hypothesised that the presence of UMO may significantly impact on patient experience of PSIU. Phase 2: Delphi methodology will be used to reduce the range of potential outcomes for the core set. Up to three Delphi rounds will be used through an online survey. Participants will be asked to rate the importance of each outcome on a 9-point Likert scale where 9 is most important. Phase 3: a consensus meeting will be held with key stakeholders to discuss the Delphi results and ratify the final outcomes to be included in the COS. DISCUSSION: The development of an agreed COS for PSIU would help ensure that outcomes which matter to key stakeholders are captured and reported in a consistent way. A COS for PSIU would allow greater comparison and aggregation of data across trials for the better evaluation of established and emerging therapies through evidence synthesis and meta-analysis to inform clinical guidelines and health policy. TRIAL REGISTRATION: COMET. http://comet-initiative.org/studies/details/640 . August 2015.

Adapting to ulcerative colitis to try to live a 'normal' life: a qualitative study of patients' experiences in the Midlands region of England.

OBJECTIVE: To provide a framework that is able to categorise whether patients are able to adapt to and lead a 'normal' life with ulcerative colitis (UC) and to detail the factors that influence this. DESIGN: Qualitative research study using in-depth semi-structured interviews. SETTING: Four clinical sites in the West and East Midlands regions of England. PARTICIPANTS: 28 adult patients diagnosed with UC for years between 1 and 22. RESULTS: Medication was rarely sufficient for patients to adapt to UC and live as 'normal' a life as possible. Virtually all patients tested and adopted non-medical adaptation methods to improve physical and psychological well-being, to help them carry on working and to prevent embarrassment. In addition, some patients benefited from outside support providing them with practical, emotional and/or financial help. In conjunction with adaptation strategies and the time to adapt, this meant that some patients with severe clinical disease were able to maintain a sense of normality in life. Patients reported that clinicians were not always receptive to discussion of the broader context of life with UC. CONCLUSIONS: Patients' experience of UC and their ability to adapt in order to maintain a sense of normality in life is a complex interplay of symptoms, adaptation strategies and outside support. Over time patients test out a variety of non-medical adaptation strategies. Awareness of this may help clinicians and researchers to understand patients' views on the role of medical and other therapies. Further research around the utility of this framework in clinical practice and research is now required. TRIAL REGISTRATION NUMBER: ISRCTN56523019, results.

A mixed-methods feasibility and external pilot study to inform a large pragmatic randomised controlled trial of the effects of surgical wound dressing strategies on surgical site infections (Bluebelle Phase B): study protocol for a randomised controlled trial.

BACKGROUND: Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered. METHODS/DESIGN: This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients' wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4-8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial. DISCUSSION: This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed. TRIAL REGISTRATION: ISRCTN49328913 . Registered on 20 October 2015.

"The patient is speaking": discovering the patient voice in ophthalmology.

Eye disease can be devastating. The most feared impact is sight loss, but in a number of ophthalmic conditions, there can be wide-ranging systemic, psychological, emotional and social effects of both the disease and its treatment. External tests of visual function, such as visual acuity, are inadequate to understand the overall impact of ophthalmic disease on a patient's functional vision or daily life. This can lead to a discordance between the patient's priorities and perspective on the one hand and the efforts of clinicians and other stakeholders on the other hand. In this review, we discuss how the patient is uniquely placed to understand the impact of the disease and can use that position to transform ophthalmic care at the individual and collective level, from research to care delivery. We highlight how the "patient voice" can contribute to key areas, including priority setting in the research agenda, communicating the wide-ranging impact of disease and its treatment as assessed through qualitative research, identifying the outcome measures that matter to the patient through core outcome set development and reporting these outcomes through appropriate patient-reported outcome measures. We also consider the increasing power of the patient voice on health institutions, ranging from broadcasting an individual's experience of care he/she has received to patient societies influencing future health policy. Finally, we reflect on the challenges that need to be overcome for the patient voice to increasingly influence and improve the delivery of eye care in the future.