147 results found
Phillips R, Cornelius V, 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, ISSN: 2044-6055
Hadfield DJ, Rose L, Reid F, et al., 2020, Neurally adjusted ventilatory assist versus pressure support ventilation: a randomized controlled feasibility trial performed in patients at risk of prolonged mechanical ventilation., Crit Care, Vol: 24
BACKGROUND: The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV). METHODS: An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary-≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality. RESULTS: In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0-97.1%) and 100% (100-100%), and protocol compliance was 66.7% (50.3-80.0%) and 100% (89.0-100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0-11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2-0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality. CONCLUSIONS: This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01826890. Registered 9 April 2013.
Raad H, Cornelius V, Chan S, et al., 2020, An evaluation of inverse probability weighting using the propensity score for baseline covariate adjustment in smaller population randomised controlled trials with a continuous outcome, BMC Medical Research Methodology, Vol: 20, Pages: 1-12, ISSN: 1471-2288
BackgroundIt is important to estimate the treatment effect of interest accurately and precisely within the analysis of randomised controlled trials. One way to increase precision in the estimate and thus improve the power for randomised trials with continuous outcomes is through adjustment for pre-specified prognostic baseline covariates. Typically covariate adjustment is conducted using regression analysis, however recently, Inverse Probability of Treatment Weighting (IPTW) using the propensity score has been proposed as an alternative method. For a continuous outcome it has been shown that the IPTW estimator has the same large sample statistical properties as that obtained via analysis of covariance. However the performance of IPTW has not been explored for smaller population trials (< 100 participants), where precise estimation of the treatment effect has potential for greater impact than in larger samples.MethodsIn this paper we explore the performance of the baseline adjusted treatment effect estimated using IPTW in smaller population trial settings. To do so we present a simulation study including a number of different trial scenarios with sample sizes ranging from 40 to 200 and adjustment for up to 6 covariates. We also re-analyse a paediatric eczema trial that includes 60 children.ResultsIn the simulation study the performance of the IPTW variance estimator was sub-optimal with smaller sample sizes. The coverage of 95% CI’s was marginally below 95% for sample sizes < 150 and ≥ 100. For sample sizes < 100 the coverage of 95% CI’s was always significantly below 95% for all covariate settings. The minimum coverage obtained with IPTW was 89% with n = 40. In comparison, regression adjustment always resulted in 95% coverage. The analysis of the eczema trial confirmed discrepancies between the IPTW and regression estimators in a real life small population setting.ConclusionsThe IPTW variance e
Sin J, Henderson C, Cornelius V, et al., 2020, COPe-support-a multi-component digital intervention for family carers for people affected by psychosis: study protocol for a randomized controlled trial, BMC Psychiatry, Vol: 20, Pages: 1-14, ISSN: 1471-244X
BackgroundPsychosis often causes significant distress and impacts not only in the individuals, but also those close to them. Many relatives and friends (‘carers’) provide long-term support and need resources to assist them. We have co-produced a digital mental health intervention called COPe-support (Carers fOr People with Psychosis e-support) to provide carers with flexible access to high quality psychoeducation and interactive support from experts and peers. This study evaluates the effectiveness of COPe-support to promote mental wellbeing and caregiving experiences in carers.MethodsThis study is a single-blind, parallel arm, individually randomized controlled trial (RCT) comparing COPe-support, with attention control. Both groups continue to receive usual care. COPe-support provides interactive web-based psychoeducation on psychosis-related issues, wellbeing-promotion and network support through forums. The attention-control is a non-interactive online information resource pack. Carers living in England are eligible if they provide at least weekly support to a family member or close friend affected by psychosis, and use internet communication (including emails) daily. All trial procedures are run online, including collection of outcome measurements which participants will directly input into our secure platform. Following baseline assessment, a web-based randomization system will be used to allocate 360 carers to either arm. Participants have unlimited access to the allocated condition for 40 weeks. Data collection is at three time points (10, 20, and 40 weeks after randomization). Analyses will be conducted by trial statisticians blinded to allocation. The primary outcome is mental wellbeing measured by Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), at 20 weeks. As well as an intention-to-treat analysis, a complier average causal effect (CACE) analysis will be conducted to estimate the intervention effect in participants who
Cro S, Patel P, Barker J, et al., A randomised placebo controlled trial of anakinra for treating pustular psoriasis: statistical analysis plan for stage two of the APRICOT trial, Trials, Vol: 21, ISSN: 1745-6215
Background:Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan.Methods:APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial.Discussion:This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP.Trial registration:ISCRTN, ISCRTN13127147. Registered on 1 August 2016. EudraCT Number 2015-003600-23. Registered on 1 April 2016.
Kelleher MM, Cro S, Cornelius V, et al., 2020, Skincare interventions in infants for preventing eczema and food allergy, Cochrane Database of Systematic Reviews, Vol: 2020
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:. Primary objective. To assess the effects of skincare interventions, such as emollients, for prevention of eczema and food allergy in infants. Secondary objectives. To ascertain whether active skincare interventions, commenced in early infancy, influence risk of developing eczema or food allergy To identify features of the study populations such as age, hereditary risk and adherence to the interventions, which are associated with the greatest treatment benefit or harm for both eczema and food allergy.
Chan S, Cornelius V, Cro S, et al., 2020, Treatment effect of omalizumab on severe pediatric atopic dermatitis: The ADAPT randomized clinical trial, JAMA Pediatrics, Vol: 174, Pages: 29-37, ISSN: 2168-6203
Importance: Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published. Objective: To determine the effectiveness of omalizumab in treating severe atopic dermatitis in children. Design, Setting, and Participants: The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up. Conducted from November 20, 2014, to August 31, 2017, at Guy's and St Thomas' Hospital NHS Foundation Trust and King's College London in the United Kingdom, this trial recruited participants after a screening visit. Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index >40) that was unresponsive to optimum therapy. Statistical analysis was conducted using the intention-to-treat principle. Interventions: Subcutaneous omalizumab or placebo for 24 weeks. The drug manufacturer's dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization. Main Outcomes and Measures: Objective SCORAD index after 24 weeks of treatment. Results: In total, 62 children (mean [SD] age, 10.3 [4.2] years; 32 (52%) were male) were randomized to either omalizumab (n = 30) or placebo (n = 32). Five participants withdrew from treatment (4 [13%] from the placebo group, and 1 [3%] from the omalizumab group). Follow-up attendance was 97% at week 24 and 98% at week 48. After adjustment for baseline objective SCORAD index, age, and IgE level, the mean difference in objective SCORAD index improvement between groups at week 24 was -6.9 (95% CI, -12.2 to -1.5; P = .01), significantly favoring omalizumab therapy and reflec
Sanfilippo KRM, McConnell B, Cornelius V, et al., 2019, A study protocol for testing the feasibility of a randomised stepped wedge cluster design to investigate a Community Health Intervention through Musical Engagement (CHIME) for perinatal mental health in The Gambia., Pilot Feasibility Stud, Vol: 5, Pages: 1-8, ISSN: 2055-5784
Background: Perinatal mental health problems affect up to one in five women worldwide. Mental health problems in the perinatal period are a particular challenge in low- and middle-income countries (LMICs) where they can be at least twice as frequent as in higher-income countries. It is thus of high priority to develop new low-cost, low-resource, non-stigmatising and culturally appropriate approaches to reduce symptoms of anxiety and depression perinatally, for the benefit of both mother and child. Music-centred approaches may be particularly useful in The Gambia since a range of musical practices that specifically engage pregnant women and new mothers already exist. Methods: This protocol is for a study to examine the feasibility of undertaking a stepped wedge trial to test how a Community Health Intervention through Musical Engagement (CHIME) could be beneficial in alleviating perinatal mental distress in The Gambia. In this study, we plan to recruit 120 pregnant women (n = 60 intervention, n = 60 control) at four antenatal clinics over two 6-week stepped sequences. Women in the intervention will participate in weekly group-singing sessions, led by local Kanyeleng singing groups, for 6 weeks. The control group will receive standard care. We will assess symptoms of anxiety and depression using the Edinburgh Postnatal Depression Scale (EPDS) and the Self-Reporting Questionnaire (SRQ-20). The feasibility of the design will be assessed through recruitment, retention and attrition rates of participants, clinics' adherence to the schedule and completeness of data by site. Qualitative interviews and video and audio recordings will be used to evaluate the acceptability of the intervention. Discussion: This feasibility trial will allow us to determine whether a larger trial with the same intervention and target group is feasible and acceptable in The Gambia. Trial registration: Retrospectively registered (24/01/2019) with Pan African Clinica
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
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
Sanfilippo KRM, Cornelius V, McConnell B, et al., 2019, Testing the Feasibility of a Complex Intervention for Perinatal Mental Health in The Gambia, Publisher: BMC
Babalis D, Saglani S, Cornelius V, 2019, To fund or not to fund a paediatric severe asthma trial: that is the question, Publisher: BMC
Cornelius V, Cro S, 2019, Designing trials for small populations, Publisher: BMC
Cro S, Chan S, Cornelius V, 2019, Controlled multiple imputation: an accessible flexible tool for estimating hypothetical estimands in clinical trials, Publisher: BMC
Ster AMC, Cornelius V, Cro S, 2019, Statistical approaches to adjust for the use of rescue medication in randomised controlled trials, Publisher: BMC
Chen T, Li C, Wang Y, et al., 2019, Overestimation of Event Rate and Target Difference among Randomized Clinical in sample size calculations Trials: a cross-sectional survey review, Publisher: BMC
Cornelius V, Johnston CL, 2019, The enhanced peri-operative care for high-risk patients trial: an independent discussion and commentary, British Journal of Anaesthesia, Vol: 123, Pages: 261-266, ISSN: 0007-0912
Gimeno H, Brown R, Lin JP, et al., 2019, AUGMENTING FUNCTIONAL PERFORMANCE FOLLOWING DEEP BRAIN STIMULATION WITH A COGNITIVE APPROACH FOR INDIVIDUALS WITH HYPERKINETIC MOVEMENT DISORDERS, Publisher: SAGE PUBLICATIONS LTD, Pages: 52-53, ISSN: 0308-0226
Sayar Z, Czuprynska J, Patel JP, et al., 2019, What are the difficulties in conducting randomised controlled trials of thromboprophylaxis in myeloma patients and how can we address these? Lessons from apixaban versus LMWH or aspirin as thromboprophylaxis in newly diagnosed multiple myeloma (TiMM) feasibility clinical trial, Journal of Thrombosis and Thrombolysis, Vol: 48, Pages: 315-322, ISSN: 0929-5305
Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King’s College Hospital and Guy’s Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice.
Chen T, Li C, Qin R, et al., 2019, Comparison of clinical trial changes in primary outcome and reported intervention effect size between trial registration and publication., JAMA Network Open, Vol: 2, Pages: 1-12, ISSN: 2574-3805
Importance: Primary outcome change could threaten the validity of a clinical trial; however, evidence about the consequences on the reported intervention effect size is unclear. Objectives: To examine the status of randomized clinical trials whose primary outcome changed between trial registration and publication and to quantify the association of this change with the reported intervention effect size. Design, Setting, and Participants: In this cross-sectional study on the primary report of randomized clinical trials with clear prospectively registered primary outcomes, PubMed and Embase were searched for articles published between January 1, 2011, and December 31, 2015. The search was conducted in January 2016, identifying randomized clinical trials and the combination of keywords and text words related to registry. Main Outcomes and Measures: Based on the developed approach, trials were classified as having primary outcome change when there was a major discrepancy between the registered and published primary outcomes. Intervention effect was estimated or recalculated using the odds ratio (OR) for each comparison. Each component OR is structured so that an OR is less than 1 if the intervention group has a more favorable result than the control group. The ratio of ORs (ROR), which is the summary OR for trials with primary outcome change divided by those without, and its 95% CI were calculated, with a value less than 1 indicating a larger reported intervention effect size in trials with primary outcome change than those without. Results: Among 29 749 searched articles (28 810 MEDLINE and 939 Embase), 1488 articles were randomly selected for review. Of 389 trials with clear primary outcomes prospectively described in the registry (416 outcomes reported), 33.4% (130 of 389) of trials had at least 1 primary outcome change. Most (66 of 130) of the changes were either not reporting or omitting the primary outcome. In total, 338 trials (365 outcomes and 487 comparisons) we
Gulati S, Dubois P, Carter B, et al., 2019, A Randomized Crossover Trial of Conventional vs Virtual Chromoendoscopy for Colitis Surveillance: Dysplasia Detection, Feasibility, and Patient Acceptability (CONVINCE), INFLAMMATORY BOWEL DISEASES, Vol: 25, Pages: 1096-1106, ISSN: 1078-0998
Ojji DB, Mayosi B, Francis V, et al., 2019, Comparison of dual therapies for lowering blood pressure in black Africans, New England Journal of Medicine, Vol: 380, Pages: 2429-2439, ISSN: 0028-4793
BACKGROUND: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS: Thes
Gimeno H, Brown RG, Lin J-P, et al., 2019, Cognitive approach to rehabilitation in children with hyperkinetic movement disorders post-DBS, NEUROLOGY, Vol: 92, Pages: E1212-E1224, ISSN: 0028-3878
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
Hemming K, Carroll K, Thompson J, et al., 2019, Quality of stepped-wedge trial reporting can be reliably assessed using an updated CONSORT: crowd-sourcing systematic review, Journal of Clinical Epidemiology, Vol: 107, Pages: 77-88, ISSN: 0895-4356
The Consolidated Standards Of Reporting Trials (CONSORT) extension for the stepped-wedge cluster randomised trial (SW-CRT) is a recently published reporting guideline for SW-CRTs. We assess the quality of reporting of a recent sample of SW-CRTs according to the 26 items in the new guideline using a novel crowd sourcing methodology conducted independently and in duplicate, with random assignment, by 50 reviewers. We assessed reliability of the quality assessments, proposing this as a novel way to assess robustness of items in reporting guidelines.Several items were well reported. Some items were very poorly reported, including several items that have unique requirements for the SW-CRT, such as the rationale for use of the design, description of the design, identification and recruitment of participants within clusters, and concealment of cluster allocation (not reported in more than 50% of the reports). Agreement across items was moderate (median percentage agreement was 76% [IQR 64 to 86]). Agreement was low for several items including the description of the trial design and why trial ended or stopped for example.When reporting SW-CRTs authors should pay particular attention to ensure clear reporting on the exact format of the design with justification, as well as how clusters and individuals were identified for inclusion in the study, and whether this was done before or after randomisation of the clusters, which are crucial for risk of bias assessments. Some items, including why the trial ended might either not be relevant to SW-CRTs, or might be unclearly described in the statement.
Wheeler GM, Mander AP, Bedding A, et al., 2019, How to design a dose-finding study using the continual reassessment method, BMC Medical Research Methodology, Vol: 19, ISSN: 1471-2288
IntroductionThe continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM’s uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce.MethodsTo help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM.ResultsAn initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design.ConclusionsThe framework and resources we provide are aimed at clinicians
Mehta S, Cro S, Coomber B, et al., 2019, A randomised controlled feasibility trial to evaluate local heat preconditioning on wound healing after reconstructive breast surgery: the preHEAT trial, Pilot and Feasibility Studies, Vol: 5, ISSN: 2055-5784
ObjectivepreHEAT was a randomised controlled feasibility trial to determine how best to measure skin necrosis in breast reconstruction to inform the design of a larger multicentre trial.BackgroundMastectomy skin flap necrosis (MSFN) is a serious complication resulting in prolonged wound healing. Local heat preconditioning of the MSF before surgery has been shown to reduce skin necrosis in immediate breast reconstruction patients (IBR).MethodpreHEAT was a single-centre, randomised control two-arm single-blind parallel arm feasibility trial of local heat preconditioning in breast cancer patients undergoing SSM and NSM at Guy’s and St Thomas’ Hospital, London, UK. All patients undergoing IBR above the age of 18 were included. Intervention patients heated breast skin to 43 °C in three, 30-min cycles interrupted by spontaneous cooling using hot water bottles. The primary aim was to compare measurement of skin necrosis using binary ‘yes/no’ assessment, the SKIN score, and wound area.ResultsOne hundred forty-one patients were randomised over a 2-year period (71 heated group, 70 controls). There was near perfect agreement between assessors using the “yes/no” measurement of necrosis. The proportion of patients experiencing necrosis in controls was 35% (n = 23/66) in the heated 26% (n = 18/68]). In the control group, 17% (n = 4/23) patients experiencing necrosis required surgical intervention for necrosis compared to 11% (n = 2/18) in the heated group.ConclusionThe binary outcome of MSFN “yes/no” is a suitable and reliable primary outcome measure of necrosis and was superior to the SKIN Score or necrosis area. The trial study design is feasible for a larger definitive trial.
Selby A, Munro A, Grimshaw KE, et al., 2018, Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort, Thorax, Vol: 73, Pages: 1049-1061, ISSN: 1468-3296
BACKGROUND: Preschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken. OBJECTIVE: To assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure. METHODS: Infants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze. RESULTS: 12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from <2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze. CONCLUSION: The prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.
Cro S, Smith C, Wilson R, et al., 2018, Treatment of pustular psoriasis with anakinra: a statistical analysis plan for stage 1 of an adaptive two-staged randomised placebo-controlled trial, Trials, Vol: 19, ISSN: 1745-6215
BackgroundPalmoplantar pustulosis (PPP) is a rare, chronic inflammatory skin disease. It is known to affect quality of life at a level comparable to that from major medical and psychiatric illness, yet current treatment options are remarkably limited. Recent evidence however suggests that interleukin-1 (IL-1) blockade with anakinra will deliver therapeutic benefit in PPP.MethodsAnakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) is a two-staged, adaptive, double-blind, randomised placebo-controlled trial which aims to test the hypothesis that IL-1 blockade with anakinra will deliver therapeutic benefit in PPP. During stage 1 a total of 24 patients will be randomised (1:1) to receive either placebo or anakinra. The two candidate primary outcomes are fresh pustule count (across palms and soles) and the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score, recorded at baseline and at weeks 1, 4 and 8. Analysis at the end of stage 1 will compare treatment arms to ensure sufficient efficacy and safety in order to progress to stage 2. The primary outcome for stage 2 will also be identified following an assessment of the reliability and discriminative ability of fresh pustule count and PPPASI. The trial is powered to detect efficacy and will recruit an additional 40 patients in stage 2 (n = 64 in total). Analysis will follow the intention-to-treat principle and analyse patients as randomised.DiscussionThis manuscript describes the important features of the small population trial design for APRICOT and the pre-specified statistical analysis plan for stage 1. The statistical analysis plan has been developed prior to data extraction and in compliance with international guidelines. It will increase the transparency of the data analysis for the APRICOT trial. The findings of the trial will help to clarify the role of anakinra in the treatment of PPP.
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