National prevalence of vision impairment and blindness and associated risk factors in adults aged 40 years and older with known or undiagnosed diabetes: results from the SMART-India cross-sectional study.

BACKGROUND: National estimates of the prevalence of vision impairment and blindness in people with diabetes are required to inform resource allocation. People with diabetes are more susceptible to conditions such as diabetic retinopathy that can impair vision; however, these are often missed in national studies. This study aims to determine the prevalence and risk factors of vision impairment and blindness in people with diabetes in India. METHODS: Data from the SMART-India study, a cross-sectional survey with national coverage of 42 147 Indian adults aged 40 years and older, collected using a complex sampling design, were used to obtain nationally representative estimates for the prevalence of vision impairment and blindness in people with diabetes in India. Vulnerable adults (primarily those who did not have capacity to provide consent); pregnant and breastfeeding women; anyone deemed too ill to be screened; those who did not provide consent; and people with type 1 diabetes, gestational diabetes, or secondary diabetes were excluded from the study. Vision impairment was defined as presenting visual acuity of 0·4 logMAR or higher and blindness as presenting a visual acuity of 1·0 logMAR or higher in the better-seeing eye. Demographic, anthropometric, and laboratory data along with geographic distribution were analysed in all participants with available data. Non-mydriatic retinal images were used to grade diabetic retinopathy, and risk factors were also assessed. FINDINGS: A total of 7910 people with diabetes were included in the analysis, of whom 5689 had known diabetes and 2221 were undiagnosed. 4387 (55·5%) of 7909 participants with available sex data were female and 3522 (44·5%) participants were male. The estimated national prevalence of vision impairment was 21·1% (95% CI 15·7-27·7) and blindness 2·4% (1·7-3·4). A higher prevalence of any vision impairment (29·2% vs 19·6%; p=0·016) and blindness (6·7% vs 1·6%; p<0·0001) was observed in those with ungradable images. In known diabetes, diabetic retinopathy (adjusted odds ratio [aOR] 3·06 [95% CI 1·25-7·51]), vision-threatening diabetic retinopathy (aOR 7·21 [3·52-14·75]), and diabetic macular oedema (aOR 5·41 [2·20-13·33]) were associated with blindness in adjusted analysis. Common sociodemographic risk factors for vision impairment and blindness include older age, lower educational attainment, and unemployment. INTERPRETATION: Based on the estimated 101 million people with diabetes in 2021 and the interpretation of the data from this study, approximately 21 million people with diabetes have vision impairment in India, of whom 2·4 million are blind. Higher prevalence is observed in those from lower socio-economic strata and policy makers should focus on these groups to reduce inequalities in health care. FUNDING: Global Challenge Research Fund of United Kingdom Research and Innovation through the Medical Research Council.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

Burden of undiagnosed and suboptimally controlled diabetes in selected regions of India: Results from the SMART India population-level diabetes screening study.

AIMS: To estimate the prevalence of undiagnosed diabetes and suboptimally controlled diabetes and the associated risk factors by community screening in India. METHODS: In this multi-centre, cross-sectional study, house-to-house screening was conducted in people aged ≥40 years in urban and rural areas across 10 states and one union territory in India between November 2018 and March 2020. Participants underwent anthropometry, clinical and biochemical assessments. Capillary random blood glucose and point-of-care glycated haemoglobin (HbA1c ) were used to diagnose diabetes. The prevalence of undiagnosed diabetes and suboptimal control (HbA1c ≥53 mmol/mol [≥7%]) among those with known diabetes was assessed. RESULTS: Among the 42,146 participants screened (22,150 urban, 19,996 rural), 5689 had known diabetes. The age-standardised prevalence of known diabetes was 13.1% (95% CI 12.8-13.4); 17.2% in urban areas and 9.4% in rural areas. The age-standardised prevalence of undiagnosed diabetes was 6.0% (95% CI 5.7-6.2); similar in both urban and rural areas with the highest proportions seen in the East (8.0%) and South (7.8%) regions. When we consider all people with diabetes in the population, 22.8% of individuals in urban areas and 36.7% in rural areas had undiagnosed diabetes. Almost 75% of the individuals with known diabetes had suboptimal glycaemic control. CONCLUSIONS: High prevalence of undiagnosed diabetes and suboptimally controlled diabetes emphasises the urgent need to identify and optimally treat people with diabetes to reduce the burden of diabetes.

Prevalence of diabetic retinopathy in India stratified by known and undiagnosed diabetes, urban-rural locations, and socioeconomic indices: results from the SMART India population-based cross-sectional screening study.

BACKGROUND: National and subnational estimates of the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy (VTDR) are needed to inform the stepwise implementation of systematic retinal screening for people with diabetes in India to decrease the rate of blindness. We aimed to assess these national and subnational estimates and to stratify the prevalence of diabetic retinopathy and VTDR on the basis of people with known versus undiagnosed diabetes, urban versus rural residence, and epidemiological transition level (ETL) and Socio-demographic Index (SDI) categories of states. METHODS: We did a multicentre cross-sectional screening study for diabetic retinopathy using a complex cluster sampling design in people aged 40 years or older in ten Indian states and one union territory between Dec 20, 2018, and March 20, 2020. We did non-mydriatic retinal screening and assessed risk factor burden for people with diabetes. We estimated nationally weighted prevalence of diabetic retinopathy and VTDR for individuals with known and undiagnosed diabetes by urban versus rural residence, and by state categorisation by ETL and SDI. We also assessed adjusted risk factors. FINDINGS: From 42 146 participants screened, 7910 (18·8%) were identified to have diabetes. Of these, 6133 (77·5%; 4350 with known diabetes and 1783 with undiagnosed diabetes) had gradable retinal images. 3411 (56%) participants were women and 2722 (44%) were men, and the median age was 56 years (IQR 49-65). The estimated national prevalence was 12·5% (95% CI 11·0-14·2) for diabetic retinopathy and 4·0% (3·4-4·8) for VTDR, with no significant differences between urban and rural residence for diabetic retinopathy. Compared with individuals with undiagnosed diabetes, we observed a higher prevalence of diabetic retinopathy (15·5% [13·4-17·8] vs 8·0% [6·3-10·1]) and VTDR (5·3% [4·5-6·3] vs 2·4% [1·6-3·6]) in individuals with known diabetes. The prevalence was significantly lower in low ETL-SDI states compared with high and middle ETL-SDI states for diabetic retinopathy (by 7·0%, 1·9-12·2, p=0·024) and VTDR (by 4·8%, 3·0-6·6, p<0·0001). Hyperglycaemia was the strongest modifiable risk factor. INTERPRETATION: We estimate that, in absolute numbers, approximately 3 million people aged 40 years or older have VTDR in India, with a higher prevalence in those with known diabetes residing in high and middle ETI-SDI states. FUNDING: UKRI Global Challenge Research Fund.

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

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 (n = 155), aflibercept (n = 154) or bevacizumab (n = 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; p = 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; p = 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; p = 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 Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

The eye functions like a camera. The retina, at the back of the eye, is the camera film, and the centre, the macula, allows us to see fine details. Approximately 6500 people each year in England and Wales are affected by fluid leaking out of congested tiny blood vessels, causing macular swelling or oedema. The cause is blockage of the main vein that normally drains blood from the retina. Three drugs, injected into the eye in tiny amounts every 4­8 weeks, have been shown to improve the vision of people with this condition. Two drugs, 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), are licensed for UK use, but the third, bevacizumab (1.25 mg/0.05 ml Avastin^®; F. Hoffmann-La Roche AG, Basel, Switzerland), is not, even though it is much cheaper and used extensively worldwide. To our knowledge, no trials have compared the three drugs over the typical 2-year treatment period. This multicentre, Phase III, double-masked, randomised controlled non-inferiority trial comparing the clinical effectiveness and cost-effectiveness of intravitreal therapy with ranibizumab (Lucentis) versus aflibercept (Eylea) versus bevacizumab (Avastin) for macular oedema due to central retinal Vein Occlusion (LEAVO) was designed to compare ranibizumab, aflibercept and bevacizumab in this type of macular oedema. The trial showed that all three drugs improved vision a lot, but bevacizumab improved vision to a slightly lesser degree than the other two drugs. All patients should be aware of these findings before considering their treatment options. A comparison of the costs and benefits of ranibizumab, aflibercept and bevacizumab, using data from the trial and other sources, found that all three led to similar improvements in quality of life. Because aflibercept and ranibizumab are so much more expensive, they may be poor value for money. If patients, their representatives and funders all agree, it may be possible to treat this type of macular oedema with bevacizumab, which is cheaper, keeping the other agents available if needed.

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

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.

Evaluation of a very brief pedometer-based physical activity intervention delivered in NHS Health Checks in England: The VBI randomised controlled trial.

BACKGROUND: The majority of people do not achieve recommended levels of physical activity. There is a need for effective, scalable interventions to promote activity. Self-monitoring by pedometer is a potentially suitable strategy. We assessed the effectiveness and cost-effectiveness of a very brief (5-minute) pedometer-based intervention ('Step It Up') delivered as part of National Health Service (NHS) Health Checks in primary care. METHODS AND FINDINGS: The Very Brief Intervention (VBI) Trial was a two parallel-group, randomised controlled trial (RCT) with 3-month follow-up, conducted in 23 primary care practices in the East of England. Participants were 1,007 healthy adults aged 40 to 74 years eligible for an NHS Health Check. They were randomly allocated (1:1) using a web-based tool between October 1, 2014, and December 31, 2015, to either intervention (505) or control group (502), stratified by primary care practice. Participants were aware of study group allocation. Control participants received the NHS Health Check only. Intervention participants additionally received Step It Up: a 5-minute face-to-face discussion, written materials, pedometer, and step chart. The primary outcome was accelerometer-based physical activity volume at 3-month follow-up adjusted for sex, 5-year age group, and general practice. Secondary outcomes included time spent in different intensities of physical activity, self-reported physical activity, and economic measures. We conducted an in-depth fidelity assessment on a subsample of Health Check consultations. Participants' mean age was 56 years, two-thirds were female, they were predominantly white, and two-thirds were in paid employment. The primary outcome was available in 859 (85.3%) participants. There was no significant between-group difference in activity volume at 3 months (adjusted intervention effect 8.8 counts per minute [cpm]; 95% CI -18.7 to 36.3; p = 0.53). We found no significant between-group differences in the secondary outcomes of step counts per day, time spent in moderate or vigorous activity, time spent in vigorous activity, and time spent in moderate-intensity activity (accelerometer-derived variables); as well as in total physical activity, home-based activity, work-based activity, leisure-based activity, commuting physical activity, and screen or TV time (self-reported physical activity variables). Of the 505 intervention participants, 491 (97%) received the Step it Up intervention. Analysis of 37 intervention consultations showed that 60% of Step it Up components were delivered faithfully. The intervention cost £18.04 per participant. Incremental cost to the NHS per 1,000-step increase per day was £96 and to society was £239. Adverse events were reported by 5 intervention participants (of which 2 were serious) and 5 control participants (of which 2 were serious). The study's limitations include a participation rate of 16% and low return of audiotapes by practices for fidelity assessment. CONCLUSIONS: In this large well-conducted trial, we found no evidence of effect of a plausible very brief pedometer intervention embedded in NHS Health Checks on objectively measured activity at 3-month follow-up. TRIAL REGISTRATION: Current Controlled Trials (ISRCTN72691150).

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

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.

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.

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.

Mechanistic Evaluation of Panretinal Photocoagulation Versus Aflibercept in Proliferative Diabetic Retinopathy: CLARITY Substudy.

Purpose: The purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of neovascularization in proliferative diabetic retinopathy. Methods: This is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA). Results: The AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, -0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45). Conclusions: Intravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.

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.

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.

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.

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.

Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis.

OBJECTIVES: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. METHODS: Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. RESULTS: No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. CONCLUSION: BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study. TRIAL REGISTRATION: ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.

Effectiveness and cost-effectiveness of a very brief physical activity intervention delivered in NHS Health Checks (VBI Trial): study protocol for a randomised controlled trial.

BACKGROUND: Physical activity interventions that are targeted at individuals can be effective in encouraging people to be more physically active. However, most such interventions are too long or complex and not scalable to the general population. This trial will test the effectiveness and cost-effectiveness of a very brief physical activity intervention when delivered as part of preventative health checks in primary care (National Health Service (NHS) Health Check). METHODS/DESIGN: The Very Brief Intervention (VBI) Trial is a two parallel-group, randomised, controlled trial with 1:1 individual allocation and follow-up at 3 months. A total of 1,140 participants will be recruited from 23 primary care practices in the east of England. Participants eligible for an NHS Health Check and who are considered suitable to take part by their doctor and able to provide written informed consent are eligible for the trial. Participants are randomly assigned at the beginning of the NHS Health Check to either 1) the control arm, in which they receive only the NHS Health Check, or 2) the intervention arm, in which they receive the NHS Health Check plus 'Step It Up' (a very brief intervention that can be delivered in 5 minutes by nurses and/or healthcare assistants at the end of the Health Check). 'Step It Up' includes (1) a face-to-face discussion, including feedback on current activity level, recommendations for physical activity, and information on how to use a pedometer, set step goals, and monitor progress; (2) written material supporting the discussion and tips and links to further resources to help increase physical activity; and (3) a pedometer to wear and a step chart for monitoring progress. The primary outcome is accelerometer counts per minute at 3-month follow-up. Secondary outcomes include the time spent in the different levels of physical activity, self-reported physical activity and economic measures. Trial recruitment is underway. DISCUSSION: The VBI trial will provide evidence on the effectiveness and cost-effectiveness of the Step It Up intervention delivered during NHS Health Checks and will inform policy decisions about introducing very brief interventions into routine primary care practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN72691150 . Registered on 17 July 2014.

Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.

BACKGROUND: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. METHODS: 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. RESULTS: Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%). CONCLUSIONS: The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis.

Experimental and clinical data suggest a role of sex steroids in the pathogenesis of multiple sclerosis (MS). Scant information is available about the potential effect of oral contraceptive (OC) use on the prognosis of the disease. We aimed to evaluate this. The study population consisted of 132 women with relapsing-remitting MS before receiving disease modifying treatment and a mean disease duration 6.2 (SD 5.1) years. Three groups of patients were distinguished according to their OC behavior: [1] never-users, patients who never used OC [2] past-users, patients who stopped OC use before disease onset, and [3] after-users, those who used these drugs after disease onset. Multiple linear and logistic regression models were used to analyze the association between oral contraceptive use and annualized relapse rates, disability accumulation and severity of the disease. After-user patients had lower Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) values than never users (p<0.001 and p=0.002, respectively) and past users (p=0.010 and p=0.002, respectively). These patients were also more likely to have a benign disease course (MSSS<2.5) than never and past users together (OR: 4.52, 95%CI: 2.13-9.56, p<0.001). This effect remained significant after adjustment for confounders, including smoking and childbirths (OR: 2.97, 95%CI: 1.24, 6.54, p=0.011 and for MSSS ß: -1.04; 95% C.I. -1.78, -0.30, p=0.006). These results suggest that OC use in women with relapsing-remitting MS is possible associated with a milder disabling disease course.

Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): randomised trial.

OBJECTIVE: To compare the effect of an invitation promoting informed choice for screening with a standard invitation on attendance and motivation to engage in preventive action. DESIGN: Randomised controlled trial. SETTING: Four English general practices. PARTICIPANTS: 1272 people aged 40-69 years, at risk for diabetes, identified from practice registers using a validated risk score and invited to attend for screening. INTERVENTION: Intervention was a previously validated invitation to inform the decision to attend screening, presenting diabetes as a serious potential problem, and providing details of possible costs and benefits of screening and treatment in text and pie charts. This was compared with a brief, standard invitation simply describing diabetes as a serious potential problem. MAIN OUTCOME MEASURES: The primary end point was attendance for screening. The secondary outcome measures were intention to make changes to lifestyle and satisfaction with decisions made among attenders. RESULTS: The primary end point was analysed for all 1272 participants. 55.8% (353/633) of those in the informed choice group attended for screening, compared with 57.6% (368/639) in the standard invitation group (mean difference -1.8%, 95% confidence interval -7.3% to 3.6%; P=0.51). Attendance was lower among the more deprived group (most deprived third 47.5% v least deprived third 64.3%; P<0.001). Interaction between deprivation and effect of invitation type on attendance was not significant. Among attenders, intention to change behaviour was strong and unaffected by invitation type. CONCLUSIONS: Providing information to support choice did not adversely affect attendance for screening for diabetes. Those from more socially deprived groups were, however, less likely to attend, regardless of the type of invitation received. Further attention to invitation content alone is unlikely to achieve equity in uptake of preventive services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 73125647.

Patients' perspective of botulinum toxin-A as a long-term treatment option for neurogenic detrusor overactivity secondary to spinal cord injury.

OBJECTIVE: To evaluate patients' perspective on whether they would consider botulinum toxin-A (BTX-A) injections as a long-term treatment option for managing their neurogenic detrusor overactivity (NDO) secondary to spinal cord injury (SCI). PATIENTS AND METHODS: In all, 72 patients with SCI and urodynamically confirmed NDO refractory to anticholinergics, who have had at least one or more injections with BTX-A were invited to participate in a 5-min telephone questionnaire covering various aspects of their treatment. Questions about patient satisfaction were rated on a scale from 1 to 10 (1, not satisfied; to 10, very satisfied). RESULTS: Of the 72 patients surveyed, 48 (67%) were still actively undergoing repeat BTX-A injections. The mean patient satisfaction score was 6.2. Of the 48 patients, 43 (90%) replied that they would consider continuing with BTX-A injections as a long-term treatment option. Only seven (15%) of patients still having BTX-A injections would consider an alternative permanent surgical option in the next 5 years. Of those patients considering a one-off permanent surgical solution, younger patients were likely to consider this at a later interval than those in an older group (Spearman's correlation coefficient, -0.52, 95% confidence interval -0.78 to -0.10, P = 0.02). The annual new patient recruitment rate was high (mean 14.4) and the annual withdrawal rate was low (mean 4.8). CONCLUSION: With high satisfaction and low annual withdrawal rates, there are increasingly many patients on BTX-A. Most consider continuing BTX-A injections in the long term, increasing the future demand for this service. There is an urgent need for further research into optimizing the current delivery of an intradetrusor BTX-A injection service for patients with NDO.

Patterns of complementary and alternative medicine use amongst outpatients in Tokyo, Japan.

BACKGROUND: The use of complementary and alternative medicine (CAM) has been increasing rapidly throughout the world during the past decade. The use of CAM in the general Japanese population has been previously reported to be as high as 76%. This study aims to investigate the patterns of CAM use, perceived effectiveness and disclosure of CAM use to orthodox medical practitioners amongst patients attending typical primary and secondary care clinics in a busy district general hospital in Tokyo, Japan. METHODS: The authors analysed data collected during March 2002 on patients attending general outpatient clinics held at Shiseikai Daini Hospital in Tokyo, Japan. Data was collected by use of self-completed questionnaires distributed to patients in the outpatient clinics waiting area. Statistical analysis was performed using chi-square tests of independence. RESULTS: 515 adults were approached to participate in this study and the overall response rate was 96% (n = 496). 50% of the patients were using or have used at least 1 CAM therapy within the last 12 months. The 5 most commonly used therapies were massage (n = 106, 43%), vitamins (n = 85, 35%), health foods including dietary supplements (n = 56, 23%), acupressure (n = 51, 21%) and kampo (n = 46, 19%). The majority of CAM users (75%, n = 145) found their CAM treatment to be effective (95% CI = 68-81%). Patients who were more likely to use CAM were females (p = 0.003) and those with a high number of medical conditions (p = < 0.0001). Only a small proportion of patients reported their CAM use to their physician (42%, n = 74). There was no significant difference in CAM use for the different age groups (p = 0.85), education level (p = 0.30) and financial status (p = 0.82). CONCLUSION: Patterns of CAM usage in the sample surveyed was high (50%). Despite this high prevalence rate and presumed acceptance of CAM in Japan, the reporting of CAM use by patients to their physicians was low (42%). It is therefore important that physicians are aware of the possibility that their patients may be using CAM and also increase their knowledge and understanding of these treatments.