Publications by authors named "Joanna Kelly"

53 Publications

A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

Nat Mater 2021 Sep 13. Epub 2021 Sep 13.

Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α/α signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.
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http://dx.doi.org/10.1038/s41563-021-01085-1DOI Listing
September 2021

Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity.

Cancer Cell 2021 Sep 22;39(9):1227-1244.e20. Epub 2021 Jul 22.

Systems Oncology, Cancer Research UK Manchester Institute, Alderley Park, Manchester SK10 4TG, UK. Electronic address:

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105-positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105-negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.
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http://dx.doi.org/10.1016/j.ccell.2021.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443274PMC
September 2021

Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention.

Biochem J 2021 06;478(12):2247-2263

Protein Phosphorylation Laboratory, Francis Crick Institute, Midland Road, London NE1 1AT, U.K.

A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues division failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.
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http://dx.doi.org/10.1042/BCJ20210283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238520PMC
June 2021

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT.

Health Technol Assess 2021 06;25(38):1-196

School of Health and Related Research, University of Sheffield, Sheffield, UK.

Background: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period.

Objective: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion.

Design: This was a three-arm, double-masked, randomised controlled non-inferiority trial.

Setting: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018.

Participants: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial.

Interventions: The participants were treated with repeated intravitreal injections of ranibizumab ( = 155), aflibercept ( = 154) or bevacizumab ( = 154).

Main Outcome Measures: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of -5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years.

Results: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows - ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval -2.17 to 6.63 letters;  = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference -1.73 letters, 95% confidence interval -6.12 to 2.67 letters;  = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was -3.96 letters, 95% confidence interval -8.34 to 0.42 letters;  = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means -1.8, 95% confidence interval -2.9 to -0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000-30,000 per quality-adjusted life-year.

Limitations: The comparison of aflibercept and bevacizumab was a post hoc analysis.

Conclusion: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered.

Future Work: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use.

Trial Registration: Current Controlled Trials ISRCTN13623634.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287375PMC
June 2021

Multiple House Occupancy is Associated with Mortality in Hospitalised Patients with Covid-19.

Eur J Public Health 2021 May 17. Epub 2021 May 17.

Institute of Applied Health Science, University of Aberdeen, Aberdeen Scotland.

Background: In response to the COVID-19 pandemic, many countries mandated staying at home to reduce transmission. This study examined the association between living arrangements (house occupancy numbers) and outcomes in COVID-19.

Methods: Study population was drawn from the COPE Study, a multicentre cohort study. House occupancy was defined as: living alone; living with one other person; living with multiple other people; or living in a nursing/residential home. Outcomes were time from admission to mortality and discharge (Cox regression), and Day-28 mortality (logistic regression), analyses were adjusted for key comorbidities and covariates including admission: age; sex, smoking; heart failure; admission CRP; COPD; eGFR, frailty and others.

Results: 1584 patients were included from 13 hospitals across UK and Italy: 676 (42.7%) were female, 907 (57.3%) were male, median age was 74 years (range: 19-101). At 28 days, 502 (31.7%) had died. Median admission CRP was 67, 82, 79.5 and 83mg/L for those living alone, with someone else, in a house of multiple occupancy and in a nursing/residential home, respectively. Compared to living alone, living with anyone was associated with increased mortality: within a couple (aHR 1.39, 95%CI 1.09-1.77, p = 0.007); living in a house of multiple occupancy (aHR=1.67, 95%CI 1.17-2.38, p = 0.005); and living in a residential home (aHR=1.36, 95%CI 1.03-1.80, p = 0.031).

Conclusion: For patients hospitalised with COVID-19, those living with one or more people had an increased association with mortality, they also exhibited higher CRP indicating increased disease severity suggesting they delayed seeking care.
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http://dx.doi.org/10.1093/eurpub/ckab085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247274PMC
May 2021

Cost Effectiveness of Ranibizumab vs Aflibercept vs Bevacizumab for the Treatment of Macular Oedema Due to Central Retinal Vein Occlusion: The LEAVO Study.

Pharmacoeconomics 2021 08 26;39(8):913-927. Epub 2021 Apr 26.

School of Health and Related Research, University of Sheffield, Sheffield, UK.

Background: We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion.

Methods: We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually.

Results: Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection.

Conclusions: Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents.
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http://dx.doi.org/10.1007/s40273-021-01026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298346PMC
August 2021

A cancer-associated, genome protective programme engaging PKCε.

Adv Biol Regul 2020 12 7;78:100759. Epub 2020 Oct 7.

Protein Phosphorylation Laboratory, Francis Crick Institute, London, NW1 1AT, UK.

Associated with their roles as targets for tumour promoters, there has been a long-standing interest in how members of the protein kinase C (PKC) family act to modulate cell growth and division. This has generated a great deal of observational data, but has for the most part not afforded clear mechanistic insights into the control mechanisms at play. Here, we review the roles of PKCε in protecting transformed cells from non-disjunction. In this particular cell cycle context, there is a growing understanding of the pathways involved, affording biomarker and interventional insights and opportunities.
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http://dx.doi.org/10.1016/j.jbior.2020.100759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689578PMC
December 2020

Successful and unsuccessful recruitment and retainment strategies in a UK multicentre drug trial for a rare chronic pain condition which performed above target.

Br J Pain 2020 Aug 24;14(3):171-179. Epub 2019 Dec 24.

University of Liverpool and The Walton Centre NHS Foundation Trust, Liverpool, UK.

Introduction: Recruitment into trials in rare chronic pain conditions can be challenging, so such trials consequently are underpowered or fail.

Methods: Drawing from our experience in conducting, to date, the largest academic trial in a rare chronic pain condition, complex regional pain syndrome, we have identified recruitment and retention strategies for successful trial conduct.

Results: We present 13 strategies grouped across the categories of 'setting the recruitment rate', 'networking', 'patient information', 'trial management' and 'patient retention'. Moreover, six recruitment risks are also discussed. A conservative recruitment estimate, based on audits of newly referred patients to the trial centres without taking into account availability of 'old' patients or recruitment from outside centres, and assuming a 55% patient refusal rate yielded accurate numbers.

Conclusion: Appreciation of these identified recruitment challenges and opportunities may contribute to supporting prospective investigators when they design clinical trials for chronic pain patient population groups where it has been historically difficult to conduct high-quality and robust clinical trials.
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http://dx.doi.org/10.1177/2049463719893399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453479PMC
August 2020

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

Eur Heart J 2020 12;41(47):4471-4480

Royal Brompton & Harefield NHS Foundation Trust, Sydney Street, London SW3 6NP, UK.

Aims: Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF.

Methods And Results: We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02).

Conclusion: Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA.

Clinical Trial Registration: ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.
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http://dx.doi.org/10.1093/eurheartj/ehaa658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767634PMC
December 2020

Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition.

Nat Commun 2020 06 3;11(1):2884. Epub 2020 Jun 3.

Protein Phosphorylation Laboratory, Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-16468-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271126PMC
June 2020

The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition.

Nat Commun 2020 03 13;11(1):1396. Epub 2020 Mar 13.

Protein Phosphorylation Laboratory, Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.

The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKCε phosphorylation of Aurora B S227. Assessing if this PKCε-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKCε also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKCε in by-passing the delay and resolution at anaphase entry that is associated with non-disjunction and catenation of sister chromatids. Implementation of this anaphase delay is reflected in PKCε activation following cell cycle dependent cleavage by caspase 7; knock-down of caspase 7 phenocopies PKCε loss, in a manner rescued by ectopically expressing/generating a free PKCε catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoIIα phosphorylation, a response necessary for catenation resolution during mitosis.
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http://dx.doi.org/10.1038/s41467-020-15163-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070073PMC
March 2020

Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema Secondary to Central Retinal Vein Occlusion: A Randomized Clinical Trial.

JAMA Ophthalmol 2019 Nov;137(11):1256-1264

National Institute for Health Research, Moorfields Biomedical Research Centre, London, United Kingdom.

Importance: The comparative clinical effectiveness of ranibizumab, aflibercept, and bevacizumab for the management of macular edema due to central retinal vein occlusion (CRVO) is unclear.

Objective: To determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with CRVO-related macular edema.

Design, Setting, And Participants: This prospective, 3-arm, double-masked, randomized noninferiority trial (Lucentis, Eylea, Avastin in Vein Occlusion [LEAVO] Study) took place from December 12, 2014, through December 16, 2016, at 44 UK National Health Service ophthalmology departments. Inclusion criteria included age 18 years or older, visual impairment due to CRVO-related macular edema of less than 12 months with best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent) in the study eye between 19 (20/400) and 78 (20/32), and spectral domain optical coherence tomography imaging central subfield thickness of 320 μm or greater. Data were analyzed from March 4, 2019, to April 26, 2019.

Interventions: Participants were randomized (1:1:1) to receive repeated intravitreal injections of ranibizumab (0.5 mg/0.05 mL) (n = 155), aflibercept (2.0 mg/0.05 mL) (n = 154), or bevacizumab (1.25 mg/0.05 mL) (n = 154) for 100 weeks.

Main Outcomes And Measures: Adjusted mean change in BCVA in the study eye at 100 weeks wherein noninferiority was concluded if the lower bounds of the 95% CI of both the intention-to-treat and the per protocol analyses were above -5 letters.

Results: Of 463 participants, 265 (57.2%) were male, with a mean (SD) age of 69.1 (13.0) years. The mean (SD) gain in BCVA letter score was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, 2.23 letters; 95% CI, -2.17 to 6.63 letters; P < .001). Bevacizumab was not noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, -1.73 letters; 95% CI, -6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar. Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, -1.9; 95% CI, -2.9 to -0.8).

Conclusions And Relevance: Mean changes in vision after treatment of macular edema due to CRVO were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes (ie, the change in visual acuity from baseline, on average, may be worse or may not be worse when using bevacizumab compared with ranibizumab).

Trial Registration: ISRCTN13623634.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.3305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865295PMC
November 2019

Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies.

Trials 2019 Aug 5;20(1):476. Epub 2019 Aug 5.

MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

Background: Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates.

Methods: OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants.

Discussion: Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report.

Trial Registration: ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012-004308-36 . Registered on 10 December 2012.
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http://dx.doi.org/10.1186/s13063-019-3602-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683506PMC
August 2019

Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol.

Trials 2019 Jul 15;20(1):429. Epub 2019 Jul 15.

Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Weston Education Centre, 10 Cutcombe Road, London, SE5 9RJ, UK.

Trial Design: We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis.

Methods: The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other's assessments for the duration of the study.

Conclusions: There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the "at risk" state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA.

Trial Registration: Current Controlled Trials, ID: ISRCTN46017566 . Registered on 4 July 2014.
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http://dx.doi.org/10.1186/s13063-019-3403-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633323PMC
July 2019

Ensuring trial conduct is consistent with trial design: assumption is the enemy of quality.

Trials 2019 Jul 10;20(1):416. Epub 2019 Jul 10.

Kings College London Clinical Trials Unit, Research Management and Innovation Directorate, King's College London, M2.06, 16 De Crespigny Park, London, SE5 8AF, UK.

'Assumptions are made and most assumptions are wrong' (Albert Einstein) Clinical trial conduct must be consistent with trial design, yet conducting the trial according to plan remains a major challenge.We discuss the importance of optimal co-applicant team formation in trial leadership, appropriate delegation of tasks and staff supervision arrangements. Finally, we discuss five standard documents which we believe require particular attention. With appropriate engagement by or with co-applicants during the preparation of these five standard documents, we believe many of the pitfalls trials commonly experience can be avoided. The risks inherent in failing to identify and address mistaken assumptions during the preparation of these documents are discussed and recommendations for best practice suggested.
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http://dx.doi.org/10.1186/s13063-019-3516-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617665PMC
July 2019

Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial.

Lancet Psychiatry 2019 May 2;6(5):391-402. Epub 2019 Apr 2.

Lambeth Addictions, South London and Maudsley NHS Mental Health Foundation Trust, London, UK.

Background: Opioid use disorder is a chronic, debilitating, and costly disorder that has increased in prevalence in many countries, with an associated sharp rise in mortality. Maintenance opioid agonist therapy is the first-line treatment, but many patients do not stop using illicit or non-prescribed drugs concomitantly. We aimed to test the efficacy and cost-effectiveness of a personalised psychosocial intervention implemented with a toolkit of behaviour-change techniques as an adjunct to opioid agonist therapy.

Methods: We did a pragmatic, open-label, randomised controlled trial at a specialist UK National Health Service community addictions clinic in London, UK. Eligible patients were aged 18 years or older, met criteria for opioid or cocaine dependence, or both, in the past 12 months, and voluntarily sought continued oral maintenance opioid agonist therapy, which they had been prescribed for at least 6 weeks. All participants were treatment resistant (ie, had used illicit or non-prescribed opioids or cocaine on one or more days in the past 28 days at study screening, which was verified by positive urine drug screen). Participants were allocated (1:1) by a web-accessed randomisation sequence (stratified by opioid agonist medication, current cocaine use, and current rug use) to receive a personalised psychosocial intervention (comprising a flexible toolkit of psychological-change methods, including contingency management to reinforce abstinence, recovery activities, and clinic attendance) in addition to treatment as usual, or treatment as usual only (control group). The primary outcome was treatment response at 18 weeks, which was defined as abstinence from illicit and non-prescribed opioids and cocaine in the past 28 days, as measured with treatment outcomes profiles and urine drug screening. Taking a societal cost perspective, we did an evaluation of cost-effectiveness with a wide range of willingness-to-pay values for a unit improvement in the probability of treatment response. We also calculated quality-adjusted life-years (QALYs). Efficacy was analysed in a modified-intention-to-treat population, including all participants who were randomly allocated but excluding those who had previously completed the intervention. This trial is registered with ISRCTN, number ISRCTN69313751. The trial is completed.

Findings: Between June 7, 2013, and Dec 21, 2015, we randomly allocated 136 participants to the psychosocial intervention group and 137 to the control group. The trial database was locked on April 19, 2017. Three patients (one in the psychosocial intervention group and two in the control group) who were re-randomised in error were excluded from the analysis. 22 (16%) of 135 patients in the psychosocial intervention group had a treatment response, compared with nine (7%) of 135 in the control group (adjusted log odds 1·20 [95% CI 0·01-2·37]; p=0·048). The psychosocial intervention had a higher probability of being cost-effective than treatment as usual. There was a probability range of 47-87% for willingness-to-pay thresholds of £0-1000 for a unit improvement in the probability of treatment response. QALYs were higher in the psychosocial intervention group than in the control group (mean difference 0·048 [95% CI 0·016-0·080]; p=0·004) in adjusted analyses, with 60% and 67% probabilities of cost-effectiveness at the UK National Institute for Health and Care Excellence's willingness-to-pay thresholds of £20 000 and £30 000 per QALY, respectively. The number of adverse events was similar between groups, and no severe adverse events in either group were judged to be treatment related. One participant in the control group was hospitalised with drug-injection-related sepsis and died.

Interpretation: In maintenance opioid agonist therapy, an adjunctive personalised psychosocial intervention in addition to standard therapy was efficacious and cost-effective compared with standard therapy alone at helping treatment-resistant patients abstain from using illicit and non-prescribed opioids and cocaine.

Funding: Indivior.
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May 2019

How can we successfully recruit depressed people? Lessons learned in recruiting depressed participants to a multi-site trial of a brief depression intervention (the 'CLASSIC' trial).

Trials 2019 Feb 13;20(1):131. Epub 2019 Feb 13.

Biostatistics & Health Informatics Department (PO20), Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.

Background: There are enormous problems in recruiting depressed people into randomised controlled trials (RCTs), with numerous studies consistently failing to recruit to target (Sully et al., Trials 14:166, 2013). Given the high prevalence of-and disability associated with-depression, it is important to find ways of effectively recruiting to RCTs evaluating interventions. This study aimed to test the feasibility of using a self-referral system to recruit to a brief intervention in a multi-site trial, the CLASSIC trial of self-confidence workshops for depression. In that trial, participants referred themselves to a depression intervention with a positive non-diagnostic title of 'self-confidence', given the close relationship of depression and self-esteem (Horrell et al., Br J Psychiatry 204:222-233, 2014).

Method: We analysed uptake and retention rates by recruitment to the study, attendance at the workshops and follow-up rates. However, because of the rapid rate of recruitment, we decided to pause the trial and revise our original single-site research protocol in months 5-6. We report findings under three main headings: recruitment rates for the 12 months of the project before and after the pause; data regarding attendance at the workshops before and after the pause; and the follow-up rates before and after the pause.

Results: We recruited 459 participants within 12 months, representing 38 participants recruited per month. Improved uptake of the intervention and retention after the development of multi-site research protocols are reported.

Discussion: Based on previous evidence from RCT recruitment among depressed participants, our recruitment rate demonstrates that a self-referral system using a non-diagnostic title of self-confidence is a successful recruitment method. The implications of rapid recruitment using a self-referral system are described, including the impact on uptake of the intervention as well as participant retention. Because of the potential for recruiting many participants quickly, research teams need to be adequately resourced and the oversight committees prepared to meet at shorter intervals with RCTs of brief interventions.

Short Conclusion: Self-referral to a brief intervention for depression with a non-diagnostic title can be a very effective way of recruiting depressed people into trials. However, there are also some challenges.

Trial Registration: ISRCTN, ISRCTN26634837 . Registered on 10 June 2010.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375167PMC
February 2019

Perivascular epithelioid cell tumour and mesonephric adenocarcinoma of the uterine cervix: an unknown co-existence.

Oxf Med Case Reports 2019 Jan 24;2019(1):omy115. Epub 2019 Jan 24.

Department of Midwifery, Midwifery School, 'Alexander' Technological Educational Institute of Thessaloniki, PC, Greece.

A 67-year-old woman with post-menopausal bleeding and a suspicious endocervical mass was referred to gynaecology outpatients' for diagnosis and management. Cervical punch biopsies taken showed a benign cervical perivascular epithelioid cell tumour (PEComa), with MRI imaging and PET-CT scan indicating a 3-4 cm endocervical tumour with malignant features. The patient underwent radical hysterectomy with lymph node dissection and the surgical specimen histopathology demonstrated a residual benign PEComa and a stage IIB mesonephric adenocarcinoma (MNA) of the cervix. There is no disease recurrence 12 months after surgery. Cervical PEComas are extremely rare tumours of mesenchymal origin deriving from the perivascular epithelioid cells with only 14 cases described so far. Cervical MNAs are rare tumours originating from the remnants of the mesonephric duct of Wolff with only 40 cases reported. Our case adds to the existing literature and highlights the challenges with regard to preoperative diagnosis, treatment and prognosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345091PMC
January 2019

Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial.

Lancet Diabetes Endocrinol 2018 05 5;6(5):382-391. Epub 2018 Mar 5.

Institute of Ophthalmology and Moorfields Eye Hospital, London, UK.

Background: We aimed to assess 24-month outcomes of wearing an organic light-emitting sleep mask as an intervention to treat and prevent progression of non-central diabetic macular oedema.

Methods: CLEOPATRA was a phase 3, single-blind, parallel-group, randomised controlled trial undertaken at 15 ophthalmic centres in the UK. Adults with non-centre-involving diabetic macular oedema were randomly assigned (1:1) to wearing either a light mask during sleep (Noctura 400 Sleep Mask, PolyPhotonix Medical, Sedgefield, UK) or a sham (non-light) mask, for 24 months. Randomisation was by minimisation generated by a central web-based computer system. Outcome assessors were masked technicians and optometrists. The primary outcome was the change in maximum retinal thickness on optical coherence tomography (OCT) at 24 months, analysed using a linear mixed-effects model incorporating 4-monthly measurements and baseline adjustment. Analysis was done using the intention-to-treat principle in all randomised patients with OCT data. Safety was assessed in all patients. This trial is registered with Controlled-Trials.com, number ISRCTN85596558.

Findings: Between April 10, 2014, and June 15, 2015, 308 patients were randomly assigned to wearing the light mask (n=155) or a sham mask (n=153). 277 patients (144 assigned the light mask and 133 the sham mask) contributed to the mixed-effects model over time, including 246 patients with OCT data at 24 months. The change in maximum retinal thickness at 24 months did not differ between treatment groups (mean change -9·2 μm [SE 2·5] for the light mask vs -12·9 μm [SE 2·9] for the sham mask; adjusted mean difference -0·65 μm, 95% CI -6·90 to 5·59; p=0·84). Median compliance with wearing the light mask at 24 months was 19·5% (IQR 1·9-51·6). No serious adverse events were related to either mask. The most frequent adverse events related to the assigned treatment were discomfort on the eyes (14 with the light mask vs seven with the sham mask), painful, sticky, or watery eyes (14 vs six), and sleep disturbance (seven vs one).

Interpretation: The light mask as used in this study did not confer long-term therapeutic benefit on non-centre-involving diabetic macular oedema and the study does not support its use for this indication.

Funding: The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908782PMC
May 2018

Catheter Ablation versus Thoracoscopic Surgical Ablation in Long Standing Persistent Atrial Fibrillation (CASA-AF): study protocol for a randomised controlled trial.

Trials 2018 Feb 20;19(1):117. Epub 2018 Feb 20.

Royal Brompton and Harefield NHS Trust, London, UK.

Background: Atrial fibrillation is the commonest arrhythmia which raises the risk of heart failure, thromboembolic stroke, morbidity and death. Pharmacological treatments of this condition are focused on heart rate control, rhythm control and reduction in risk of stroke. Selective ablation of cardiac tissues resulting in isolation of areas causing atrial fibrillation is another treatment strategy which can be delivered by two minimally invasive interventions: percutaneous catheter ablation and thoracoscopic surgical ablation. The main purpose of this trial is to compare the effectiveness and safety of these two interventions.

Methods/design: Catheter Ablation versus Thoracoscopic Surgical Ablation in Long Standing Persistent Atrial Fibrillation (CASA-AF) is a prospective, multi-centre, randomised controlled trial within three NHS tertiary cardiovascular centres specialising in treatment of atrial fibrillation. Eligible adults (n = 120) with symptomatic, long-standing, persistent atrial fibrillation will be randomly allocated to either catheter ablation or thoracoscopic ablation in a 1:1 ratio. Pre-determined lesion sets will be delivered in each treatment arm with confirmation of appropriate conduction block. All patients will have an implantable loop recorder (ILR) inserted subcutaneously immediately following ablation to enable continuous heart rhythm monitoring for at least 12 months. The devices will be programmed to detect episodes of atrial fibrillation and atrial tachycardia ≥ 30 s in duration. The patients will be followed for 12 months, completing appropriate clinical assessments and questionnaires every 3 months. The ILR data will be wirelessly transmitted daily and evaluated every month for the duration of the follow-up. The primary endpoint in the study is freedom from atrial fibrillation and atrial tachycardia at the end of the follow-up period.

Discussion: The CASA-AF Trial is a National Institute for Health Research-funded study that will provide first-class evidence on the comparative efficacy, safety and cost-effectiveness of thoracoscopic surgical ablation and conventional percutaneous catheter ablation for long-standing persistent atrial fibrillation. In addition, the results of the trial will provide information on the effects on patients' quality of life.

Trial Registration: ISRCTN Registry, ISRCTN18250790 . Registered on 24 April 2015.
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http://dx.doi.org/10.1186/s13063-018-2487-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819216PMC
February 2018

Training nurses in a competency framework to support adults with epilepsy and intellectual disability: the EpAID cluster RCT.

Health Technol Assess 2018 02;22(10):1-104

School of Health and Population Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: People with an intellectual (learning) disability (ID) and epilepsy have an increased seizure frequency, higher frequencies of multiple antiepileptic drug (AED) use and side effects, higher treatment costs, higher mortality rates and more behavioural problems than the rest of the population with epilepsy. The introduction of nurse-led care may lead to improvements in outcome for those with an ID and epilepsy; however, this has not been tested in a definitive clinical trial.

Objective: To determine whether or not ID nurses, using a competency framework developed to optimise nurse management of epilepsy in people with an ID, can cost-effectively improve clinical and quality-of-life outcomes in the management of epilepsy compared with treatment as usual.

Design: Cluster-randomised two-arm trial.

Setting: Community-based secondary care delivered by members of community ID teams.

Participants: Participants were adults aged 18-65 years with an ID and epilepsy under the care of a community ID team and had had at least one seizure in the 6 months before the trial.

Interventions: The experimental intervention was the Learning Disability Epilepsy Specialist Nurse Competency Framework. This provides guidelines describing a structure and goals to support the delivery of epilepsy care and management by ID-trained nurses.

Main Outcome Measures: The primary outcome was the seizure severity scale from the Epilepsy and Learning Disabilities Quality of Life questionnaire. Measures of mood, behaviour, AED side effects and carer strain were also collected. A cost-utility analysis was undertaken along with a qualitative examination of carers' views of participants' epilepsy management.

Results: In total, 312 individuals were recruited into the study from 17 research clusters. Using an intention-to-treat analysis controlling for baseline individual-level and cluster-level variables there was no significant difference in seizure severity score between the two arms. Altogether, 238 complete cases were included in the non-imputed primary analysis. Analyses of the secondary outcomes revealed no significant differences between arms. A planned subgroup analysis identified a significant interaction between treatment arm and level of ID. There was a suggestion in those with mild to moderate ID that the competency framework may be associated with a small reduction in concerns over seizure severity (standard error 2.005, 95% confidence interval -0.554 to 7.307;  = 0.092). However, neither subgroup showed a significant intervention effect individually. Family members' perceptions of nurses' management depended on the professional status of the nurses, regardless of trial arm. Economic analysis suggested that the competency framework intervention was likely to be cost-effective, primarily because of a reduction in the costs of supporting participants compared with treatment as usual.

Limitations: The intervention could not be delivered blinded. Treatment as usual varied widely between the research sites.

Conclusions: Overall, for adults with an ID and epilepsy, the framework conferred no clinical benefit compared with usual treatment. The economic analysis suggested that there may be a role for the framework in enhancing the cost-effectiveness of support for people with epilepsy and an ID. Future research could explore the specific value of the competency framework for those with a mild to moderate ID and the potential for greater long-term benefits arising from the continuing professional development element of the framework.

Trial Registration: Current Controlled Trials ISRCTN96895428.

Funding: This trial was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 10. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta22100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485678PMC
February 2018

Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial.

Ann Intern Med 2017 Oct 12;167(7):476-483. Epub 2017 Sep 12.

From University of Liverpool and The Walton Centre National Health Service (NHS) Foundation Trust, Liverpool; Institute of Psychiatry, Psychology and Neuroscience, Guy's and St Thomas' Hospital, and University College London, London; Modepharma Limited, Beckenham; Queen Elizabeth University Hospital, Glasgow; University West of England, Bristol; Swansea University, Swansea; Norfolk and Norwich University NHS Trust, Norwich; Cambridge University Hospitals, Cambridge; and University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.

Background: Two small trials suggest that low-dose intravenous immunoglobulin (IVIg) may improve the symptoms of complex regional pain syndrome (CRPS), a rare posttraumatic pain condition.

Objective: To confirm the efficacy of low-dose IVIg compared with placebo in reducing pain during a 6-week period in adult patients who had CRPS from 1 to 5 years.

Design: 1:1 parallel, randomized, placebo-controlled, multicenter trial for 6 weeks, with an optional 6-week open extension. Patients were randomly assigned to 1 of 2 study groups between 27 August 2013 and 28 October 2015; the last patient completed follow-up on 21 March 2016. Patients, providers, researchers, and outcome assessors were blinded to treatment assignment. (ISRCTN42179756).

Setting: 7 secondary and tertiary care pain management centers in the United Kingdom.

Participants: 111 patients with moderate or severe CRPS of 1 to 5 years' duration.

Intervention: IVIg, 0.5 g/kg of body weight, or visually indistinguishable placebo of 0.1% albumin in saline on days 1 and 22 after randomization.

Measurements: The primary outcome was 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale. Secondary outcomes were pain interference and quality of life.

Results: The primary analysis sample consisted of 108 eligible patients, 103 of whom had outcome data. Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, -0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of -1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events.

Limitations: Results do not apply to patients who have had CRPS for less than 1 year or more than 5 years and do not extend to full-dose treatment (for example, 2 g/kg). The study was inadequately powered to detect subgroup effects.

Conclusion: Low-dose immunoglobulin treatment for 6 weeks was not effective in relieving pain in patients with moderate to severe CRPS of 1 to 5 years' duration.

Primary Funding Source: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Program, Pain Relief Foundation, and Biotest United Kingdom.
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http://dx.doi.org/10.7326/M17-0509DOI Listing
October 2017

Placing the patient at the centre of chronic wound care: A qualitative evidence synthesis.

J Tissue Viability 2017 Nov 5;26(4):254-259. Epub 2017 Sep 5.

Healthcare Improvement Scotland, Scotland, UK.

Background: Chronic wounds are a major health burden and have a severe impact on well-being. This synthesis of qualitative studies was undertaken to inform a health technology assessment of antimicrobial wound dressings. It aimed to explore patients' experiences of chronic wounds and determine improvements for clinical practice.

Method: Inclusion criteria included use of qualitative methods, and English language publication. Databases searched included MEDLINE (Ovid), MEDLINE in Process (Ovid), EMBASE (Ovid), CINAHL (EBSCOHost), and PsychInfo (EBSCOHost). Searches were limited to 1990-2014. The method of analysis was Framework synthesis.

Results: A total of 20 studies were included. The synthesis confirmed the severe physical, social and psychological impact of the chronic wound. Inadequately controlled pain and sleeplessness, restrictions to lifestyle, and the loss of previous life roles can lead to feelings of hopelessness and helplessness and therefore depression and anxiety. Dressings and dressing changes are a key aspect of treatment and provide opportunities for positive interaction and person centred-care.

Conclusion: People with chronic wounds can be supported to live well within the severe physical, psychological and social restrictions of a chronic wound. Effective clinical pain management and the recognition of the experience of acute and chronic pain are of the utmost importance to people with a chronic wound. Treatment should not be purely focused on healing but incorporate symptom management, coping and wellbeing via person-centred and holistic care.
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November 2017

A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE).

Health Technol Assess 2017 05;21(31):1-50

Department of Children's Neurosciences, Evelina Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UK.

Background: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly.

Objective: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids.

Design: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children.

Participants: Patients aged ≥ 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm).

Interventions: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy.

Main Outcome Measures: Primary outcome measure - American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures - ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets.

Results: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM.

Conclusions: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital.

Trial Registration: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581.

Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation).
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http://dx.doi.org/10.3310/hta21310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512007PMC
May 2017

Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.

Lancet 2017 Jun 7;389(10085):2193-2203. Epub 2017 May 7.

National Institute for Health Research, Moorfields Biomedical Research Centre, London, UK.

Background: Proliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept.

Methods: In this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as -5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582.

Findings: We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters [95% CI 2·3-5·6], p<0·0001) and the per-protocol population (4·0 letters [2·4-5·7], p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of -5 letters at both 12 weeks and 52 weeks.

Interpretation: Patients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care.

Funding: The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
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June 2017
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