181 results found
Hykin P, Prevost AT, Vasconcelos JC, et al., 2019, 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
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 d
Al-Laith M, Jasenecova M, Abraham S, et al., 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, Vol: 20, ISSN: 1745-6215
Trial designWe 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.MethodsThe 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.ConclusionsThere 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.
Behary P, Tharakan G, Alexiadou K, et al., 2019, Combined GLP-1, oxyntomodulin, and peptide YY improves body weight and glycemia in obesity and prediabetes/type 2 diabetes: a randomized single-blinded placebo controlled study, Diabetes Care, ISSN: 0149-5992
OBJECTIVE: Roux-en-Y gastric bypass (RYGB) augments postprandial secretion of glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY). Subcutaneous infusion of these hormones ("GOP"), mimicking postprandial levels, reduces energy intake. Our objective was to study the effects of GOP on glycemia and body weight when given for 4 weeks to patients with diabetes and obesity. RESEARCH DESIGN AND METHODS: In this single-blinded mechanistic study, obese patients with prediabetes/diabetes were randomized to GOP (n = 15) or saline (n = 11) infusion for 4 weeks. We also studied 21 patients who had undergone RYGB and 22 patients who followed a very low-calorie diet (VLCD) as unblinded comparators. Outcomes measured were 1) body weight, 2) fructosamine levels, 3) glucose and insulin during a mixed meal test (MMT), 4) energy expenditure (EE), 5) energy intake (EI), and 6) mean glucose and measures of glucose variability during continuous glucose monitoring. RESULTS: GOP infusion was well tolerated over the 4-week period. There was a greater weight loss (P = 0.025) with GOP (mean change -4.4 [95% CI -5.3, -3.5] kg) versus saline (-2.5 [-4.1, -0.9] kg). GOP led to a greater improvement (P = 0.0026) in fructosamine (-44.1 [-62.7, -25.5] µmol/L) versus saline (-11.7 [-18.9, -4.5] µmol/L). Despite a smaller weight loss compared with RYGB and VLCD, GOP led to superior glucose tolerance after a mixed-meal stimulus and reduced glycemic variability compared with RYGB and VLCD. CONCLUSIONS: GOP infusion improves glycemia and reduces body weight. It achieves superior glucose tolerance and reduced glucose variability compared with RYGB and VLCD. GOP is a viable alternative for the treatment of diabetes with favorable effects on body weight.
Santhakumaran S, Gordon AC, Prevost A, et al., 2019, Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials, Critical Care, Vol: 23, ISSN: 1364-8535
BackgroundRandomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design.MethodsWe assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term.ResultsThe ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin.ConclusionsWe assessed HTE in three recent ICU RCTs, using m
Goldberg R, Scotta C, Cooper D, et al., 2019, Correction of defective T-regulatory cells from patients with Crohn's disease by Ex Vivo ligation of retinoic acid receptor alpha, Gastroenterology, Vol: 156, Pages: 1775-1787, ISSN: 0016-5085
BACKGROUND & AIMS: Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities. METHODS: We measured levels of the integrin α4β7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor alpha (RARA) and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts. RESULTS: We found that Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. The pathway that regulates expression of integrin subunit alpha is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4β7, as well as CD62L and FOXP3, compared to cells incubated with rapamycin or rapamycin and ATRA. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labelled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium. CONCLUSIONS: Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. Incubation of patients' ex vivo ex
Gulliford MC, Juszczyk D, Prevost AT, et al., 2019, Electronically delivered interventions to reduce antibiotic prescribing for respiratory infections in primary care: cluster RCT using electronic health records and cohort study., Health Technology Assessment, Vol: 23, ISSN: 1366-5278
BACKGROUND: Unnecessary prescribing of antibiotics in primary care is contributing to the emergence of antimicrobial drug resistance. OBJECTIVES: To develop and evaluate a multicomponent intervention for antimicrobial stewardship in primary care, and to evaluate the safety of reducing antibiotic prescribing for self-limiting respiratory infections (RTIs). INTERVENTIONS: A multicomponent intervention, developed as part of this study, including a webinar, monthly reports of general practice-specific data for antibiotic prescribing and decision support tools to inform appropriate antibiotic prescribing. DESIGN: A parallel-group, cluster randomised controlled trial. SETTING: The trial was conducted in 79 general practices in the UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: All registered patients were included. MAIN OUTCOME MEASURES: The primary outcome was the rate of antibiotic prescriptions for self-limiting RTIs over the 12-month intervention period. COHORT STUDY: A separate population-based cohort study was conducted in 610 CPRD general practices that were not exposed to the trial interventions. Data were analysed to evaluate safety outcomes for registered patients with 45.5 million person-years of follow-up from 2005 to 2014. RESULTS: There were 41 intervention trial arm practices (323,155 patient-years) and 38 control trial arm practices (259,520 patient-years). There were 98.7 antibiotic prescriptions for RTIs per 1000 patient-years in the intervention trial arm (31,907 antibiotic prescriptions) and 107.6 per 1000 patient-years in the control arm (27,923 antibiotic prescriptions) [adjusted antibiotic-prescribing rate ratio (RR) 0.88, 95% confidence interval (CI) 0.78 to 0.99; p = 0.040]. There was no evidence of effect in children aged < 15 years (RR 0.96, 95% CI 0.82 to 1.12) or adults aged ≥ 85 years (RR 0.97, 95% CI 0.79 to 1.18). Antibiotic prescribing was reduced in adults aged between 15 and 84 years (RR 0.
Gulliford M, Prevost A, Charlton J, et al., 2019, Effectiveness and safety of electronically-delivered prescribing feedback and decision support on antibiotic utilisation for respiratory illness in primary care. REDUCE cluster-randomised trial, BMJ, Vol: 364, ISSN: 0959-8138
Objectives To evaluate the effectiveness and safety at population scale of electronically delivered prescribing feedback and decision support interventions at reducing antibiotic prescribing for self limiting respiratory tract infections.Design Open label, two arm, cluster randomised controlled trial.Setting UK general practices in the Clinical Practice Research Datalink, randomised between 11 November 2015 and 9 August 2016, with final follow-up on 9 August 2017.Participants 79 general practices (582 675 patient years) randomised (1:1) to antimicrobial stewardship (AMS) intervention or usual care.Interventions AMS intervention comprised a brief training webinar, automated monthly feedback reports of antibiotic prescribing, and electronic decision support tools to inform appropriate prescribing over 12 months. Intervention components were delivered electronically, supported by a local practice champion nominated for the trial.Main outcome measures Primary outcome was the rate of antibiotic prescriptions for respiratory tract infections from electronic health records. Serious bacterial complications were evaluated for safety. Analysis was by Poisson regression with general practice as a random effect, adjusting for covariates. Prespecified subgroup analyses by age group were reported.Results The trial included 41 AMS practices (323 155 patient years) and 38 usual care practices (259 520 patient years). Unadjusted and adjusted rate ratios for antibiotic prescribing were 0.89 (95% confidence interval 0.68 to 1.16) and 0.88 (0.78 to 0.99, P=0.04), respectively, with prescribing rates of 98.7 per 1000 patient years for AMS (31 907 prescriptions) and 107.6 per 1000 patient years for usual care (27 923 prescriptions). Antibiotic prescribing was reduced most in adults aged 15-84 years (adjusted rate ratio 0.84, 95% confidence interval 0.75 to 0.95), with one antibiotic prescription per year avoided for every 62 patients (95% confide
Sivaprasad S, Hykin P, Prevost AT, et al., 2018, Intravitreal aflibercept compared with panretinal photocoagulation for proliferative diabetic retinopathy: the CLARITY non-inferiority RCT, Efficacy and Mechanism Evaluation, Vol: 5, ISSN: 2050-4365
Panretinal photocoagulation (PRP) has been the standard of care for patients with proliferative diabetic retinopathy (PDR) for the last 40 years. It prevents severe visual loss in PDR but is also associated with adverse effects on visual functions.The clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (CLARITY) trial evaluated the clinical efficacy, mechanisms and cost-effectiveness of intravitreal aflibercept (Eylea®, Regeneron, Tarrytown, NY, USA/Bayer Pharma AG, Berlin, Germany therapy for PDR.A multicentre, prospective, individually randomised, single-masked, active-controlled trial with concurrent economic evaluation that tested the non-inferiority of intravitreal aflibercept versus standard care PRP at 52 weeks. A subset of the participants enrolled in a mechanistic evaluation substudy.22 UK NHS clinical sites.Patients aged at least 18 years having either treatment-naive PDR or active retinal neovascularisation (NV) despite prior PRP requiring treatment and best corrected visual acuity (BCVA) of 54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or better in the study eye were included. Eyes with evidence of macular oedema at baseline confirmed by central subfield thickness > 320 µm on spectral-domain optical coherence tomography were excluded.In the intervention arm, intravitreal aflibercept injections were given at baseline, 4 and 8 weeks and patients were subsequently reviewed every month and injected pro re nata based on the treatment response defined by degree of regression of retinal NV. In the comparator arm, PRP was completed in 2-weekly sessions and then supplemented if necessary at 8-weekly intervals.The primary outcome was the mean change in BCVA at 52 weeks utilising a linear mixed-effects model incorporating data from both week 12 and week 52.A total of 232 participants (116 per arm) were recruited between August 2014 and November 2015. A total of 221 and 210 par
Nicholson L, Crosby-Nwaobi R, Vasconcelos JC, et al., 2018, Mechanistic evaluation of panretinal photocoagulation versus aflibercept in proliferative diabetic retinopathy: CLARITY substudy, Investigative Ophthalmology & Visual Science, Vol: 59, Pages: 4277-4284, ISSN: 1552-5783
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.
Sivaprasad S, Vasconcelos JC, Prevost AT, et al., 2018, 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 and Endocrinology, Vol: 6, Pages: 382-391, ISSN: 2213-8595
BackgroundWe 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.MethodsCLEOPATRA 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.FindingsBetween 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 a
Crocketta RA, King SE, Marteau TM, et al., 2018, Nutritional labelling for healthier food or non-alcoholic drink purchasing and consumption, Cochrane Database of Systematic Reviews, Vol: 2, ISSN: 1469-493X
BackgroundNutritional labelling is advocated as a means to promote healthier food purchasing and consumption, including lower energy intake. Internationally, many different nutritional labelling schemes have been introduced. There is no consensus on whether such labelling is effective in promoting healthier behaviour.ObjectivesTo assess the impact of nutritional labelling for food and non-alcoholic drinks on purchasing and consumption of healthier items. Our secondary objective was to explore possible effect moderators of nutritional labelling on purchasing and consumption.Search methodsWe searched 13 electronic databases including CENTRAL, MEDLINE and Embase to 26 April 2017. We also handsearched references and citations and sought unpublished studies through websites and trials registries.Selection criteriaEligible studies: were randomised or quasi-randomised controlled trials (RCTs/Q-RCTs), controlled before-and-after studies, or interrupted time series (ITS) studies; compared a labelled product (with information on nutrients or energy) with the same product without a nutritional label; assessed objectively measured purchasing or consumption of foods or non-alcoholic drinks in real-world or laboratory settings.Data collection and analysisTwo authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of bias' tool and GRADE to assess the quality of evidence. We pooled studies that evaluated similar interventions and outcomes using a random-effects meta-analysis, and we synthesised data from other studies in a narrative summary.Main resultsWe included 28 studies, comprising 17 RCTs, 5 Q-RCTs and 6 ITS studies. Most (21/28) took place in the USA, and 19 took place in university settings, 14 of which mainly involved university students or staff. Most (20/28) studies assessed the impact of labelling on menus or menu boards, or nutritional labelling placed on, or adjacent to, a range of foods or drinks from which partic
Sivaprasad S, Prevost AT, Vasconcelos J, et al., 2017, Intravitreal aflibercept for proliferative diabetic retinopathy Reply, Lancet, Vol: 390, Pages: 2141-2142, ISSN: 0140-6736
Prevost A, 2017, P108: A journey from statistical consultation to funded adaptive trial, 4th International Clinical Trials Methodology Conference, Publisher: BioMed Central, ISSN: 1745-6215
Vasconcelos J, Turner R, Prevost A, 2017, 060: A way to assess the impact of an omitted study on the overallmeta-analysis estimate, International Clinical Trials Methodology Conference, Publisher: BioMed Central, Pages: 210-210, ISSN: 1745-6215
Sivaprasad S, Prevost AT, Vasconcelos JC, et al., 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, Vol: 389, Pages: 2193-2203, ISSN: 0140-6736
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
Hollands GJ, French DP, Griffin SJ, et al., 2016, Impact of communicating genetic risk estimates on risk-reducing health behaviour: systematic review with meta-analysis, The 14th International Congress of Behavioral Medicine, Publisher: Springer Verlag, Pages: S6-S7, ISSN: 1070-5503
Kirkham B, Chaabo K, Hall C, et al., 2016, Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis, RHEUMATOLOGY, Vol: 55, Pages: 1993-2000, ISSN: 1462-0324
Gulliford MC, Charlton J, Prevost T, et al., 2016, Costs and Outcomes of Increasing Access to Bariatric Surgery: Cohort Study and Cost-Effectiveness Analysis Using Electronic Health Records, Value in Health, Vol: 20, Pages: 85-92, ISSN: 1098-3015
ObjectivesTo estimate costs and outcomes of increasing access to bariatric surgery in obese adults and in population subgroups of age, sex, deprivation, comorbidity, and obesity category.MethodsA cohort study was conducted using primary care electronic health records, with linked hospital utilization data, for 3,045 participants who underwent bariatric surgery and 247,537 participants who did not undergo bariatric surgery. Epidemiological analyses informed a probabilistic Markov model to compare bariatric surgery, including equal proportions with adjustable gastric banding, gastric bypass, and sleeve gastrectomy, with standard nonsurgical management of obesity. Outcomes were quality-adjusted life-years (QALYs) and net monetary benefits at a threshold of £30,000 per QALY.ResultsIn a UK population of 250,000 adults, there may be 7,163 people with morbid obesity including 1,406 with diabetes. The immediate cost of 1,000 bariatric surgical procedures is £9.16 million, with incremental discounted lifetime health care costs of £15.26 million (95% confidence interval £15.18–£15.36 million). Patient-years with diabetes mellitus will decrease by 8,320 (range 8,123–8,502). Incremental QALYs will increase by 2,142 (range 2,032–2,256). The estimated cost per QALY gained is £7,129 (range £6,775–£7,506). Net monetary benefits will be £49.02 million (range £45.72–£52.41 million). Estimates are similar for subgroups of age, sex, and deprivation. Bariatric surgery remains cost-effective if the procedure is twice as costly, or if intervention effect declines over time.ConclusionsDiverse obese individuals may benefit from bariatric surgery at acceptable cost. Bariatric surgery is not cost-saving, but increased health care costs are exceeded by health benefits to obese individuals.
Gulliford MC, Booth HP, Reddy M, et al., 2016, Effect of Contemporary Bariatric Surgical Procedures on Type 2 Diabetes Remission. A Population-Based Matched Cohort Study, OBESITY SURGERY, Vol: 26, Pages: 2308-2315, ISSN: 0960-8923
Pears S, Bijker M, Morton K, et al., 2016, A randomised controlled trial of three very brief interventions for physical activity in primary care, BMC Public Health, Vol: 16, ISSN: 1471-2458
BackgroundVery brief interventions (VBIs) for physical activity are promising, but there is uncertainty about their potential effectiveness and cost. We assessed potential efficacy, feasibility, acceptability, and cost of three VBIs in primary care, in order to select the most promising intervention for evaluation in a subsequent large-scale RCT.MethodsThree hundred and ninety four adults aged 40–74 years were randomised to a Motivational (n = 83), Pedometer (n = 74), or Combined (n = 80) intervention, delivered immediately after a preventative health check in primary care, or control (Health Check only; n = 157). Potential efficacy was measured as the probability of a positive difference between an intervention arm and the control arm in mean physical activity, measured by accelerometry at 4 weeks.ResultsFor the primary outcome the estimated effect sizes (95 % CI) relative to the Control arm for the Motivational, Pedometer and Combined arms were respectively: +20.3 (−45.0, +85.7), +23.5 (−51.3, +98.3), and −3.1 (−69.3, +63.1) counts per minute. There was a73% probability of a positive effect on physical activity for each of the Motivational and Pedometer VBIs relative to control, but only 46 % for the Combined VBI. Only the Pedometer VBI was deliverable within 5 min. All VBIs were acceptable and low cost.ConclusionsBased on the four criteria, the Pedometer VBI was selected for evaluation in a large-scale trial.
Juszczyk D, Charlton J, McDermott L, et al., 2016, Electronically delivered, multicomponent intervention to reduce unnecessary antibiotic prescribing for respiratory infections in primary care: a cluster randomised trial using electronic health records-REDUCE Trial study original protocol, BMJ Open, Vol: 6, ISSN: 2044-6055
Introduction Respiratory tract infections (RTIs) account for about 60% of antibiotics prescribed in primary care. This study aims to test the effectiveness, in a cluster randomised controlled trial, of electronically delivered, multicomponent interventions to reduce unnecessary antibiotic prescribing when patients consult for RTIs in primary care. The research will specifically evaluate the effectiveness of feeding back electronic health records (EHRs) data to general practices.Methods and analysis 2-arm cluster randomised trial using the EHRs of the Clinical Practice Research Datalink (CPRD). General practices in England, Scotland, Wales and Northern Ireland are being recruited and the general population of all ages represents the target population. Control trial arm practices will continue with usual care. Practices in the intervention arm will receive complex multicomponent interventions, delivered remotely to information systems, including (1) feedback of each practice's antibiotic prescribing through monthly antibiotic prescribing reports estimated from CPRD data; (2) delivery of educational and decision support tools; (3) a webinar to explain and promote effective usage of the intervention. The intervention will continue for 12 months. Outcomes will be evaluated from CPRD EHRs. The primary outcome will be the number of antibiotic prescriptions for RTIs per 1000 patient years. Secondary outcomes will be: the RTI consultation rate; the proportion of consultations for RTI with an antibiotic prescribed; subgroups of age; different categories of RTI and quartiles of intervention usage. There will be more than 80% power to detect an absolute reduction in antibiotic prescription for RTI of 12 per 1000 registered patient years. Total healthcare usage will be estimated from CPRD data and compared between trial arms.Ethics and dissemination Trial protocol was approved by the National Research Ethics Service Committee (14/LO/1730). The pragmatic design of the trial will
Gulliford MC, Moore MV, Little P, et al., 2016, Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records, BMJ: British Medical Journal, Vol: 354, ISSN: 0959-8138
Objective To determine whether the incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre’s syndrome is higher in general practices that prescribe fewer antibiotics for self limiting respiratory tract infections (RTIs).Design Cohort study.Setting 610 UK general practices from the UK Clinical Practice Research Datalink.Participants Registered patients with 45.5 million person years of follow-up from 2005 to 2014.Exposures Standardised proportion of RTI consultations with antibiotics prescribed for each general practice, and rate of antibiotic prescriptions for RTIs per 1000 registered patients.Main outcome measures Incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre’s syndrome, adjusting for age group, sex, region, deprivation fifth, RTI consultation rate, and general practice.Results From 2005 to 2014 the proportion of RTI consultations with antibiotics prescribed decreased from 53.9% to 50.5% in men and from 54.5% to 51.5% in women. From 2005 to 2014, new episodes of meningitis, mastoiditis, and peritonsillar abscess decreased annually by 5.3%, 4.6%, and 1.0%, respectively, whereas new episodes of pneumonia increased by 0.4%. Age and sex standardised incidences for pneumonia and peritonsillar abscess were higher for practices in the lowest fourth of antibiotic prescribing compared with the highest fourth. The adjusted relative risk increases for a 10% reduction in antibiotic prescribing were 12.8% (95% confidence interval 7.8% to 17.5%, P<0.001) for pneumonia and 9.9% (5.6% to 14.0%, P<0.001) for peritonsillar abscess. If a general practice with an average list size of 7000 patients reduces the proportion of RTI consultations with antibiotics prescribed by 10%, then it might observe 1.1 (95% confidence interval 0.6 to 1.5) more cases of pneumonia each year and 0.9 (0.5 to 1.3) more cases of peritonsillar abscess each decade.
Mitchell J, Hardeman W, Pears S, et al., 2016, 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, Trials, Vol: 17, ISSN: 1745-6215
Ibrahim F, Tom BDM, Scott DL, et al., 2016, A systematic review of randomised controlled trials in rheumatoid arthritis: the reporting and handling of missing data in composite outcomes, Trials, Vol: 17, ISSN: 1745-6215
BackgroundMost reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations.MethodsA systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals.ResultsA total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2–53 % and were above 30 % in 9 trials, 20–30 % in 11 trials, 10–20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines.ConclusionsThis review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant’s flow diagram. However, there is a need to improve the
Gulliford MC, Charlton J, Booth HP, et al., 2016, Costs and outcomes of increasing access to bariatric surgery for obesity: cohort study and cost-effectiveness analysis using electronic health records, Health Services and Delivery Research, Vol: 4, ISSN: 2050-4349
Bariatric surgery is known to be an effective treatment for extreme obesity but access to these procedures is currently limited.This study aimed to evaluate the costs and outcomes of increasing access to bariatric surgery for severe and morbid obesity.Primary care electronic health records from the UK Clinical Practice Research Datalink were analysed for 3045 participants who received bariatric surgery and 247,537 general population controls. The cost-effectiveness of bariatric surgery was evaluated in severe and morbid obesity through a probabilistic Markov model populated with empirical data from electronic health records.In participants who did not undergo bariatric surgery, the probability of participants with morbid obesity attaining normal body weight was 1 in 1290 annually for men and 1 in 677 for women. Costs of health-care utilisation increased with body mass index category but obesity-related physical and psychological comorbidities were the main drivers of health-care costs. In a cohort of 3045 adult obese patients with first bariatric surgery procedures between 2002 and 2014, bariatric surgery procedure rates were greatest among those aged 35–54 years, with a peak of 37 procedures per 100,000 population per year in women and 10 per 100,000 per year in men. During 7 years of follow-up, the incidence of diabetes diagnosis was 28.2 [95% confidence interval (CI) 24.4 to 32.7] per 1000 person-years in controls and 5.7 (95% CI 4.2 to 7.8) per 1000 person-years in bariatric surgery patients (adjusted hazard ratio was 0.20, 95% CI 0.13 to 0.30; p < 0.0001). In 826 obese participants with type 2 diabetes mellitus who received bariatric surgery, the relative rate of diabetes remission, compared with controls, was 5.97 (95% CI 4.86 to 7.33; p < 0.001). There was a slight reduction in depression in the first 3 years following bariatric surgery that was not maintained. Incremental lifetime costs associated with bariatric surger
Robertson DS, Prevost AT, Bowden J, 2016, Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules, Statistics in Medicine, Vol: 35, Pages: 3907-3922, ISSN: 1097-0258
Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
Farquhar MC, Prevost AT, McCrone P, et al., 2016, The clinical and cost effectiveness of a Breathlessness Intervention Service for patients with advanced non-malignant disease and their informal carers: mixed findings of a mixed method randomised controlled trial, Trials, Vol: 17, ISSN: 1745-6215
BackgroundBreathlessness is the most common and intrusive symptom of advanced non-malignant respiratory and cardiac conditions. The Breathlessness Intervention Service (BIS) is a multi-disciplinary complex intervention, theoretically underpinned by a palliative care approach, utilising evidence-based non-pharmacological and pharmacological interventions to support patients with advanced disease in managing their breathlessness. Having published the effectiveness and cost effectiveness of BIS for patients with advanced cancer and their carers, we sought to establish its effectiveness, and cost effectiveness, in advanced non-malignant conditions.MethodsThis was a single-centre Phase III fast-track single-blind mixed method RCT of BIS versus standard care for breathless patients with non-malignant conditions and their carers. Randomisation was to one of two groups (randomly permuted blocks). Eighty-seven patients referred to BIS were randomised (intervention arm n = 44; control arm n = 43 received BIS after four-week wait); 79 (91 %) completed to key outcome measurement. The primary outcome measure was 0–10 numeric rating scale for patient distress due to breathlessness at four weeks. Secondary outcome measures were Chronic Respiratory Questionnaire, Hospital Anxiety and Depression Scale, Client Service Receipt Inventory, EQ-5D and topic-guided interviews.ResultsQualitative analyses showed the positive impact of BIS on patients with non-malignant conditions and their carers; quantitative analyses showed a non-significant greater reduction in the primary outcome (‘distress due to breathlessness’), when compared to standard care, of –0.24 (95 % CI: –1.30, 0.82). BIS resulted in extra mean costs of £799, reducing to £100 when outliers were excluded; neither difference was statistically significant. The quantitative findings contrasted with those previously reported for patients with cancer and their car
Robertson DS, Prevost AT, Bowden J, 2016, Accounting for selection and correlation in the analysis of two-stage genome-wide association studies, Biostatistics, Vol: 17, Pages: 634-649, ISSN: 1468-4357
The problem of selection bias has long been recognized in the analysis of two-stage trials, where promising candidates are selected in stage 1 for confirmatory analysis in stage 2. To efficiently correct for bias, uniformly minimum variance conditionally unbiased estimators (UMVCUEs) have been proposed for a wide variety of trial settings, but where the population parameter estimates are assumed to be independent. We relax this assumption and derive the UMVCUE in the multivariate normal setting with an arbitrary known covariance structure. One area of application is the estimation of odds ratios (ORs) when combining a genome-wide scan with a replication study. Our framework explicitly accounts for correlated single nucleotide polymorphisms, as might occur due to linkage disequilibrium. We illustrate our approach on the measurement of the association between 11 genetic variants and the risk of Crohn's disease, as reported in Parkes and others (2007. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Gen.39(7), 830–832.), and show that the estimated ORs can vary substantially if both selection and correlation are taken into account.
Hollands GJ, French DP, Griffin SJ, et al., 2016, The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis, BMJ, Vol: 352, ISSN: 1756-1833
Objective To assess the impact of communicating DNA based disease risk estimates on risk-reducing health behaviours and motivation to engage in such behaviours.Design Systematic review with meta-analysis, using Cochrane methods.Data sources Medline, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials up to 25 February 2015. Backward and forward citation searches were also conducted.Study selection Randomised and quasi-randomised controlled trials involving adults in which one group received personalised DNA based estimates of disease risk for conditions where risk could be reduced by behaviour change. Eligible studies included a measure of risk-reducing behaviour.Results We examined 10 515 abstracts and included 18 studies that reported on seven behavioural outcomes, including smoking cessation (six studies; n=2663), diet (seven studies; n=1784), and physical activity (six studies; n=1704). Meta-analysis revealed no significant effects of communicating DNA based risk estimates on smoking cessation (odds ratio 0.92, 95% confidence interval 0.63 to 1.35, P=0.67), diet (standardised mean difference 0.12, 95% confidence interval −0.00 to 0.24, P=0.05), or physical activity (standardised mean difference −0.03, 95% confidence interval −0.13 to 0.08, P=0.62). There were also no effects on any other behaviours (alcohol use, medication use, sun protection behaviours, and attendance at screening or behavioural support programmes) or on motivation to change behaviour, and no adverse effects, such as depression and anxiety. Subgroup analyses provided no clear evidence that communication of a risk-conferring genotype affected behaviour more than communication of the absence of such a genotype. However, studies were predominantly at high or unclear risk of bias, and evidence was typically of low quality.Conclusions Expectations that communicating DNA based risk estimates changes behaviour is not supported by existing evidence.
Booth HP, Khan O, Fildes A, et al., 2016, Changing Epidemiology of Bariatric Surgery in the UK: Cohort Study Using Primary Care Electronic Health Records, OBESITY SURGERY, Vol: 26, Pages: 1900-1905, ISSN: 0960-8923
BackgroundThis study aimed to use primary care electronic health records to evaluate the epidemiology of bariatric surgery in the UK.MethodsA cohort comprising all obese patients with a bariatric surgical procedure was drawn from the Clinical Practice Research Datalink (CPRD). Rates of bariatric surgery were estimated using the registered CPRD population as denominator.ResultsThere were 3039 adult obese patients with first bariatric surgery procedures between 2002 and 2014, including laparoscopic adjustable gastric banding (LAGB), 1297; gastric bypass (GBP), 1265; and sleeve gastrectomy (SG), 477. Annual procedures increased from one in 2002 to a maximum of 525 in 2010. Intervention rates were greatest among those aged 35–54, with a peak of 37 procedures per 100,000 population per year in women and 10 per 100,000 per year in men. The mean age and body mass index of participants increased, as did the proportion of men and proportion with diabetes. Between 2002 and 2006, LAGB accounted for >90 % of procedures; in 2014, GBP accounted for 52 % and SG 26 %. Among patients initially receiving LAGB, the rate of band removal was 1.6 (95 % confidence interval 1.3–2.0) per 100 patient years; the rate of a second procedure of a different type was 1.2 (0.9–1.5) per 100 patient years.ConclusionsNumbers of bariatric surgical procedures have increased with increasing use of GBP and SG. Rates of bariatric surgery per 100,000 population remain low and provide evidence of limited access to bariatric surgical procedures in relation to need.
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