Publications
217 results found
Perkin MR, Ussher M, Goldsmith LP, et al., 2024, BabyBathe study protocol: A randomised controlled feasibility trial to change baby bathing practice during the first months of life., Clin Exp Allergy
Kawano-Dourado L, Kulkarni T, Ryerson CJ, et al., 2024, Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases, Thorax, Pages: 1-8, ISSN: 0040-6376
BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.
Goldsmith LP, Perkin MR, Wahlich C, et al., 2024, Development of an intervention for reducing infant bathing frequency, PLoS One, Vol: 19, Pages: e0298335-e0298335, ISSN: 1932-6203
BACKGROUND: Bathing babies less frequently and intensively in the first six months of life may prevent eczema, but this has not yet been definitively tested in a randomised controlled trial. Such a trial would require evidence-based support to help parents engage with a minimal bathing routine. The present study reports the development of this support. METHODS: We adopted a four-stage design process: (i) Pregnant women and their families (n = 31) were interviewed to ascertain key barriers and facilitators towards following the minimal bathing intervention. (ii) These barriers and facilitators were mapped to behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, alongside appropriate modes of delivery, and prototype intervention materials were developed. (iii) We iteratively refined these materials in a workshop with multidisciplinary experts and Patient and Public Involvement and Engagement (PPIE) representatives (n = 13) and an (iv) intervention walkthrough with families (n = 5). The design process was informed by the Behaviour Change Wheel, Theoretical framework of acceptability and the Template for intervention description and replication. RESULTS: Social influences and motivational factors are likely to influence both uptake and adherence to the intervention. Anticipated emotional reward from participating in research for the benefit of others was indicated to be a strong facilitator for intervention uptake. Alternatives to bathing, having fun with the baby and the night-time routine, alongside family support, were notable facilitators suggested to aid adherence to the intervention. Barriers included hygiene concerns and anticipated negative social appraisal. Barriers and facilitators were mapped to thirty-six behaviour change techniques, focussing on the intervention types of education, persuasion and environmental restructuring, all of which were embedded into the package of support. The proto
Sanfilippo KRM, Glover V, Cornelius V, et al., 2024, Expression of antenatal symptoms of common mental disorders in The Gambia and the UK: a cross-sectional comparison study, BMJ Open, Vol: 13, ISSN: 2044-6055
Objectives It is important to be able to detect symptoms of common mental disorders (CMDs) in pregnant women. However, the expression of these disorders can differ across cultures and depend on the specific scale used. This study aimed to (a) compare Gambian pregnant women’s responses to the Edinburgh Postnatal Depression Scale (EPDS) and Self-reporting Questionnaire (SRQ-20) and (b) compare responses to the EPDS in pregnant women in The Gambia and UK.Design This cross-sectional comparison study investigates Gambian EPDS and SRQ-20 scores through correlation between the two scales, score distributions, proportion of women with high levels of symptoms, and descriptive item analysis. Comparisons between the UK and Gambian EPDS scores were made by investigating score distributions, proportion of women with high levels of symptoms, and descriptive item analysis.Setting This study took place in The Gambia, West Africa and London, UK.Participants 221 pregnant women from The Gambia completed both the SRQ-20 and the EPDS; 368 pregnant women from the UK completed the EPDS.Results Gambian participants’ EPDS and SRQ-20 scores were significantly moderately correlated (rs=0.6, p<0.001), had different distributions, 54% overall agreement, and different proportions of women identified as having high levels of symptoms (SRQ-20=42% vs EPDS=5% using highest cut-off score). UK participants had higher EPDS scores (M=6.5, 95% CI (6.1 to 6.9)) than Gambian participants (M=4.4, 95% CI (3.9 to 4.9)) (p<0.001, 95% CIs (−3.0 to –1.0), Cliff’s delta = −0.3).Conclusions The differences in scores from Gambian pregnant women to the EPDS and SRQ-20 and the different EPDS responses between pregnant women in the UK and The Gambia further emphasise how methods and understanding around measuring perinatal mental health symptoms developed in Western countries need to be applied with care in other cultures.
Casswell EJ, Cro S, Cornelius VR, et al., 2024, Randomised controlled trial of adjunctive triamcinolone acetonide in eyes undergoing vitreoretinal surgery following open globe trauma: the ASCOT study, British Journal of Ophthalmology, Vol: 108, Pages: 440-448, ISSN: 0007-1161
BACKGROUND/AIMS: To investigate the clinical effectiveness of adjunctive triamcinolone acetonide (TA) given at the time of vitreoretinal surgery following open globe trauma (OGT). METHODS: A phase 3, multicentre, double-masked randomised controlled trial of patients undergoing vitrectomy following OGT comparing adjunctive TA (intravitreal and subtenons) against standard care (2014-2020). The primary outcome was the proportion of patients with at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter improvement in corrected visual acuity (VA) at 6 months. Secondary outcomes included: change in ETDRS, retinal detachment (RD) secondary to PVR, retinal reattachment, macular reattachment, tractional RD, number of operations, hypotony, elevated intraocular pressure and quality of life. RESULTS: 280 patients were randomised over 75 months, of which 259 completed the study. 46.9% (n=61/130) of patients in the treatment group had a 10-letter improvement in VA compared with 43.4% (n=56/129) of the control group (difference 3.5% (95% CI -8.6% to 15.6%), OR=1.03 (95% CI 0.61 to 1.75), p=0.908)). Secondary outcome measures also failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal and macular reattachment, outcomes were worse in the treatment group compared with controls, respectively, 51.6% (n=65/126) vs 64.2% (n=79/123), OR=0.59 (95% CI 0.36 to 0.99), and 54.0% (n=68/126) vs 66.7% (n=82/123), OR=0.59 (95% CI 0.35 to 0.98), for TA vs control. CONCLUSION: The use of combined intraocular and sub-Tenons capsule TA is not recommended as an adjunct to vitrectomy surgery following OGT. TRIAL REGISTRATION NUMBER: NCT02873026.
Li W, Cornelius V, Finfer S, et al., 2023, Adaptive designs in critical care trials: a simulation study, BMC Medical Research Methodology, Vol: 23, ISSN: 1471-2288
BACKGROUND: Adaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation. METHODS: Using two large critical care trials (ADRENAL. CLINICALTRIALS: gov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR. CLINICALTRIALS: gov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05. RESULTS: Across all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O'Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became i
Kanagaratnam P, Francis DP, Chamie D, et al., 2023, A randomised controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalised with COVID-19: the C19-ACS trial, Journal of Thrombosis and Haemostasis, Vol: 21, Pages: 2213-2222, ISSN: 1538-7836
BACKGROUND: Patients hospitalised with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. OBJECTIVES: To investigate efficacy of an acute coronary syndrome regimen in patients hospitalised with COVID-19 and coronary disease risk factors. PATIENTS/METHODS: A randomised controlled open-label trial across acute hospitals (UK and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28-days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, death). RESULTS: 320 patients from 9 centres were randomised. The trial terminated early due to low recruitment. At 30 days there was no significant difference in mortality (intervention: 11.5% vs control: 15%, unadjusted OR 0.73, 95%CI 0.38 to 1.41, p=0.355). Significant bleeds were infrequent and not significantly different between the arms (intervention: 1.9% vs control 1.9%, p>0.999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR 1.46, 95% CrI 0.88 to 2.37, Pr(Beta>0)=93%; adjusted OR 1.50, 95% CrI 0.91 to 2.45, Pr(Beta>0)=95%) and median time to discharge home was two days shorter (95% CrI -4 to 0, 2% probability that it was worse). CONCLUSIONS: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.
Charteris DG, Cro S, Casswell E, et al., 2023, A randomised controlled trial of adjunctive triamcinolone acetonide in eyes undergoing vitreoretinal surgery for open globe trauma – the ASCOT study, Health Technology Assessment, Vol: 27, Pages: 1-50, ISSN: 1366-5278
Background: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Proliferative vitreoretinopathy is the most common cause of retinal detachment and visual loss in eyes with open globe trauma. There is evidence from experimental studies and pilot clinical trials that the use of adjunctive steroid medication triamcinolone acetonide can reduce the incidence of proliferative vitreoretinopathy and improve outcomes of surgery for open globe trauma. Objective: The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study aimed to investigate the clinical effectiveness of adjunctive triamcinolone acetonide given at the time of vitreoretinal surgery for open globe trauma. Design: A phase 3 multicentre double-masked randomised controlled trial randomising patients undergoing vitrectomy following open globe trauma to either adjunctive triamcinolone acetonide or standard care. Setting: Hospital vitreoretinal surgical services dealing with open globe trauma. Participants: Patients undergoing vitrectomy surgery who had sustained open globe trauma. Interventions: Triamcinolone acetonide 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s or standard vitreoretinal surgery and postoperative care. Main outcome measures: The primary outcome was the proportion of patients with at least 10 letters of improvement in corrected visual acuity at six months. Secondary outcomes included retinal detachment secondary to proliferative vitreoretinopathy, retinal reattachment, macula reattachment, tractional retinal detachment, number of operations, hypotony, elevated intraocular pressure and quality of life. Health-related quality of life was assessed using the EuroQol Five Domain and Visual Function Questionnaire 25 questionnaires.Results: A total of 280 patients were randomised; 129 were analysed from the control group and 130 from the treatment group. The treatment group appeared, by chance, to have more severe pathology on presentation. The pr
Liu X, Munro APS, Wright A, et al., 2023, Persistence of immune responses after heterologous and homologous third COVID-19 vaccine dose schedules in the UK: eight-month analyses of the COV-BOOST trial, Journal of Infection, Vol: 87, Pages: 18-26, ISSN: 0163-4453
BACKGROUND: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms. METHODS: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation. RESULTS: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26.COV2.S (Janssen; hereafter ref
Modi N, Ribas R, Johnson S, et al., 2023, Pilot feasibility study of a digital technology approach to the systematic electronic capture of parent-reported data on cognitive and language development in children aged 2 years, BMJ Health & Care Informatics, Vol: 30, Pages: 1-5, ISSN: 2632-1009
Background The assessment of language and cognition in children at risk of impaired neurodevelopment following neonatal care is a UK standard of care but there is no national, systematic approach for obtaining these data. To overcome these challenges, we developed and evaluated a digital version of a validated parent questionnaire to assess cognitive and language development at age 2 years, the Parent Report of Children’s Abilities-Revised (PARCA-R).Methods We involved clinicians and parents of babies born very preterm who received care in north-west London neonatal units. We developed a digital version of the PARCA-R questionnaire using standard software. Following informed consent, parents received automated notifications and an invitation to complete the questionnaire on a mobile phone, tablet or computer when their child approached the appropriate age window. Parents could save and print a copy of the results. We evaluated ease of use, parent acceptability, consent for data sharing through integration into a research database and making results available to the clinical team.Results Clinical staff approached the parents of 41 infants; 38 completed the e-registration form and 30 signed the e-consent. The digital version of the PARCA-R was completed by the parents of 21 of 23 children who reached the appropriate age window. Clinicians and parents found the system easy to use. Only one parent declined permission to integrate data into the National Neonatal Research Database for approved secondary purposes.Discussion This electronic data collection system and associated automated processes enabled efficient systematic capture of data on language and cognitive development in high-risk children, suitable for national delivery at scale.
Cro S, Partington G, Cornelius VR, et al., 2023, Presenting clinical characteristics of open globe injuries in ocular trauma: baseline analysis of cases in the ASCOT national clinical trial, Eye, Vol: 37, Pages: 1732-1740, ISSN: 0950-222X
Background/ObjectivesThe Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a unique pragmatic, multi-centre, patient and assessor masked, randomised controlled trial. We evaluate the clinical characteristics and pathology of this large trial cohort of patients with open globe injuries undergoing vitreoretinal surgery, including the associations between patient characteristics and their baseline vision.Subjects/MethodsWe (i) summarise demographics, injury history and ocular history of the 280 participants recruited into the ASCOT trial using descriptive statistics; (ii) analyse the national and seasonal variation across England and Scotland in these participant characteristics; and (iii) explore the associations between participant demographic, trauma history, ocular history and presenting baseline visual acuity (measured using the Early Treatment Diabetic Retinopathy Study, ETDRS) using multivariable regression analyses.ResultsThe majority of participants with open globe penetrating injuries were of white ethnicity (233, 84%), male (246, 88%), with a median age of 43 years (IQR 30–55 years). There was considerable variability in presenting visual acuity with 75% unable to read any letters on the ETDRS chart, whilst the median ETDRS letter score was 58 (IQR 24–80) for those who could read ≥1 letter. The most common causes of injury were workplace related (31%) or interpersonal violence (24%). Previous eye surgery, visual axis corneal scar, lens status, hyphaemia and vitreous haemorrhaging were found to be associated with presenting vision as measured by the ETDRS chart.ConclusionThe ASCOT trial provides valuable insights into the spectrum of pathology of patients with open globe eye injuries undergoing vitreoretinal surgery. The identified causes of injury and clinical presentation of the cases will help in training and resource planning to deal with these often challenging surgical cases.Trial registrationEudraCT No. 014-002193-37. HTA
Liu X, Munro APS, Feng S, et al., 2023, Corrigendum to “Persistence of immunogenicity after seven COVID-19 vaccines given as third dose boosters following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK: Three month analyses of the COV-BOOST trial” [J Infect 84(6) (2022) 795–813, 5511], Journal of Infection, Vol: 86, Pages: 540-541, ISSN: 0163-4453
Phillips R, Cornelius V, 2023, Future directions of research into harms in randomised controlled trials., BMJ: British Medical Journal, Vol: 381, Pages: 926-926, ISSN: 0959-535X
Turner RM, Clements MN, Quartagno M, et al., 2023, Practical approaches to Bayesian sample size determination in non-inferiority trials with binary outcomes, Statistics in Medicine, Vol: 42, Pages: 1127-1138, ISSN: 0277-6715
Bayesian analysis of a non-inferiority trial is advantageous in allowing direct probability statements to be made about the relative treatment difference rather than relying on an arbitrary and often poorly justified non-inferiority margin. When the primary analysis will be Bayesian, a Bayesian approach to sample size determination will often be appropriate for consistency with the analysis. We demonstrate three Bayesian approaches to choosing sample size for non-inferiority trials with binary outcomes and review their advantages and disadvantages. First, we present a predictive power approach for determining sample size using the probability that the trial will produce a convincing result in the final analysis. Next, we determine sample size by considering the expected posterior probability of non-inferiority in the trial. Finally, we demonstrate a precision-based approach. We apply these methods to a non-inferiority trial in antiretroviral therapy for treatment of HIV-infected children. A predictive power approach would be most accessible in practical settings, because it is analogous to the standard frequentist approach. Sample sizes are larger than with frequentist calculations unless an informative analysis prior is specified, because appropriate allowance is made for uncertainty in the assumed design parameters, ignored in frequentist calculations. An expected posterior probability approach will lead to a smaller sample size and is appropriate when the focus is on estimating posterior probability rather than on testing. A precision-based approach would be useful when sample size is restricted by limits on recruitment or costs, but it would be difficult to decide on sample size using this approach alone.
Rosan C, Dijk KA-V, Darwin Z, et al., 2023, The COSI trial: a study protocol for a multi-centre, randomised controlled trial to explore the clinical and cost-effectiveness of the Circle of Security-Parenting Intervention in community perinatal mental health services in England., Trials, Vol: 24, Pages: 1-17, ISSN: 1745-6215
BACKGROUND: Perinatal mental health difficulties affect up to 27% of birthing parents during pregnancy and the first postnatal year, and if untreated are associated with difficulties in bonding and long-term adverse outcomes to children. There are large evidence gaps related to psychological treatment, particularly in group therapy approaches and parent-infant interventions. One intervention showing preliminary efficacious findings and user acceptability is Circle of Security-Parenting (COS-P), which is a brief, weekly, group programme. However, these studies were underpowered and predominantly non-randomised, and there has never been a research trial in England or with birthing parents experiencing severe and complex perinatal mental health difficulties. The aim of the research is to conduct a randomised control trial to test whether COS-P will reduce perinatal mental health symptoms in birthing parents accessing NHS perinatal mental health services, compared to treatment as usual (TAU). Secondary objectives include exploring whether the intervention improves parenting sensitivity, emotion regulation skills, attachment security and infant development. Additionally, the project aims to examine whether the intervention is acceptable to parents and NHS staff, and whether it is cost-effective. METHODS: COSI is an individually randomised, single-blind parallel arm controlled trial with an embedded internal pilot aiming to recruit 369 participants in a 2:1 ratio (intervention: TAU). Participants will be recruited from ten NHS community perinatal mental health services in England and screened based on clinical levels of both mental health symptoms (average CORE-OM score ≥ 1.1) and postnatal bonding difficulties (total PBQ score ≥ 12). This trial has 90% power to detect a MCID of 5 points on the CORE-OM. Primary and secondary outcomes will be measured at baseline, 3, 7 and 12 months after baseline. Service use and quality of life meas
Kelleher MM, Phillips R, Brown SJ, et al., 2022, Skin care interventions in infants for preventing eczema and food allergy., Cochrane Database of Systematic Reviews, Vol: 11, Pages: 1-177, ISSN: 1469-493X
BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective for preventing eczema or food allergy. OBJECTIVES: Primary objective To assess the effects of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We performed an updated search of the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase in September 2021. We searched two trials registers in July 2021. We checked the reference lists of included studies and relevant systematic reviews, and scanned conference proceedings to identify further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (≤ 12 months) without pre-existing eczema, food allergy, or other skin condition. Eligible comparisons were standard care in the locality or no treatment. Types of skin care interventions could include moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes wer
Ojji DB, Cornelius V, Partington G, et al., 2022, Effect of 3, 2-drug combinations of antihypertensive therapies on blood pressure variability in Black African patients: secondary analyses of the CREOLE trial, Hypertension, Vol: 79, Pages: 2593-2600, ISSN: 0194-911X
Background:The effect of 3 commonly recommended combinations of anti-hypertensive agents—amlodipine plus hydrochlorothiazide (calcium channel blocker [CCB]+thiazide), amlodipine plus perindopril (CCB+ACE [angiotensin-converting enzyme]-inhibitor), and perindopril plus hydrochlorothiazide (ACE-inhibitor+thiazide) on blood pressure variability (V) are unknown.Methods:We calculated the blood pressure variability (BPV) in 405 patients (130, 146, and 129 randomized to ACE-inhibitor+thiazide, CCB+thiazide, and CCB+ACE-inhibitor, respectively) who underwent ambulatory blood pressure monitoring after 6 months of treatment in the Comparisons of Three Combinations Therapies in Lowering Blood Pressure in Black Africans trial (CREOLE) of Black African patients. BPV was calculated using the SD of 30-minute interval values for 24-hour ambulatory BPs and for confirmation using the coefficient of variation. Linear mixed model regression was used to calculate mean differences in BPV between treatment arms. Within-clinic BPV was also calculated from the mean SD and coefficient of variation of 3 readings at clinic visits.Results:Baseline distributions of age, sex, and blood pressure parameters were similar across treatment groups. Participants were predominately male (62.2%) with mean age 50.4 years. Those taking CCB+thiazide had significantly reduced ambulatory systolic and diastolic BPV compared with those taking ACE-inhibitor+thiazide. The CCB+thiazide and CCB+ACE-inhibitor groups showed similar BPV. Similar patterns of BPV were apparent among groups using within-clinic blood pressures and when assessed by coefficient of variation.Conclusions:Compared with CCB-containing combinations, ACE-inhibitor plus thiazide was associated with higher levels, generally significant, of ambulatory and within-clinic systolic and diastolic BPV. These results supplement the differential ambulatory blood pressure–lowering effects of these therapies in the CREOLE trial.
Qureshi R, Chen X, Goerg C, et al., 2022, Comparing the value of data visualization methods for communicating harms in clinical trials, Epidemiologic Reviews, Vol: 44, Pages: 55-66, ISSN: 0193-936X
In clinical trials, harms (adverse events) are often reported by simply counting the number of people who experienced each event. Reporting only frequencies ignores other dimensions of the data that are important for stakeholders, including severity, seriousness, rate (recurrence), timing, and groups of related harms. Additionally, application of selection criteria to harms prevents most from being reported. Visualization of data could improve communication of multidimensional data. We replicated and compared the characteristics of six different approaches for visualizing harms-Dot Plot, Stacked Bar Chart, Volcano Plot, Heatmap, Treemap, and Tendril Plot. We considered binary events using individual participant data (IPD) from a randomized trial of gabapentin for neuropathic pain. We assessed their value using a heuristic approach and group of content experts. We produced all figures using R and share the open-source code on GitHub. Most original visualizations propose presenting individual harms (e.g., dizziness, somnolence) alone or alongside higher level (e.g., by body systems) summaries of harms, although they could be applied at either level. Visualizations are able to present different dimensions of all harms observed in trials. Except for the Tendril plot, all other plots do not require IPD. The Dot Plot and Volcano Plot are favoured as visualization approaches to present an overall summary of harms data. Our value assessment found the Dot Plot and Volcano Plot were favoured by content experts. Using visualizations to report harms could improve communication. Trialists can use our provided code to easily implement these approaches.
Sauzet O, Cornelius V, 2022, Generalised weibull model-based approaches to detect non-constant hazard to signal adverse drug reactions in longitudinal data, Frontiers in Pharmacology, Vol: 13, Pages: 1-11, ISSN: 1663-9812
Pharmacovigilance is the process of monitoring the emergence of harm from a medicine once it has been licensed and is in use. The aim is to identify new adverse drug reactions (ADRs) or changes in frequency of known ADRs. The last decade has seen increased interest for the use of electronic health records (EHRs) in pharmacovigilance. The causal mechanism of an ADR will often result in the occurrence being time dependent. We propose identifying signals for ADRs based on detecting a variation in hazard of an event using a time-to-event approach. Cornelius et al. proposed a method based on the Weibull Shape Parameter (WSP) and demonstrated this to have optimal performance for ADRs occurring shortly after taking treatment or delayed ADRs, and introduced censoring at varying time points to increase performance for intermediate ADRs. We now propose two new approaches which combined perform equally well across all time periods. The performance of this new approach is illustrated through an EHR Bisphosphonates dataset and a simulation study. One new approach is based on the power generalised Weibull distribution (pWSP) introduced by Bagdonavicius and Nikulin alongside an extended version of the WSP test, which includes one censored dataset resulting in improved detection across time period (dWSP). In the Bisphosphonates example, the pWSP and dWSP tests correctly signalled two known ADRs, and signal one adverse event for which no evidence of association with the drug exist. A combined test involving both pWSP and dWSP is reliable independently of the time of occurrence of ADRs.
Cro S, Kahan BC, Rehal S, et al., 2022, Evaluating the clarity of the questions being addressed in randomised trials: a systematic review of estimands, BMJ: British Medical Journal, Vol: 378, Pages: 1-12, ISSN: 0959-535X
Objective: To evaluate how often the precise question being addressed about an intervention (the estimand) is stated or can be worked out from reported methods, and to identify what types of questions are addressed in phase II-IV randomised trials.Design: A systematic review of the clarity of research questions addressed in randomised trials in 2020 in six leading general medical journals.Eligibility criteria: Phase II-IV randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, cross-over, non-inferiority, and equivalence trials were excluded. Data source: A search of PubMed was performed in February 2021.Main outcome measures: The number of trials which stated the precise primary question being addressed about an intervention (the primary estimand) or for which this could be unambiguously worked out from the reported methods using statistical knowledge. The strategies being used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional medications (termed intercurrent events), and the corresponding types of questions being addressed. Results: A total of 255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117/255 (46%) trials the primary question addressed could be worked out from the reported methods. Intercurrent events occurred in 95% of trials; but the handling of these could only be determined in 125/255 (49%) trials. Most trials which provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and addressed the effect of the intervention regardless (96/125, 76%) i.e. as if introduced into routine practice (treatment policy strategy). 4/99 (4%) trials with treatment non-adherence due to adverse events estimated the treatment effect in a hypothetical setting (the effect as if participants
Hunter H, Ue KL, Cornelius V, et al., 2022, Improvements in quality of life and food neophobia scores in adults after peanut oral immunotherapy, Joint Conference of the British-Society-for-Allergy-and-Immunology (BSACI) and World-Allergy-Organization (WAO), Publisher: WILEY, Pages: 1028-1028, ISSN: 0954-7894
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Moss R, Lammons W, Johnson S, et al., 2022, More than words: Parent, Patient and Public Involvement perspectives on language used by clinical researchers in neonatal care, Early Human Development, Vol: 171, Pages: 1-3, ISSN: 0378-3782
In this qualitative study exploring parent views of information about research studies, we found they accepted uncertainty as justification, and that three key aspects of language - words, tone, and pace - influence parents' decision about their baby's inclusion. We recommend parents are routinely involved in developing information materials.
Munro APS, Feng S, Janani L, et al., 2022, Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial, Lancet Infectious Diseases, Vol: 22, Pages: 1131-1141, ISSN: 1473-3099
BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19. METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing. FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70
Clements MN, White IR, Copas AJ, et al., 2022, Improving clinical trial interpretation with ACCEPT analyses, NEJM Evidence, Vol: 1, ISSN: 2766-5526
Chevance A, Ravaud P, Cornelius V, et al., 2022, Designing clinically useful psychopharmacological trials: challenges and ways forward, The Lancet Psychiatry, Vol: 9, Pages: 584-594, ISSN: 2215-0366
The clinical guidelines that underpin the use of drugs for mental disorders are informed by evidence from randomised controlled trials (RCTs). RCTs are performed to obtain marketing authorisation from regulators. The methods used in these RCTs could be appropriate for early phases of drug development because they identify drugs with important harms and drugs that are efficacious for specific health problems and populations. RCTs done before marketing authorisation do not tend to address clinical questions that concern the effectiveness of a drug in heterogeneous and comorbid populations, the optimisation of drug sequencing and discontinuation, or the comparative benefits and harms of different drugs that could be used for the same health problem. This Review proposes an overview of some shortcomings of RCTs, at an individual level and at the whole portfolio level, and identifies some methods in planning, conducting, and carrying out analyses in RCTs that could enhance their ability to support therapeutic decisions. These suggestions include: identifying patient-important questions to be investigated by psychopharmacological RCTs; embedding pragmatic RCTs within clinical practice to improve generalisability to target populations; collecting evidence about drugs in overlooked populations; developing methods to facilitate the recruitment of patients with mental disorders and to reduce the number of patients who drop out, using specific methods; using core outcome sets to standardise the assessment of benefits and harms; and recording systematically serious objective outcomes, such as suicide or hospitalisation, to be evaluated in meta-analyses. This work is a call to address questions relevant to patients using diverse design of RCTs, thus contributing to the development of a patient-centred, evidence-based psychiatry.
Chan SMH, Cro S, Cornelius V, et al., 2022, Omalizumab for severe atopic dermatitis in 4- to 19-year-olds: the ADAPT RCT, Efficacy and Mechanism Evaluation, Vol: 9, Pages: 1-110, ISSN: 2050-4365
AbstractBackgroundEvidence for systemic treatments for severe childhood eczema is limited. Systemic immunosuppressants are unlicensed for use in children and are associated with unwanted side effects.ObjectiveTo examine the role of anti-immunoglobulin E (IgE) [omalizumab (Xolair®, Novartis Pharmaceuticals UK Ltd, Frimley, UK)] in children and young people with severe eczema.DesignA double-blind, placebo-controlled, parallel-arm randomised (1 : 1) trial.SettingA single specialist centre – Guy’s and St Thomas’ NHS Foundation Trust, London.ParticipantsAtopic children and young people (aged 4–19 years) with severe eczema.InterventionsTreatment with omalizumab or placebo for 24 weeks.Main outcome measuresThe primary outcome was eczema severity, measured using the objective SCORing Atopic Dermatitis (SCORAD) at 24 weeks. Secondary outcomes included validated measures of eczema severity, quality of life (QoL) and potent topical steroid use.ResultsSixty-two participants, with a median baseline total IgE level of 8373 kU/l, received treatment with omalizumab (n = 30) or placebo (n = 32). The unadjusted mean objective SCORAD score at week 24 was 43.1 [standard deviation (SD) 12.5] for participants in the omalizumab arm and 49.2 (SD 11.3) for participants in the placebo arm. After adjustment for baseline objective SCORAD score, age and IgE level, the mean difference between arms at 24 weeks was –6.9 [95% confidence interval (CI) –12.2 to –1.5; p = 0.013], in favour of omalizumab. The mean objective SCORAD scores improved by –12.4 and –5.1 in the omalizumab and placebo arms, respectively, by 24 weeks. Secondary outcome measure estimates were also in favour of omalizumab for eczema severity at 24 weeks: the adjusted mean treatment arm difference was –8.3 (95% CI –15.1 to –1.1; p = 0.024) for total combined objective and subjecti
Liu X, Munro APS, Feng S, et al., 2022, Persistence of immunogenicity after seven COVID-19 vaccines given as third dose boosters following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK: Three month analyses of the COV-BOOST trial, Journal of Infection, Vol: 84, Pages: 795-813, ISSN: 0163-4453
OBJECTIVES: To evaluate the persistence of immunogenicity three months after third dose boosters. METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study. RESULTS: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 μg) or BNT (30 μg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 μg) versus BNT (30 μg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. CONCLUSIONS: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new
Chen K, Li C, Cornelius V, et al., 2022, Prognostic value of time in blood pressure target range among patients with heart failure, JACC: Heart Failure, Vol: 10, Pages: 369-379, ISSN: 2213-1787
BackgroundBlood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time.ObjectivesThis study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF).MethodsThe authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg.ResultsA total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (Ptrend <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP.ConclusionsTTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.
Phillips R, Cro S, Wheeler G, et al., 2022, Visualising harms in publications of randomised controlled trials: consensus and recommendations, BMJ: British Medical Journal, Vol: 377, ISSN: 0959-535X
Objective: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes.Design: Consensus study.Setting: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and TheBMJ.Participants: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians.Main outcome measures: A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached.Results: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation.Conclusions: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alt
chen T, Cornelius V, 2022, Time to Clinical Benefit of Intensive Blood Pressure Lowering in Patients 60 Years and Older With HypertensionA Secondary Analysis of Randomized Clinical Trials, JAMA Internal Medicine, ISSN: 2168-6106
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