190 results found
Nagendran M, Russell JA, Brett S, et al., 2019, Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials, Intensive Care Medicine, Vol: 45, Pages: 844-855, ISSN: 0342-4642
PurposeWe performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.MethodsOur pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.ResultsFour trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86–1.12] or serious adverse events (RR 1.02, 95% CI 0.82–1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD − 2.8%, 95% CI − 0.2% to − 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).ConclusionsVasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.
Modi N, Ashby D, Battersby C, et al., Using routinely recorded clinical data for research: the Medicines for Neonates research programme, Programme Grants for Applied Research, ISSN: 2050-4322
Background: Clinical data offer potential to advance patient care. Neonatal specialised care is a high cost NHS service received by approximately 80,000 newborn infants each year. Objectives: To 1) develop the use of routinely recorded operational clinical data from Electronic Patient Records (EPR), secure national coverage, evaluate and improve the quality of clinical data, and develop their use as a national resource to improve neonatal healthcare and outcomes; test the hypotheses that 2) clinical and research data are of comparable quality; 3) routine NHS clinical assessment at age two-years reliably identifies children with neurodevelopmental impairment; and 4) trial-based economic evaluations of neonatal interventions can be reliably conducted using clinical data; 5) test methods to link NHS datasets; 6) evaluate parent views of personal data in research Design: Six interrelated work-streams; quarterly extractions of predefined data from neonatal EPR; approvals from the National Research Ethics Service, Health Research Authority Confidentiality Advisory Group, Caldicott Guardians and lead neonatal clinicians of participating NHS Trusts Setting: NHS neonatal unitsParticipants: Neonatal clinical teams; parents of babies admitted to NHS neonatal unitsInterventions: In work-stream 3 we employed the Bayley-III scales to evaluate neurodevelopmental status and the Quantitative Checklist of Autism in Toddlers (Q-CHAT) to evaluate social-communication skills. In work-stream 6 we recruited parents with previous experience of a child in neonatal care to assist in the design of a questionnaire directed at the parents of infants admitted to neonatal units. Data sources: Data extracted from the EPR of admissions to NHS neonatal units Main outcomes and results: We created a National Neonatal Research Database (NNRD) containing a defined extract from real-time, point-of-care, clinician-entered EPR from all NHS neonatal units in England, Wales and Scotland (n=200), establish
Cook JA, Julious SA, Sones W, et al., 2018, DELTA(2) guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial, BMJ-BRITISH MEDICAL JOURNAL, Vol: 363, ISSN: 1756-1833
Cook JA, Julious SA, Sones W, et al., 2018, DELTA(2) guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial, Trials, Vol: 19, ISSN: 1745-6215
BackgroundA key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adequate statistical power) of detecting a target difference between the treatments should one exist.The sample size has many implications for the conduct and interpretation of the study. Despite the critical role that the target difference has in the design of a RCT, the way in which it is determined has received little attention. In this article, we summarise the key considerations and messages from new guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation. This article on choosing the target difference for a randomised controlled trial (RCT) and undertaking and reporting the sample size calculation has been dual published in the BMJ and BMC Trials journalsMethodsThe DELTA2 (Difference ELicitation in TriAls) project comprised five major components: systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2); a Delphi study (stage 3); a two-day consensus meeting bringing together researchers, funders and patient representatives (stage 4); and the preparation and dissemination of a guidance document (stage 5).Results and DiscussionThe key messages from the DELTA2 guidance on determining the target difference and sample size calculation for a randomised caontrolled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided.
Antcliffe D, Burnham K, Al-Beidh F, et al., 2018, Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration but conflicting survival effects. Two transcriptomic sepsis response signatures (SRS) have been identified. SRS1 is relatively immunosuppressed whilst SRS2 is relatively immunocompetent. Objectives: We aimed to categorized patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. Methods: A post-hoc analysis was performed of a double-blind randomized clinical trial in septic shock (VANISH). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined using a previously established model using seven discriminant genes. Measurements and Main Results: Samples were available from 176 patients, 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (p=0·50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (p=0·02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (OR 7·9, 95%CI 1·6-39·9). Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immuno-competent SRS2 endotype had significantly higher mortality when given corticosteroids compared to placebo. Clinical trial registration available at www.isrctn.com, ID ISRCTN20769191.
Gordon AC, Santhakumaran S, Al-Beidh F, et al., 2018, Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial, Efficacy and Mechanism Evaluation, ISSN: 2050-4365
Background:In septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy but catecholamines have important side-effects. Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may have a role in sepsis.Objectives: In adult septic shock1. Does levosimendan reduce the incidence and severity of acute organ dysfunction ?2. What is the effect of levosimendan on individual organ function ?3. What is the safety profile of levosimendan?Design: Multi-centre, randomised, double-blind, parallel-group, placebo-controlled study.Setting: UK Intensive Care UnitsParticipants: Adult patients who have sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation.Interventions: Levosimendan 0.05 to 0.2 µg/kg/min vs. placebo for 24 hour, in addition to standard care, within 24 hours of meeting inclusion criteria.Primary outcome measure: Mean SOFA score on ICU after randomisation to a maximum of 28 days.Secondary outcome measures: Time to extubationSurvival upto 6 monthsSerious Adverse EventsResults: 2382 patients were screened at 34 centres, of whom 516 were randomised to treatment, 259 allocated to levosimendan and 257 to placebo. Baseline characteristics were well balanced across treatment arms.There was no significant difference in mean (±SD) SOFA score in the levosimendan group (6.7 ± 4.0) compared with placebo (6.1 ± 3.9); (mean difference 0.61, 95%CI -0.07 to 1.29). 28-day mortality was 34.5% versus 30.9% in the levosimendan and placebo groups respectively (absolute difference 3.6%, 95%CI -4.5 to 11.7). Patients in the levosimendan group were less likely to be successfully extubated over 28 days than the placebo group (hazard ratio 0.77, 95%CI 0.60 to 0.97). More patients in the levosimendan group had supraventricular tachyarrhythmias, (3.1% versus 0.4% absolute difference 2.7%, 95%CI 0.1 to 5.3), but there was no
Dunning J, Blankley S, Hoang LT, et al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, ISSN: 1529-2916
Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
Mora-Peris B, Bouliotis G, Kulasegaram R, et al., 2018, Changes in cerebral function parameters with maraviroc intensified antiretroviral therapy in treatment naïve HIV-Positive individuals; A randomised controlled study, AIDS, Vol: 32, Pages: 1007-1015, ISSN: 0269-9370
Background: Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits.Methods: Therapy-naive, cognitively asymptomatic, HIV-positive individuals were randomly allocated on a 1 : 1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed.Results: Of 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4+ cell count 428 (209) and 414 (229) cells/μl, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, P = 0.96 for differences between study arms]. A greater increase in frontal grey matter N-acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change −0.097 (SD 0.18), P = 0.009], although this was not associated with changes in cognitive function (P = 0.17).Conclusion: Maraviroc-intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment.
Santhakumaran S, Gray D, Statnikov Y, et al., 2017, Survival of very preterm infants admitted to neonatal care in England 2008-2014: time trends and regional variation, Archives of Disease in Childhood-Fetal and Neonatal Edition, Vol: 103, Pages: F208--F215, ISSN: 1468-2052
ObjectiveTo analyse survival trends and regional variation for very preterm infants admitted to neonatal care.SettingAll neonatal units in EnglandPatientsInfants born at 22+0-31+6 weeks+days gestational age (GA) over 2008-2014 and admitted to neonatal care; published data for admitted infants 22+0-25+6 weeks+days GA in 1995 and 2006, and for live births at 22+0-31+6 weeks+days GA in 2013.MethodsWe obtained data from the National Neonatal Research Database (NNRD). We used logistic regression to model survival probability with birth-weight, GA, sex, antenatal steroid exposure, and multiple birth included in the risk-adjustment model, and calculated Average Percentage Change (APC) for trends using joinpoint regression. We evaluated survival over a 20-year period for infants <26 weeks GA using additional published data from the EPICure studies.ResultsWe identified 50,112 eligible infants. There was an increase in survival over 2008-2014 (2008 88.0%, 2014 91.3%; adjusted APC 0.46% (95% Confidence Interval 0.30 to 0.62) p<0.001). The greatest improvement was at 22+0-23+6 weeks (APC 6.03% (2.47 to 3.53) p=0.002). Improvement largely occurred in London and South of England (APC: London 1.26% (0.60 to 1.96); South of England 1.09% (0.36 to 1.82); Midlands and East of England 0.15%(-0.56 to 0.86); North of England 0.26% (-0.54 to 1.07)). Survival at the earliest gestations improved at a similar rate over 1995-2014 (22+0-25+6 weeks, APC 2.73% (2.35 to 3.12) p-value for change=0.25). ConclusionsContinued national improvement in the survival of very preterm admissions masks important regional variation. Timely assessment of preterm survival is feasible using electronic records.
quinn K, Traboni C, Dily Penchala S, et al., 2017, A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol., Scientific Reports, Vol: 7, ISSN: 2045-2322
Abstract:Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10mg, 10mg and 20mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was > 72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.
Sydes MR, Ashby D, 2017, Data Authorship as an Incentive to Data Sharing, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 377, Pages: 402-402, ISSN: 0028-4793
Saunders P, Tsipouri V, Keir GJ, et al., 2017, Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial, TRIALS, Vol: 18, ISSN: 1745-6215
Background:Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population.Methods/design:RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity
Martyn M, Liu X, Wilhelm-Benartzi C, et al., 2017, Issues with over-fitting in predictive models produced for stratified medicine: a case study on an ovarian cancer trial, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Santhakumaran S, Mason AJ, Gordon AC, et al., 2017, Bayesian methods for informative missingness in longitudinal intensive care data, 3rd International Clinical Trials Methodology Conference, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Tsipouri V, Saunders P, Keir GJ, et al., 2017, Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): a randomised controlled trial, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Embleton A, Ashby D, Flemyng E, et al., 2017, If a tree falls in a forest: abstract view statistics as a measure of research impact, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Mason A, Winston A, Ashby D, 2017, Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Achana F, Petrou S, Khan K, et al., 2017, A methodological framework for assessing agreement between cost-effectiveness outcomes estimated using alternative sources of data on treatment costs and effects for trial-based economic evaluations., European Journal of Health Economics, Vol: 19, Pages: 75-86, ISSN: 1618-7601
A new methodological framework for assessing agreement between cost-effectiveness endpoints generated using alternative sources of data on treatment costs and effects for trial-based economic evaluations is proposed. The framework can be used to validate cost-effectiveness endpoints generated from routine data sources when comparable data is available directly from trial case report forms or from another source. We illustrate application of the framework using data from a recent trial-based economic evaluation of the probiotic Bifidobacterium breve strain BBG administered to babies less than 31 weeks of gestation. Cost-effectiveness endpoints are compared using two sources of information; trial case report forms and data extracted from the National Neonatal Research Database (NNRD), a clinical database created through collaborative efforts of UK neonatal services. Focusing on mean incremental net benefits at £30,000 per episode of sepsis averted, the study revealed no evidence of discrepancy between the data sources (two-sided p values >0.4), low probability estimates of miscoverage (ranging from 0.039 to 0.060) and concordance correlation coefficients greater than 0.86. We conclude that the NNRD could potentially serve as a reliable source of data for future trial-based economic evaluations of neonatal interventions. We also discuss the potential implications of increasing opportunity to utilize routinely available data for the conduct of trial-based economic evaluations.
Bird SM, Strang J, Ashby D, et al., 2017, External data required timely response by the Trial Steering-Data Monitoring Committee for the NALoxone InVEstigation (N-ALIVE) pilot trial, Contemporary Clinical Trials Communications, Vol: 5, Pages: 100-106, ISSN: 2451-8654
The prison-based N-ALIVE pilot trial had undertaken to notify the Research Ethics Committee and participantsif we had reason to believe that the N-ALIVE pilot trial would not proceed to the main trial. Inthis paper, we describe how external data for the third year of before/after evaluation from Scotland'sNational Naloxone Programme, a related public health policy, were anticipated by eliciting prior opinionabout the Scottish results in the month prior to their release as official statistics. We summarise howdeliberations by the N-ALIVE Trial Steering-Data Monitoring Committee (TS-DMC) on N-ALIVE's owninterim data, together with those on naloxone-on-release (NOR) from Scotland, led to the decision tocease randomization in the N-ALIVE pilot trial and recommend to local Principal Investigators that NORbe offered to already-randomized prisoners who had not yet been released.
Wilhelm-Benartzi CS, Mt-Isa S, Fiorentino F, et al., 2016, Challenges and methodology in the incorporation of biomarkers in cancer clinical trials., Critical Reviews in Oncology/Hematology, Vol: 110, Pages: 49-61, ISSN: 1040-8428
Biomarkers can be used to establish more homogeneous groups using the genetic makeup of the tumour to inform the selection of treatment for each individual patient. However, proper preclinical work and stringent validation are needed before taking forward biomarkers into confirmatory studies. Despite the challenges, incorporation of biomarkers into clinical trials could better target appropriate patients, and potentially be lifesaving. The authors conducted a systematic review to describe marker-based and adaptive design methodology for their integration in clinical trials, and to further describe the associated practical challenges. Studies published between 1990 to November 2015 were searched on PubMed. Titles, abstracts and full text articles were reviewed to identify relevant studies. Of the 4438 studies examined, 57 studies were included. The authors conclude that the proposed approaches may readily help researchers to design biomarker trials, but novel approaches are still needed.
Mason AJ, Gonzalez-Maffe J, Quinn K, et al., 2016, Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment, Statistics in Medicine, Vol: 36, Pages: 754-771, ISSN: 1097-0258
The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34-PEG4-Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding. During the study workup, Bayesian adaptive designs based on the continual reassessment method were compared with a more standard rule-based design, with the aim of choosing a design that would maximise the scientific information gained from the study. The process of specifying and evaluating the design options was time consuming and required the active involvement of all members of the trial's protocol development team. However, the effort was worthwhile as the originally proposed rule-based design has been replaced by a more efficient Bayesian adaptive design. While the outcome to be modelled, design details and evaluation criteria are trial specific, the principles behind their selection are general. This case study illustrates the steps required to establish a design in a novel context.
Johnston SL, Szigeti M, Cross M, et al., 2016, Azithromycin for Acute Exacerbations of Asthma The AZALEA Randomized Clinical Trial, JAMA INTERNAL MEDICINE, Vol: 176, Pages: 1630-1637
Gordon AC, Perkins GD, Singer M, et al., 2016, Levosimendan for the prevention of acute organ dysfunction in sepsis, New England Journal of Medicine, Vol: 375, Pages: 1638-1648, ISSN: 0028-4793
BACKGROUNDLevosimendan is a calcium-sensitizing drug with inotropic and other propertiesthat may improve outcomes in patients with sepsis.METHODSWe conducted a double-blind, randomized clinical trial to investigate whether levosimendanreduces the severity of organ dysfunction in adults with sepsis. Patientswere randomly assigned to receive a blinded infusion of levosimendan (at a dose of0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placeboin addition to standard care. The primary outcome was the mean daily SequentialOrgan Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scoresfor each of five systems range from 0 to 4, with higher scores indicating more severedysfunction; maximum score, 20). Secondary outcomes included 28-day mortality,time to weaning from mechanical ventilation, and adverse events.RESULTSThe trial recruited 516 patients; 259 were assigned to receive levosimendan and257 to receive placebo. There was no significant difference in the mean (±SD) SOFAscore between the levosimendan group and the placebo group (6.68±3.96 vs.6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29;P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9%in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendangroup were less likely than those in the placebo group to be successfullyweaned from mechanical ventilation over the period of 28 days (hazard ratio,0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group thanin the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolutedifference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04).CONCLUSIONSThe addition of levosimendan to standard treatment in adults with sepsis was notassociated with less severe organ dysfunction or lower mortality. Levosim
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
Bicknell CD, Kiru G, Falaschetti E, et al., 2016, An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: A randomised placebo controlled trial (AARDVARK), European Heart Journal, Vol: 37, Pages: 3213-3221, ISSN: 1522-9645
Aims The AARDVARK (Aortic Aneurysmal Regression of Dilation: Value of ACE-Inhibition on RisK) trial investigated whether ACE-inhibition reduces small abdominal aortic aneurysms (AAA) growth rate, independent of blood pressure (BP) lowering.Methods and results A three-arm, multi-centre, single-blind, and randomized controlled trial (ISRCTN51383267) was conducted in 14 hospitals in England. Subjects aged ≥55 years with AAA diameter 3.0–5.4 cm were randomized 1:1:1 to receive perindopril arginine 10 mg, or amlodipine 5 mg, or placebo and followed 3–6 monthly over 2 years. The primary outcome was aneurysm growth rate (based on external antero-posterior ultrasound measurements in the longitudinal plane), determined by multi-level modelling to provide maximum likelihood estimates. Two hundred and twenty-four subjects were randomized (2011–2013) to placebo (n = 79), perindopril (n = 73), or amlodipine (n = 72). Mean (SD) changes in mid-trial systolic BP (12 months) were 0.5 (14.3) mmHg, P = 0.78 compared with baseline, −9.5 (13.1) mmHg (P < 0.001), and −6.7 (12.0) mmHg (P < 0.001), respectively. No significant differences in the modelled annual growth rates were apparent [1.68 mm (SE 0.2), 1.77 mm (0.2), and 1.81 mm (0.2), respectively]. The estimated difference in annual growth between the perindopril and placebo groups was 0.08 mm (CI −0.50, 0.65). Similar numbers of AAAs in each group reached 5.5 cm diameter and/or underwent elective surgery: 11 receiving placebo, 10 perindopril, and 11 amlodipine.Conclusion Small AAA growth rates were lower than anticipated, but there was no significant impact of perindopril compared with placebo or placebo and amlodipine, combined despite more effective BP lowering.
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.
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