Publications
73 results found
Cornelius V, Cro S, Phillips R, 2020, Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials, Trials, Vol: 21, ISSN: 1745-6215
BackgroundRandomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data.MethodsIn this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata.Results/case studyVisualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors’ conclusion. In the Parkinson’s disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary.ConclusionsVisualisations can better support investigators to assimilate large volumes of data and ena
Phillips R, Cornelius V, Sauzet O, 2020, Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy, BMC Medical Research Methodology, Vol: 20, ISSN: 1471-2288
BackgroundStatistical methods for the analysis of harm outcomes in randomised controlled trials (RCTs) are rarely used, and there is a reliance on simple approaches to display information such as in frequency tables. We aimed to identify whether any statistical methods had been specifically developed to analyse prespecified secondary harm outcomes and non-specific emerging adverse events (AEs).MethodsA scoping review was undertaken to identify articles that proposed original methods or the original application of existing methods for the analysis of AEs that aimed to detect potential adverse drug reactions (ADRs) in phase II-IV parallel controlled group trials. Methods where harm outcomes were the (co)-primary outcome were excluded.Information was extracted on methodological characteristics such as: whether the method required the event to be prespecified or could be used to screen emerging events; and whether it was applied to individual events or the overall AE profile. Each statistical method was appraised and a taxonomy was developed for classification.ResultsForty-four eligible articles proposing 73 individual methods were included. A taxonomy was developed and articles were categorised as: visual summary methods (8 articles proposing 20 methods); hypothesis testing methods (11 articles proposing 16 methods); estimation methods (15 articles proposing 24 methods); or methods that provide decision-making probabilities (10 articles proposing 13 methods). Methods were further classified according to whether they required a prespecified event (9 articles proposing 12 methods), or could be applied to emerging events (35 articles proposing 61 methods); and if they were (group) sequential methods (10 articles proposing 12 methods) or methods to perform final/one analyses (34 articles proposing 61 methods).ConclusionsThis review highlighted that a broad range of methods exist for AE analysis. Immediate implementation of some of these could lead to improved inference for
Phillips R, Sauzet O, Cornelius V, 2020, Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy
<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background</jats:bold>Statistical methods for the analysis of harm outcomes in randomised controlled trials (RCTs) are rarely used, and there is a reliance on simple approaches to display information such as in frequency tables. We aimed to identify whether any statistical methods had been specifically developed to analyse prespecified secondary harm outcomes and non-specific emerging adverse events (AEs).<jats:bold>Methods</jats:bold>A scoping review was undertaken to identify articles that proposed original methods or the original application of existing methods for the analysis of AEs that aimed to detect potential adverse drug reactions (ADRs) in phase II-IV parallel controlled group trials. Methods where harm outcomes were the (co)-primary outcome were excluded.Information was extracted on methodological characteristics such as: whether the method required the event to be prespecified or could be used to screen emerging events; and whether it was applied to individual events or the overall AE profile. Each statistical method was appraised and a taxonomy was developed for classification.<jats:bold>Results</jats:bold>Forty-four eligible articles proposing 73 individual methods were included. A taxonomy was developed and articles were categorised as: visual summary methods (8 articles proposing 20 methods); hypothesis testing methods (11 articles proposing 16 methods); estimation methods (15 articles proposing 24 methods); or methods that provide decision-making probabilities (10 articles proposing 13 methods). Methods were further classified according to whether they required a prespecified event (9 articles proposing 12 methods), or could be applied to emerging events (35 articles proposing 61 methods); and if they were (group) sequential methods (10 articles proposing 12 methods) or methods to perform final/one analyses (34 articles proposing 61 met
Phillips R, Sauzet O, Cornelius V, 2020, Statistical methods for the analysis of adverse event data in randomised controlled trials: a comprehensive review and taxonomy, Publisher: Research Square
<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background </jats:bold>Statistical methods for the analysis of harm outcomes in randomised controlled trials (RCTs) are rarely used, and there is a reliance on simple approaches to display information such as in frequency tables. We aimed to identify whether any statistical methods had been specifically developed to analyse prespecified secondary harm outcomes and non-specific emerging adverse events (AEs).<jats:bold> </jats:bold><jats:bold>Methods </jats:bold>A scoping review was undertaken to identify articles that proposed original methods or the original application of existing methods for the analysis of AEs that aimed to detect potential adverse drug reactions (ADRs) in phase II-IV parallel controlled group trials. Methods where harm outcomes were the (co)-primary outcome were excluded. Information was extracted on methodological characteristics such as: whether the method required the event to be prespecified or could be used to screen emerging events; and whether it was applied to individual events or aggregate events. Each statistical method was appraised and a taxonomy was developed for classification.<jats:bold>Results </jats:bold>Forty-four eligible articles proposing 73 individual methods were included. A taxonomy was developed and articles were categorised as: visual summary methods (8 articles proposing 20 methods); hypothesis testing methods (11 articles proposing 16 methods); estimation methods (15 articles proposing 24 methods); or methods that provide decision-making probabilities (10 articles proposing 13 methods). Methods were further classified according to whether they required a prespecified event (9 articles proposing 12 methods), or could be applied to emerging events (35 articles proposing 61 methods); and if they were (group) sequential methods (10 articles proposing 12 methods) or methods to perform final/one anal
Molton JS, Chan M, Kalimuddin S, et al., 2020, Oral vs intravenous antibiotics for patients with klebsiella pneumoniae liver abscess: A randomized, controlled noninferiority study, Clinical Infectious Diseases, Vol: 71, Pages: 952-959, ISSN: 1058-4838
BackgroundKlebsiella pneumoniae liver abscess (KLA) is emerging worldwide due to hypermucoviscous strains with a propensity for metastatic infection. Treatment includes drainage and prolonged intravenous antibiotics. We aimed to determine whether oral antibiotics were noninferior to continued intravenous antibiotics for KLA.MethodsThis noninferiority, parallel group, randomized, clinical trial recruited hospitalized adults with liver abscess and K. pneumoniae isolated from blood or abscess fluid who had received ≤7 days of effective antibiotics at 3 sites in Singapore. Patients were randomized 1:1 to oral (ciprofloxacin) or intravenous (ceftriaxone) antibiotics for 28 days. If day 28 clinical response criteria were not met, further oral antibiotics were prescribed until clinical response was met. The primary endpoint was clinical cure assessed at week 12 and included a composite of absence of fever in the preceding week, C-reactive protein <20 mg/L, and reduction in abscess size. A noninferiority margin of 12% was used.ResultsBetween November 2013 and October 2017, 152 patients (mean age, 58.7 years; 25.7% women) were recruited, following a median 5 days of effective intravenous antibiotics. A total of 106 (69.7%) underwent abscess drainage; 71/74 (95.9%) randomized to oral antibiotics met the primary endpoint compared with 72/78 (92.3%) randomized to intravenous antibiotics (risk difference, 3.6%; 2-sided 95% confidence interval, −4.9% to 12.8%). Effects were consistent in the per-protocol population. Nonfatal serious adverse events occurred in 12/72 (16.7%) in the oral group and 13/77 (16.9%) in the intravenous group.ConclusionsOral antibiotics were noninferior to intravenous antibiotics for the early treatment of KLA.
Fleming C, Drennan VM, Kerry-Barnard S, et al., 2020, Understanding the acceptability, barriers and facilitators for chlamydia and gonorrhoea screening in technical colleges: qualitative process evaluation of the "Test n Treat" trial., BMC Public Health, Vol: 20, ISSN: 1471-2458
BACKGROUND: Low uptake of sexually transmitted infection testing by sexually active young people is a worldwide public health problem. Screening in non-medical settings has been suggested as a method to improve uptake. The "Test n Treat" feasibility trial offered free, on-site rapid chlamydia/gonorrhoea tests with same day treatment for chlamydia (and gonorrhoea treatment at a local clinic,) to sexually active students (median age 17 years) at six technical colleges in London. Despite high rates of chlamydia (6% prevalence), uptake of testing was low (< 15%). In a qualitative study we explored the acceptability, including barriers and facilitators to uptake, of on-site chlamydia screening. METHODS: In 2016-17 we conducted a qualitative study in the interpretative tradition using face to face or telephone semi-structured interviews with students (n = 26), teaching staff (n = 3) and field researchers (n = 4). Interviews were digitally recorded, transcribed and thematically analysed. RESULTS: From the student perspective, feelings of embarrassment and the potential for stigma were deterrents to sexually transmitted infection testing. While the non-medical setting was viewed as mitigating against stigma, for some students volunteering to be screened exposed them to detrimental judgements by their peers. A small financial incentive to be screened was regarded as legitimising volunteering in a non-discrediting way. Staff and researchers confirmed these views. The very low level of knowledge about sexually transmitted infections influenced students to not view themselves as candidates for testing. There were also suggestions that some teenagers considered themselves invulnerable to sexually transmitted infections despite engaging in risky sexual behaviours. Students and researchers reported the strong influence peers had on uptake, or not, of sexually transmitted infection testing. CONCLUSIONS: This study
Phillips R, Cornelius V, 2020, Understanding current practice, identifying barriers and exploring priorities for Adverse Event analysis in Randomised Controlled Trials: an online, cross-sectional survey of statisticians from academia and industry, BMJ Open, Vol: 10, ISSN: 2044-6055
Objectives To gain a better understanding of current adverse event (AE) analysis practices and the reasons for the lack of use of sophisticated statistical methods for AE data analysis in randomised controlled trials (RCTs), with the aim of identifying priorities and solutions to improve practice.Design A cross-sectional, online survey of statisticians working in clinical trials, followed up with a workshop of senior statisticians working across the UK.Participants We aimed to recruit into the survey a minimum of one statistician from each of the 51 UK Clinical Research Collaboration registered clinical trial units (CTUs) and industry statisticians from both pharmaceuticals and clinical research organisations.Outcomes To gain a better understanding of current AE analysis practices, measure awareness of specialist methods for AE analysis and explore priorities, concerns and barriers when analysing AEs.Results Thirty-eight (38/51; 75%) CTUs, 5 (5/7; 71%) industry and 21 attendees at the 2019 Promoting Statistical Insights Conference participated in the survey. Of the 64 participants that took part, 46 participants were classified as public sector participants and 18 as industry participants. Participants indicated that they predominantly (80%) rely on subjective comparisons when comparing AEs between treatment groups. Thirty-eight per cent were aware of specialist methods for AE analysis, but only 13% had undertaken such analyses. All participants believed guidance on appropriate AE analysis and 97% thought training specifically for AE analysis is needed. These were both endorsed as solutions by workshop participants.Conclusions This research supports our earlier work that identified suboptimal AE analysis practices in RCTs and confirms the underuse of more sophisticated AE analysis approaches. Improvements are needed, and further research in this area is required to identify appropriate statistical methods. This research provides a unanimous call for the development
Phillips R, Cornelius V, Sauzet O, 2019, Opportunities and experiences of accessing pharmaceutical individual patient data for statistical research, 5th International Clinical Trials Methodology Conference, Publisher: BMC
Phillips R, Cornelius V, Sauzet O, 2019, An evaluation and application of statistical methods designed to analyse adverse event data in RCTs, 5th International Clinical Trials Methodology Conference, Publisher: BMC
Phillips R, Cornelius V, Cro S, et al., 2019, The use of visual analytics for clinical trial safety outcomes: a methodological review, 5th International Clinical Trials Methodology Conference, Publisher: BMC
Oakeshott P, Kerry-Barnard S, Fleming C, et al., 2019, 'Test n Treat' (TnT): a cluster randomized feasibility trial of on-site rapid Chlamydia trachomatis tests and treatment in ethnically diverse, sexually active teenagers attending technical colleges, Clinical Microbiology and Infection, Vol: 25, Pages: 865-871, ISSN: 1198-743X
OBJECTIVES: We conducted a cluster-randomized feasibility trial of 90-minute Chlamydia trachomatis tests and same day on-site treatment ('Test n Treat/TnT') in six technical colleges in London, England, to assess TnT uptake rates; follow-up rates; prevalence of C. trachomatis at baseline and 7 months; time to treatment; acceptability of TnT. METHODS: Participants completed questionnaires and provided genitourinary samples at baseline and 7 months. Participants were informed that baseline samples would not be tested for 7 months and were advised to get screened independently. Colleges were randomly allocated 1:1 to intervention (TnT) or control (no TnT). One month and 4 months post recruitment, participants at intervention colleges were texted invitations for on-site free C. trachomatis tests. A purposive sample of students who did/did not attend for screening were interviewed (n = 26). RESULTS: Five hundred and nine sexually active students were recruited: median age 17.9 years, 47% male, 50% black ethnicity, 55% reporting two or more sexual partners in the previous year. TnT uptake was 13% (33/259; 95% CI 8.9-17.4%) at 1 month and 10% (26/259; 6.7-14.4%) at 4 months with overall C. trachomatis positivity 5.1% (3/59; 1.1-14.2%). Follow-up at 7 months was 62% (317/509) for questionnaires and 52% (264/509) for samples. C. trachomatis prevalence was 6.2% (31/503) at baseline and 6.1% (16/264) at 7 months. Median time from test to treatment was 15 h. Interviews suggested low test uptake was associated with not feeling at risk, perceptions of stigma, and little knowledge of sexually transmitted infections (STIs). CONCLUSIONS: Despite high C. trachomatis rates at baseline and follow-up, uptake of testing was low. Like many countries, England urgently needs better sex education, including making STI testing routine/normal. Trial registration ISRCTN58038795.
Lwin SM, Syed F, Di W-L, et al., 2019, Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa, JCI insight, Vol: 4, Pages: 1-19, ISSN: 2379-3708
BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation.METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin.RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected.CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation.
Phillips R, Hazell L, Sauzet O, et al., 2019, Analysis and reporting of adverse events in randomised controlled trials: a review, BMJ Open, Vol: 9, ISSN: 2044-6055
ObjectiveTo ascertain contemporaryapproaches to the collection, reporting and analysis of adverse events (AEs)inrandomised controlled trials(RCTs)with a primary efficacy outcome.DesignA reviewof clinical trials of drug interventions from four high impactmedical journals.Data sourcesElectronic contents table of the BMJ, the Journal of the American Medical Association, the Lancet,andthe New England Journal of Medicine were searchedfor reports of original RCTs published between September 2015 and September 2016.MethodsA pre-piloted checklist was used and single data extraction was performed by three reviewers with independent check of a randomly sampled subset to verify quality. We extracted data on collection methods, assessment of severity and causality, reporting criteria, analysis methods and presentation of AE data.ResultsWe identified 184 eligible reports (BMJ n=3; JAMA n=38, Lancet n=62; and NEJM n=81).Sixty-two percent reported some form of spontaneous AE collection but only 29% included details of specific prompts used to ascertain AE data. Numbers that withdrew from the trial were well reported (80%), however only 35% of these reported whether withdrawals were due toAEs.Results presented and analysis performed was predominantly on ‘patients with at least 1event’ with 84% of studies ignoring repeated events. Despite a lack of power to undertake formal hypothesis testing, 47% performed such tests for binary outcomes. ConclusionsThis review highlighted that the collection, reporting and analysis of AE data in clinical trials is inconsistent and RCTs as a source of safety data are underutilised. Areas to improve include reducing information loss when analysing at patient level and inappropriate practice of underpowered multiple hypothesis testing. Implementation of standard reporting practices could enable a more accurate synthesis of safety data and development of guidance for statistical methodology to assesscausality ofAEs could facilitate better s
Karyotaki E, Kemmeren L, Riper H, et al., 2018, Is self-guided internet-based cognitive behavioural therapy (iCBT) harmful? An individual participant data meta-analysis, Psychological Medicine, Vol: 48, Pages: 2456-2466, ISSN: 0033-2917
Background: Little is known about potential harmful effects as a consequence of self-guided internet-based cognitive behaviour therapy (iCBT), such as symptom deterioration rates. Thus, safety concerns remain and hamper the implementation of self-guided iCBT into clinical practice. We aimed to conduct an individual participant data (IPD) meta-analysis to determine the prevalence of clinically significant deterioration (symptom worsening) in adults with depressive symptoms who received self-guided iCBT compared with control conditions. Several socio-demographic, clinical and study-level variables were tested as potential moderators of deterioration. Methods: Randomised controlled trials that reported results of self-guided iCBT compared with control conditions in adults with symptoms of depression were selected. Mixed effects models with participants nested within studies were used to examine possible clinically significant deterioration rates. Results: Thirteen out of 16 eligible trials were included in the present IPD meta-analysis. Of the 3805 participants analysed, 7.2% showed clinically significant deterioration (5.8% and 9.1% of participants in the intervention and control groups, respectively). Participants in self-guided iCBT were less likely to deteriorate (OR 0.62, p < 0.001) compared with control conditions. None of the examined participant- and study-level moderators were significantly associated with deterioration rates. Conclusions: Self-guided iCBT has a lower rate of negative outcomes on symptoms than control conditions and could be a first step treatment approach for adult depression as well as an alternative to watchful waiting in general practice.
Kerry-Barnard S, Fleming C, Reid F, et al., 2018, 'Test n Treat (TnT)'- Rapid testing and same-day, on-site treatment to reduce rates of chlamydia in sexually active further education college students: study protocol for a cluster randomised feasibility trial, Trials, Vol: 19, ISSN: 1745-6215
BACKGROUND: Sexually active young people attending London further education (FE) colleges have high rates of chlamydia, but screening rates are low. We will conduct a cluster randomised feasibility trial of frequent, rapid, on-site chlamydia testing and same-day treatment (Test and Treat (TnT)) in six FE colleges (with parallel qualitative and economic assessments) to assess the feasibility of conducting a future trial to investigate if TnT reduces chlamydia rates. METHODS: We will recruit 80 sexually active students aged 16-24 years from public areas at each of six colleges. All participants (total n = 480) will be asked to provide samples (urine for males, self-taken vaginal swabs for females) and complete questionnaires on sexual lifestyle and healthcare use at baseline and after 7 months. Participants will be informed that baseline samples will not be tested for 7 months and be advised to get screened separately. Colleges will be randomly allocated to the intervention (TnT) or the control group (no TnT). One and 4 months after recruitment, participants at each intervention college (n = 3) will be texted and invited for on-site chlamydia tests using the 90-min Cepheid GeneXpert system. Students with positive results will be asked to see a visiting nurse health adviser for same-day treatment and partner notification, (backed by genitourinary medicine follow-up). Participants in control colleges (n = 3) will receive 'thank you' texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to students with positive results. Acceptability of TnT will be assessed by qualitative interviews of purposively sampled students (n = 30) and college staff (n = 12). We will collect data on costs of TnT and usual healthcare. DISCUSSION: Findi
Phillips R, Oakeshott P, Kerry-Barnard S, et al., 2018, 'Test n Treat (TnT)': a cluster-randomised feasibility trial of frequent, rapid-testing and same-day, on-site treatment to reduce rates of chlamydia in high-risk further education college students: statistical analysis plan, Trials, Vol: 19, ISSN: 1745-6215
BackgroundThere are high rates of sexually transmitted infections (STIs) in ethnically diverse, sexually active students aged 16–24 years attending London further education (FE) colleges. However, uptake of chlamydia screening remains low. The TnT study aims to assess the feasibility of conducting a future trial in FE colleges to investigate if frequent, rapid, on-site testing and treatment (TnT) reduces chlamydia rates. This article presents the statistical analysis plan for the main study publication as approved and signed off by the Trial Management Group prior to the first data extraction for the final report.Methods/designTnT is a cluster-randomised feasibility trial conducted over 7 months with parallel qualitative and economic assessments. Colleges will be randomly allocated into the intervention (TnT) or the control group (no TnT). Six FE colleges in London will be included. At each college for 2 days, 80 consecutive sexually active students aged 16–24 years (total 480 students across all six colleges) will be recruited from public areas and asked to provide baseline samples. One and 4 months after recruitment intervention colleges will be visited on two consecutive days by the TnT team where participating students will be texted and invited to come for same-day, on-site, rapid chlamydia testing and, if positive, treatment. Participants in the control colleges will receive ‘thank you’ texts 1 and 4 months after recruitment. Seven months after recruitment, participants from both groups will be invited to complete questionnaires and provide samples for TnT. All samples will be tested, and same-day treatment offered to participants with positive results. Key feasibility outcomes include: recruitment rates, testing and treatment uptake rates (at 1 and 4 months) and follow-up rates (at 7 months).
Kalimuddin S, Chan YFZ, Phillips R, et al., 2018, A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations - results of a prematurely terminated study, Trials, Vol: 19, ISSN: 1745-6215
BACKGROUND: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations. METHODS: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60. RESULTS: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3-5 days in the vancomycin arm and 3-7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in both arms. There was one case of musculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection. CONCLUSION: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01975662 . Registered on 5 November 2013.
Tham LP, Wah W, Phillips R, et al., 2018, Epidemiology and outcome of paediatric out-of-hospital cardiac arrests: A paediatric sub-study of the Pan-Asian resuscitation outcomes study (PAROS), Resuscitation, Vol: 125, Pages: 111-117, ISSN: 0300-9572
Background: The Pan Asian Resuscitation Outcomes Study (PAROS) is a retrospective study of out- of-hospital cardiac arrest(OHCA), collaborating with EMS agencies and academic centers in Japan, South Korea, Malaysia, Singapore, Taiwan, Thailand and UAE-Dubai. The objectives of this study is to describe the characteristics and outcomes, and to find factors associated with survival after paediatric OHCA. Methods: We studied all children less than 17 years of age with OHCA conveyed by EMS and non-EMS transports from January 2009 to December 2012. We did univariate and multivariate logistic regression analyses to assess the factors associated with survival-to-discharge outcomes. Results: A total of 974 children with OHCA were included. Bystander cardiopulmonary resuscitation rates ranged from 53.5% (Korea), 35.6% (Singapore) to 11.8% (UAE). Overall, 8.6% (range 0%–9.7%) of the children survived to discharge from hospital. Adolescents (13–17 years) had the highest survival rate of 13.8%. 3.7% of the children survived with good neurological outcomes of CPC 1 or 2. The independent pre-hospital factors associated with survival to discharge were witnessed arrest and initial shockable rhythm. In the sub-group analysis, pre-hospital advanced airway [odds ratio (OR) = 3.35, 95% confidence interval (CI) = 1.23–9.13] was positively associated with survival-to-discharge outcomes in children less than 13 years-old. Among adolescents, bystander CPR (OR = 2.74, 95%CI = 1.03–7.3) and initial shockable rhythm (OR = 20.51, 95%CI = 2.15–195.7) were positive factors. Conclusion: The wide variation in the survival outcomes amongst the seven countries in our study may be due to the differences in the delivery of pre-hospital interventions and bystander CPR rates.
Tey VHS, Phillips R, Tan K, 2017, Patient-related outcome measures with implant therapy after 5 years, Clinical Oral Implants Research, Vol: 28, Pages: 683-688, ISSN: 0905-7161
ObjectiveTo analyze patients’ perception of implant therapy in partial edentulism, after 5 years with implant‐supported reconstructions.Material and methodsPatients who received dental implants at the National Dental Centre, Singapore 3–9 years earlier (mean: 5.2 years) were invited to participate in the study. Responders were examined clinically, and asked to answer a questionnaire with 13 statements.ResultsOf the 880 patients, 206 patients, with 329 implants, agreed to participate. Of the implants, 82% supported single crowns, while 18% were reconstructed with splinted crowns or fixed dental prostheses. Function and chewing comfort yielded high patient satisfaction. Comparing chewing comfort for teeth and implants, respectively, 51% perceived no difference between the two. Patients were largely satisfied with the phonetic function and esthetic outcome. Only two in three patients were able to cleanse the implant reconstruction well, and majority of the patients reported no difference comparing the time taken to clean implants and teeth. Patients were generally unsure if the tissues around their implants or teeth bled more. Pertaining to expectations, most patients were satisfied with the treatment, and majority were willing to undergo the same treatment again. Most patients would recommend such treatment to friends, if indicated. Only slightly over one‐third of the patients felt certain that the cost of the treatment was justified.ConclusionThe large majority was satisfied with the functional outcomes of implant treatment. However, the patients had a less than ideal understanding of gingival health around teeth and implants. Patients were less discerning than clinicians in the assessment of esthetic outcomes.
Phillips R, Cornelius V, 2017, Lessons to learn from the reporting of adverse events (AEs) in randomised controlled trials published in high impact journals, The 4th International Clinical Trials Methodology Conference, Publisher: BioMed Central, ISSN: 1745-6215
Phillips R, Cornelius V, 2017, Overview of statistical methods to monitor harms during the conduct of a randomised controlled trial, The 4th International Clinical Trials Methodology Conference., Publisher: BioMed Central, ISSN: 1745-6215
Tey VHS, Phillips R, Tan K, 2017, Five-year retrospective study on success, survival and incidence of complications of single crowns supported by dental implants, CLINICAL ORAL IMPLANTS RESEARCH, Vol: 28, Pages: 620-625, ISSN: 0905-7161
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Karyotaki E, Riper H, Twisk J, et al., 2017, Efficacy of Self-guided Internet-Based Cognitive Behavioral Therapy in the Treatment of Depressive Symptoms A Meta-analysis of Individual Participant Data, JAMA PSYCHIATRY, Vol: 74, Pages: 351-359, ISSN: 2168-622X
Lo JW, Bunce C, Charteris D, et al., 2016, A phase III, multi-centre, double-masked randomised controlled trial of adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): statistical analysis plan., Trials, Vol: 17, ISSN: 1745-6215
BACKGROUND: Open globe ocular trauma complicated by intraocular scarring (proliferative vitreoretinopathy) is a relatively rare, blinding, but potentially treatable condition for which, at present, surgery is often unsatisfactory and visual results frequently poor. To date, no pharmacological adjuncts to surgery have been proven to be effective. The aim of the Adjunctive Steroid Combination in Ocular Trauma (ASCOT) randomised controlled trial is to determine whether adjunctive steroid (triamcinolone acetonide), given at the time of surgery, can improve the outcome of vitreoretinal surgery in patients with open globe ocular trauma. This article presents the statistical analysis plan for the main publication as approved and signed off by the Trial Steering Committee prior to the first data extraction for the Data Monitoring Committee meeting report. METHODS/DESIGN: ASCOT is a pragmatic, multi-centre, parallel-group, double-masked randomised controlled trial. The aim of the study is to recruit from 20-25 centres in the United Kingdom and randomise 300 eyes (from 300 patients) into two treatment arms. Both groups will receive standard surgical treatment and care; the intervention arm will additionally receive a pre-operative steroid combination (triamcinolone acetonide) into the vitreous cavity consisting of 4 mg/0.1 ml and 40 mg/1 ml sub-Tenon's. Participants will be followed for 6 months post-surgery. The primary outcome is the proportion of patients achieving a clinically meaning improvement in visual acuity in the study eye at 6 months after initial surgery, defined as a 10 letter score improvement in the ETDRS (the standard scale to test visual acuity). TRIAL REGISTRATION: ISRCTN30012492 . Registered on 5 September 2014. EudraCT2014-002193-37 . Registered on 5 September 2014.
Banerjee PJ, Cornelius VR, Phillips R, et al., 2016, Adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): study protocol for a phase III, multi-centre, double-masked randomised controlled trial, Trials, Vol: 17, ISSN: 1745-6215
BACKGROUND: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Ocular injuries which result in visual loss invariably affect the posterior segment of the eye, and prevention of visual loss involves posterior segment (vitreoretinal) surgery. Despite improvements in vitreoretinal surgical techniques, outcomes in these patients remain unsatisfactory, and development of the intraocular scarring response proliferative vitreoretinopathy is the leading cause. Proliferative vitreoretinopathy is the most common cause of recurrent retinal detachment in these eyes; it is reported to occur in up to 45 % of cases. METHODS/DESIGN: The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a multi-centre, double-masked, parallel-arm randomised controlled trial with an internal pilot designed to investigate the effectiveness and cost-effectiveness of using intravitreal and sub-Tenon's triamcinolone acetonide peri-operatively in patients undergoing vitrectomy following open globe trauma. In total, 300 eyes of 300 patients will be recruited and randomly allocated to one of two treatment groups. Both groups will receive standard surgical treatment and routine pre-operative and post-operative treatment and care. The treatment group will receive an adjunctive peri-operative steroid combination (triamcinolone acetonide) consisting of 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml into the sub-Tenon's space. The trial incorporates a two-stage internal pilot to examine projected recruitment and retention rates. Progression criteria from the internal pilot study will enable us to determine whether to undertake the main trial. Patients and primary outcome assessors will be masked to treatment allocation. The primary outcome will be an improvement from baseline to 6 months of at least 10 on the corrected visual acuity as measured by ETDRS letter score. Secondary outcomes will be development of scarring, retinal detachme
Phillips R, Cheung YB, Collinson SL, et al., 2015, The Equivalence and Difference between the English and Chinese Language Versions of the Repeatable Battery for the Assessment of Neuropsychological Status, CLINICAL NEUROPSYCHOLOGIST, Vol: 29, Pages: 1-18, ISSN: 1385-4046
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- Citations: 10
Lim HCS, Salandanan EA, Phillips R, et al., 2015, Inter-rater reliability of J-point location and measurement of the magnitude of ST segment elevation at the J-point on ECGs of STEMI patients by emergency department doctors, EMERGENCY MEDICINE JOURNAL, Vol: 32, Pages: 809-+, ISSN: 1472-0205
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- Citations: 4
Phillips R, Gandhi M, Cheung YB, et al., 2015, Summary scores captured changes in subjects' QoL as measured by the multiple scales of the EORTC QLQ-C30, JOURNAL OF CLINICAL EPIDEMIOLOGY, Vol: 68, Pages: 895-902, ISSN: 0895-4356
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- Citations: 21
Lee T-S, Quek SY, Goh SJA, et al., 2015, A pilot randomized controlled trial using EEG-based brain-computer interface training for a Chinese-speaking group of healthy elderly, Clinical Interventions in Aging, Vol: 10, Pages: 217-227, ISSN: 1176-9092
Background: There is growing evidence that cognitive training (CT) can improve the cognitive functioning of the elderly. CT may be influenced by cultural and linguistic factors, but research examining CT programs has mostly been conducted on Western populations. We have developed an innovative electroencephalography (EEG)-based brain–computer interface (BCI) CT program that has shown preliminary efficacy in improving cognition in 32 healthy English-speaking elderly adults in Singapore. In this second pilot trial, we examine the acceptability, safety, and preliminary efficacy of our BCI CT program in healthy Chinese-speaking Singaporean elderly.Methods: Thirty-nine elderly participants were randomized into intervention (n=21) and waitlist control (n=18) arms. Intervention consisted of 24 half-hour sessions with our BCI-based CT training system to be completed in 8 weeks; the control arm received the same intervention after an initial 8-week waiting period. At the end of the training, a usability and acceptability questionnaire was administered. Efficacy was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was translated and culturally adapted for the Chinese-speaking local population. Users were asked about any adverse events experienced after each session as a safety measure.Results: The training was deemed easily usable and acceptable by senior users. The median difference in the change scores pre- and post-training of the modified RBANS total score was 8.0 (95% confidence interval [CI]: 0.0–16.0, P=0.042) higher in the intervention arm than waitlist control, while the mean difference was 9.0 (95% CI: 1.7–16.2, P=0.017). Ten (30.3%) participants reported a total of 16 adverse events – all of which were graded “mild” except for one graded “moderate”.Conclusion: Our BCI training system shows potential in improving cognition in both English- and Chinese-speaking elderly
Phillips R, Qi G, Collinson SL, et al., 2015, The Minimum Clinically Important Difference in the Repeatable Battery for the Assessment of Neuropsychological Status, CLINICAL NEUROPSYCHOLOGIST, Vol: 29, Pages: 905-923, ISSN: 1385-4046
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- Citations: 18
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