Publications
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Mason MD, Moore R, Jones G, et al., 2016, Radiotherapy for Prostate Cancer: is it ‘what you do’ or ‘the way that you do it’? A UK Perspective on Technique and Quality Assurance, Clinical Oncology, Vol: 28, Pages: e92-e100, ISSN: 0936-6555
© 2016Aims The treatment of prostate cancer has evolved markedly over the last 40 years, including radiotherapy, notably with escalated dose and targeting. However, the optimal treatment for localised disease has not been established in comparative randomised trials. The aim of this article is to describe the history of prostate radiotherapy trials, including their quality assurance processes, and to compare these with the ProtecT trial. Materials and methods The UK ProtecT randomised trial compares external beam conformal radiotherapy, surgery and active monitoring for clinically localised prostate cancer and will report on the primary outcome (disease-specific mortality) in 2016 following recruitment between 1999 and 2009. The embedded quality assurance programme consists of on-site machine dosimetry at the nine trial centres, a retrospective review of outlining and adherence to dose constraints based on the trial protocol in 54 participants (randomly selected, around 10% of the total randomised to radiotherapy, n = 545). These quality assurance processes and results were compared with prostate radiotherapy trials of a comparable era. Results There has been an increasingly sophisticated quality assurance programme in UK prostate radiotherapy trials over the last 15 years, reflecting dose escalation and treatment complexity. In ProtecT, machine dosimetry results were comparable between trial centres and with the UK RT01 trial. The outlining review showed that most deviations were clinically acceptable, although three (1.4%) may have been of clinical significance and were related to outlining of the prostate. Seminal vesicle outlining varied, possibly due to several prostate trials running concurrently with different protocols. Adherence to dose constraints in ProtecT was considered acceptable, with 80% of randomised participants having two or less deviations and planning target volume coverage was excellent. Conclusion The ProtecT trial quality assur
Lane A, Metcalfe C, Young GJ, et al., 2016, Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life, BJU International, Vol: 118, Pages: 869-879, ISSN: 1464-4096
Objectives: To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations. Materials and Methods: A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men's age at biopsy and PSA testing time points for selected measures. Results: A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physica
Gordon AC, Mason AJ, Thirunavukkarasu N, et al., 2016, Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial, The Journal of the American Medical Association, Vol: 316, Pages: 509-518, ISSN: 0002-9955
IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1
Uthaya SN, Liu X, Babalis D, et al., 2016, Nutritional Evaluation and Optimisation in Neonates (NEON): a randomised double-blind controlled trial of amino-acid regimen and intravenous lipid composition in preterm parenteral nutrition, American Journal of Clinical Nutrition, Vol: 103, Pages: 1443-1452, ISSN: 1938-3207
BackgroundParenteral nutrition is central to the care of very immature infants. Current international recommendations favour higher amino-acid intakes and fish oil-containing lipid emulsions. ObjectiveThe aim of this two-by-two factorial, double-blind multicentre randomised controlled trial was to compare the effect of high (immediate Recommended Daily Intake: Imm-RDI) versus low (incremental introduction: Inc-AA) parenteral amino-acid delivery, commenced within 24 hours of birth, on body composition, and a multi-component lipid emulsion containing 30% soy bean oil, 30% medium chain triglycerides, 25% olive oil and 15% fish oil (SMOF) versus soybean oil based lipid emulsion (SO) on Intra-Hepato-Cellular Lipid (IHCL) content. ResultsWe randomised 168 infants born <31 weeks gestation. We evaluated outcomes at term in 133 infants. There were no significant differences between Imm-RDI and Inc-AA groups for non-adipose mass (adjusted mean difference (95% CI): 1.0g (-108, 111) p=0.98) or between SMOF and SO groups for IHCL (adjusted mean ratio SMOF:SO (95% CI): 1.1 (0.8, 1.6) p=0.58). SMOF does not affect IHCL content. There was a significant interaction (p=0.05) between the two interventions for non-adipose mass. There were no significant interactions between group differences for either primary outcome measure after adjusting for additional confounders. Imm-RDI infants were more likely than Inc-AA infants to have blood urea nitrogen levels greater than 7mmol/l or 10mmol/l respectively (75% vs 49%; p<0.01 and 49% vs 18%; p<0.01). Head circumference at term was smaller in the Imm-RDI group (mean difference (95% CI): -0.8cm (-1.5, -0.1) p= 0.02). There were no significant differences in any pre-specified secondary outcomes including adiposity, liver function tests, incidence of conjugated hyperbilirubinaemia, weight, length, mortality and brain volumes. ConclusionsImmediate delivery of Recommended Daily Intake of parenteral amino-acids does not benefit body compo
Quinn K, Bouliotis G, Doyle N, et al., 2016, A first-in-human study, in HIV-positive men, of the novel HIV-fusion inhibitor C34-PEG4-Chol, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 18-18, ISSN: 1464-2662
Hughes D, Waddingham E, Mt-Isa S, et al., 2016, Recommendations for benefit-risk assessment methodologies and visual representations., Pharmacoepidemiology & Drug Safety, Vol: 25, Pages: 251-262, ISSN: 1053-8569
PURPOSE: The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. METHODS: Eight case studies based on the benefit-risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit-risk assessment. Recommendations were drawn up based on the results of the case studies. RESULTS: A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. CONCLUSIONS: Adopting formal, structured approaches to benefit-risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit-risk assessment from multiple perspectives. Copyright © 2016 John Wiley & Sons, Ltd.
Waddingham E, Mt-Isa S, Nixon R, et al., 2016, A Bayesian approach to probabilistic sensitivity analysis in structured benefit-risk assessment, Biometrical Journal, Vol: 58, Pages: 28-42, ISSN: 1521-4036
Quantitative decision models such as multiple criteria decision analysis (MCDA) can be used in benefit-risk assessment to formalize trade-offs between benefits and risks, providing transparency to the assessment process. There is however no well-established method for propagating uncertainty of treatment effects data through such models to provide a sense of the variability of the benefit-risk balance. Here, we present a Bayesian statistical method that directly models the outcomes observed in randomized placebo-controlled trials and uses this to infer indirect comparisons between competing active treatments. The resulting treatment effects estimates are suitable for use within the MCDA setting, and it is possible to derive the distribution of the overall benefit-risk balance through Markov Chain Monte Carlo simulation. The method is illustrated using a case study of natalizumab for relapsing-remitting multiple sclerosis.
Johnston SL, Szigeti M, Cross M, et al., 2016, A Randomised, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy Of Oral Azithromycin (500 Mg Od) As A Supplement To Standard Care For Adult Patients With Acute Exacerbations Of Asthma (the Azalea Trial), Publisher: AMER THORACIC SOC
Hallgreen CE, Mt-Isa S, Lieftucht A, et al., 2015, Literature review of visual representation of the results of benefit-risk assessments of medicinal products, Pharmacoepidemiology and Drug Safety, Vol: 25, Pages: 238-250, ISSN: 1099-1557
BackgroundThe PROTECT Benefit–Risk group is dedicated to research in methods for continuous benefit–risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods.MethodsA comprehensive review was performed to identify visuals used for medical risk and benefit–risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual.ResultsSixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit–risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated.ConclusionWe have arrived at recommendations for the use of visual displays for benefit–risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience–visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit–risk analysis information. Copyright © 2015 John Wiley & Sons, Ltd.
Chambers ES, Viardot A, Psichas A, et al., 2015, Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults, Gut, Vol: 64, Pages: 1744-1754, ISSN: 0017-5749
Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
Foreman DM, Best N, Dunstan F, et al., 2015, Improving child protection by integrating research evidence and clinical experience, International Journal of Law Policy and the Family, Vol: 29, Pages: 301-312, ISSN: 1360-9939
Pignatti F, Ashby D, Brass EP, et al., 2015, Structured frameworks to increase the transparency of the assessment of benefits and risks of medicines: current status and possible future directions, Clinical Pharmacology & Therapeutics, Vol: 98, Pages: 522-533, ISSN: 1532-6535
Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.
Alton EWFW, Armstrong DK, Ashby D, et al., 2015, Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial, The Lancet Respiratory Medicine, Vol: 3, Pages: 684-691, ISSN: 2213-2600
BackgroundLung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.MethodsWe did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.FindingsBetween June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.InterpretationMonthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 yea
Alton EWFW, Armstrong DK, Ashby D, 2015, Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fi brosis: a randomised, double-blind, placebo-controlled, phase 2b trial (vol 3, pg 684, 2015), LANCET RESPIRATORY MEDICINE, Vol: 3, Pages: E33-E33, ISSN: 2213-2600
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Abbara A, Jayasena CN, Christopoulos G, et al., 2015, Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of OHSS during IVF therapy, Journal of Clinical Endocrinology and Metabolism, Vol: 100, Pages: 3322-3331, ISSN: 0368-1610
Context:In Vitro Fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication ‘ovarian hyperstimulation syndrome’ (OHSS).Objective:To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.Design:Phase 2 multi-dose open label randomized clinical trial carried out during 2013–2014.Setting:Hammersmith Hospital IVF unit, London, UK.Patients:Sixty women at high risk of developing OHSS Intervention:Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomized to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2nmol/kg, n=5; 6.4nmol/kg, n=20; 9.6nmol/kg, n=15; 12.8nmol/kg, n=20). Oocytes were retrieved 36hrs after kisspeptin-54 administration, assessed for maturation, and fertilized by intra-cytoplasmic sperm injection (ICSI) with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.Main Outcome Measure:Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥14mm on ultrasound). Secondary outcomes include rates of OHSS and pregancy. Results:Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8nmol/kg kisspeptin-54, which was +69% (CI -16%,+153%) greater than following 3.2nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy and live birth rates per transfer (n=51) were 63%, 53% and 45%, respectively. Highest pregnancy rates were observed following 9.6nmol/kg kisspeptin-54 (85%, 77% and 62%, respectively). No woman developed moderate, severe or critical OHSS.Conclusion:Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte
Chambers ES, Viardot A, Psichas A, et al., 2015, Effects of elevating colonic propionate on liver fat content in overweight adults with non-alcoholic fatty liver disease: a pilot study, Proceedings of the Nutrition Society, Vol: 74, Pages: E30-E30, ISSN: 1475-2719
Mt-Isa S, Tomlin S, Sutcliffe A, et al., 2015, Prokinetics Prescribing in Paediatrics: Evidence on Cisapride, Domperidone, and Metoclopramide, Journal of Pediatric Gastroenterology and Nutrition, Vol: 60, Pages: 508-514, ISSN: 1536-4801
Cheng K, Ashby D, Smyth RL, 2015, Oral steroids for long-term use in cystic fibrosis, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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Tsilidis KK, Capothanassi D, Allen N, et al., 2014, Metformin and cancer risk: A cohort study in the UK Clinical Practice Research Datalink analyzed like a randomized trial, 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Tsilidis KK, Capothanassi D, Allen NE, et al., 2014, Metformin does not affect cancer risk: a cohort study in the UK clinical practice research datalink analyzed like an intention-to-treat trial, Diabetes Care, Vol: 37, Pages: 2522-2532, ISSN: 0149-5992
OBJECTIVE Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis.RESEARCH DESIGN AND METHODS A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI.RESULTS A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89–1.04) and colorectal (HR 0.92; 95% CI 0.76–1.13), prostate (HR 1.02; 95% CI 0.83–1.25), lung (HR 0.85; 95% CI 0.68–1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82–1.31) cancer or any other cancer.CONCLUSIONS In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.
Jayasena CN, Abbara A, Comninos AN, et al., 2014, Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization, Journal of Clinical Investigation, Vol: 124, Pages: 3667-3677, ISSN: 0021-9738
BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos.RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54–treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively.CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy.TRIAL REGISTRATION. ClinicalTrials.gov NCT01667406.FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.
Hallgreen CE, van den Ham HA, Mt-Isa S, et al., 2014, Benefit-risk assessment in a post-market setting: a case study integrating real-life experience into benefit-risk methodology, Pharmacoepidemiology and Drug Safety, Vol: 23, Pages: 974-983, ISSN: 1099-1557
Abbara A, Jayasena CN, Comninos AN, et al., 2014, Kisspeptin - a novel physiological trigger for oocyte maturation in IVF treatment, 30th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 50-50, ISSN: 0268-1161
Mt-Isa S, Hallgreen CE, Wang N, et al., 2014, Balancing benefit and risk of medicines: a systematic review and classification of available methodologies, PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Vol: 23, Pages: 667-678, ISSN: 1053-8569
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Abbara A, Jayasena CN, Comninos AN, et al., 2014, Kisspeptin - a Novel Physiological Trigger for Oocyte Maturation in IVF Treatment, ENDOCRINE REVIEWS, Vol: 35, ISSN: 0163-769X
Orme RMLE, Perkins GD, McAuley DF, et al., 2014, An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial, Trials, Vol: 15, Pages: 1-10
Abbara A, Jayasena C, Comninos A, et al., 2014, Kisspeptin: a novel physiological trigger for oocyte maturation in in-vitro fertilisation treatment, LANCET, Vol: 383, Pages: 17-17, ISSN: 0140-6736
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Gordon AC, Mason AJ, Perkins GD, et al., 2014, The interaction of vasopressin and corticosteroids in septic shock: A pilot randomized controlled trial, Critical Care Medicine, Vol: 42, Pages: 1325-1333, ISSN: 0090-3493
OBJECTIVES: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. DESIGN: Prospective open-label randomized controlled pilot trial. SETTING: Four adult ICUs in London teaching hospitals. PATIENTS: Sixty-one adult patients who had septic shock. INTERVENTIONS: Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. MEASUREMENTS AND MAIN RESULTS: Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. CONCLUSIONS: Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or
Gordon AC, Mason AJ, Perkins GD, et al., 2014, Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH), BMJ Open, Vol: 4
Introduction Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.Methods and analysis This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0–0.06 U/min) or noradrenaline (0–12 µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50 mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation.Ethics and dissemination The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration number: ISRCTN 20769191 and EudraCT 2011-005363-24.
Cheng K, Ashby D, Smyth RL, 2014, Ursodeoxycholic acid for cystic fibrosis-related liver disease, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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