Imperial College London

DrVictoriaCornelius

Faculty of MedicineSchool of Public Health

Reader in Medical Statistics
 
 
 
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Contact

 

+44 (0)20 7594 1218v.cornelius

 
 
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Location

 

111Stadium HouseWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

195 results found

Cro S, Kahan BC, Rehal S, Chis Ster A, Carpenter JR, White IR, Cornelius VRet al., 2022, Evaluating the clarity of the questions being addressed in randomised trials: a systematic review of estimands, BMJ: British Medical Journal, ISSN: 0959-535X

Journal article

Liu X, Munro APS, Feng S, Janani L, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, Dejnirattisai W, Dodd K, Enever Y, Qureshi E, Goodman AL, Green CA, Harndahl L, Haughney J, Hicks A, van der Klaauw AA, Kwok J, Libri V, Llewelyn MJ, McGregor AC, Minassian AM, Moore P, Mughal M, Mujadidi YF, Holliday K, Osanlou O, Osanlou R, Owens DR, Pacurar M, Palfreeman A, Pan D, Rampling T, Regan K, Saich S, Serafimova T, Saralaya D, Screaton GR, Sharma S, Sheridan R, Sturdy A, Supasa P, Thomson EC, Todd S, Twelves C, Read RC, Charlton S, Hallis B, Ramsay M, Andrews N, Lambe T, Nguyen-Van-Tam JS, Cornelius V, Snape MD, Faust SN, COV-BOOST study groupet 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

Journal article

Chen K, Li C, Cornelius V, Yu D, Wang Q, Shi R, Wu Z, Su H, Yan J, Chen T, Jiang Zet al., 2022, Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure., JACC Heart Fail, Vol: 10, Pages: 369-379

BACKGROUND: Blood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time. OBJECTIVES: This study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF). METHODS: The 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. RESULTS: A 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. CONCLUSIONS: TTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.

Journal article

Phillips R, Cro S, Wheeler G, Bond S, Morris TP, Creanor S, Hewitt C, Love S, Lopes A, Schlackow I, Gamble C, MacLennan G, Habron C, Gordon A, Vergis N, Li T, Qureshi R, Everett C, Holmes J, Kirkham A, Peckitt C, Pirrie S, Ahmed N, Collett L, Cornelius Vet 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

Journal article

Munro APS, Feng S, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, Dodd K, Enever Y, Qureshi E, Goodman AL, Green CA, Harndahl L, Haughney J, Hicks A, van der Klaauw AA, Kanji N, Libri V, Llewelyn MJ, McGregor AC, Maallah M, Minassian AM, Moore P, Mughal M, Mujadidi YF, Holliday K, Osanlou O, Osanlou R, Owens DR, Pacurar M, Palfreeman A, Pan D, Rampling T, Regan K, Saich S, Bawa T, Saralaya D, Sharma S, Sheridan R, Thomson EC, Todd S, Twelves C, Read RC, Charlton S, Hallis B, Ramsay M, Andrews N, Lambe T, Nguyen-Van-Tam JS, Snape MD, Liu X, Faust SN, COV-BOOST study groupet 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 Infect Dis

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

Journal article

Chevance A, Ravaud P, Cornelius V, Mayo-Wilson E, Furukawa TAet al., 2022, Designing clinically useful psychopharmacological trials: challenges and ways forward, The Lancet Psychiatry, 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.

Journal article

Sin J, Henderson C, Elkes J, Cornelius V, Woodham LA, Batchelor R, Chen T, Corredor AM, Coughlan D, Dhital R, Evans S, Haider B, Heathcote J, Mansfield S, O'Brien A, Qassim M, Sserunkuma J, Travis CH, Williams E, Gillard Set al., 2022, Effect of digital psychoeducation and peer support on the mental health of family carers supporting individuals with psychosis in England (COPe-support): a randomised clinical trial, The Lancet Digital Health, Vol: 4, Pages: e320-e329, ISSN: 2589-7500

BACKGROUND: Psychoeducation delivered face-to-face is effective in alleviating mental health morbidities in family carers of individuals with psychosis. However, research in such interventions delivered online is scarce. We evaluated the effectiveness of a digital multicomponent intervention-COPe-support-in improving carers' mental wellbeing and caregiving-related outcomes. METHODS: In this two-arm, individually randomised, superiority trial, people aged 18 years or older who provided at least weekly support in any format for a relative or close friend affected by psychosis across England were randomly assigned (1:1) to either COPe-support or a passive online information resource using an independent online system. Participants were recruited through 30 mental health UK National Health Service trusts. The study team were masked to allocation and assessment of outcomes as all data collection took place online. Participants had access to either condition for 40 weeks and were advised to spend at least half an hour per week over the initial 20 weeks to go through materials at their own pace and to allow time to integrate knowledge and skills learned into practice. It was not feasible to mask participants or the online facilitator to intervention allocation. COPe-support provided psychoeducation on psychosis-related caregiving strategies and forums with professionals and other carers, and the control intervention comprised a passive online information resource. The primary outcome at 20 weeks was mental wellbeing measured by the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS; minimally clinically important difference [MCID] 3). This trial is registered with ISRCTN, 89563420. FINDINGS: Between March 1, 2018, and Feb 14, 2020, 407 participants were randomly assigned, with 204 allocated to COPe-support and 203 allocated to control. The participants (mean age 53·1 years, SD 13·2) were mostly female (330 [81%] of 407 participants) and White (359 [88%] of 407

Journal article

Chan SMH, Cro S, Cornelius V, Jahan R, Radulovic S, Lack Get 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

<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>Evidence for systemic treatments for severe childhood eczema is limited. Systemic immunosuppressants are unlicensed for use in children and are associated with unwanted side effects.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objective</jats:title> <jats:p>To examine the role of anti-immunoglobulin E (IgE) [omalizumab (Xolair<jats:sup>®</jats:sup>, Novartis Pharmaceuticals UK Ltd, Frimley, UK)] in children and young people with severe eczema.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>A double-blind, placebo-controlled, parallel-arm randomised (1 : 1) trial.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>A single specialist centre – Guy’s and St Thomas’ NHS Foundation Trust, London.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Atopic children and young people (aged 4–19 years) with severe eczema.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Interventions</jats:title> <jats:p>Treatment with omalizumab or placebo for 24 weeks.</jats:p> </jats:sec> <jats:sec id="abs1-7"> <jats:title>Main outcome measures</jats:title>

Journal article

Cro S, Cornelius V, Capon F, Barker J, Burden D, Griffiths C, Lachmann HJ, McAteer H, Patel P, Pink A, Reynolds N, Warren R, Smith Cet al., 2022, The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study, Efficacy and Mechanism Evaluation, Vol: 9, Pages: 1-106, ISSN: 2050-4365

BackgroundPalmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver.ObjectiveTo determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis.DesignA Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension.SettingSixteen hospitals across England, Scotland and Wales.ParticipantsAdults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy.InterventionsParticipants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks.Main outcome measuresThe primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact.ResultsA total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statis

Journal article

Stewart L, McConnell BB, Darboe B, Glover V, Huma HB, Sanfilippo KRM, Cross I, Ceesay H, Ramchandani P, Cornelius Vet al., 2022, Social singing, culture and health: interdisciplinary insights from the CHIME project for perinatal mental health in The Gambia, HEALTH PROMOTION INTERNATIONAL, Vol: 37, Pages: i18-i25, ISSN: 0957-4824

Journal article

Batchelor R, Gulshan S, Shritharan H, Williams E, Henderson C, Gillard S, Woodham LA, Cornelius V, Elkes J, Sin Jet al., 2022, Perceived Acceptability and Experiences of a Digital Psychoeducation and Peer Support Intervention (COPe-support): Interview Study With Carers Supporting Individuals With Psychosis, JOURNAL OF MEDICAL INTERNET RESEARCH, Vol: 24, ISSN: 1438-8871

Journal article

Cro S, Cornelius VR, Pink AE, Wilson R, Pushpa-Rajah A, Patel P, Abdul-Wahab A, August S, Azad J, Becher G, Chapman A, Dunnil G, Ferguson AD, Fogo A, Ghaffar SA, Ingram JR, Kavakleiva S, Ladoyanni E, Leman JA, Macbeth AE, Makrygeoegou A, Parslew R, Ryan AJ, Sharma A, Shipman AR, Sinclair C, Wachsmuth R, Woolf RT, Wright A, McAteer H, Barker JNWN, Burden AD, Griffiths CEM, Reynolds NJ, Warren RB, Lachmann HJ, Capon F, Smith CH, APRICOT Study Groupet al., 2022, Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two staged, adaptive placebo controlled trial (APRICOT)., British Journal of Dermatology, Vol: 186, Pages: 245-256, ISSN: 0007-0963

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease affecting the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVE: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit for PPP. METHODS: A randomised (1:1), double-blind, two-staged, adaptive, UK multi-centre, placebo-controlled trial. Participants had a diagnosis of PPP (>6 months) requiring systemic therapy. Treatment was eight weeks of anakinra or placebo via daily self-administered subcutaneous injections. The primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened and 64 were enrolled (31 anakinra, 33 placebo) with mean baseline PPPASI 17.8 (SD=10.5); PPP investigator's global assessment severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in intention-to-treat analysis, -1.65, 95% CI [-4.77 to 1.47], p=0.300. Secondary objective measures including fresh pustule count (2.94, 95% CI [-26.44 to 32.33] favouring anakinra), total pustule count (-30.08, 95% CI [-83.20 to 23.05] favouring placebo), and patient-reported outcomes, similarly did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect (CACE) for an individual who receives ≥90% total treatment (48% anakinra group), was -3.80, 95% CI [-10.76 to 3.16], p=0.285. No serious adverse events occurred. CONCLUSIONS: No evidence for superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Journal article

Mace S, Dzahini O, Cornelius V, Langerman H, Oloyede E, Taylor Det al., 2022, Incident infection during the first year of treatment - A comparison of clozapine and paliperidone palmitate long-acting injection, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 36, Pages: 232-237, ISSN: 0269-8811

Journal article

Van Vogt E, Cro S, Cornelius VR, Williams HC, Askie LM, Phillips R, Kelleher MM, Boyle RJet al., 2021, Individual participant data meta-analysis versus aggregate data meta-analysis: a case study in eczema and food allergy prevention., Clinical and Experimental Allergy, Vol: 52, ISSN: 0954-7894

INTRODUCTION: Meta-analysis traditionally uses aggregate data from published reports. Individual Participant Data (IPD) meta-analysis, which obtains and synthesises participant-level data, is potentially more informative, but resource-intensive. The impact on the findings of meta-analyses using IPD in comparison to aggregate data has rarely been formally evaluated. METHODS: We conducted a secondary analysis of a Cochrane systematic review of skin care interventions for preventing eczema and food allergy in infants to identify the impact of the analytical choice on the review's findings. We used aggregate data meta-analysis only and contrasted the results against those of the originally published IPD meta-analysis. All meta-analysis used random effects inverse variance models. Certainty of evidence was evaluated using GRADE. RESULTS: The pooled treatment effects for the Cochrane systematic review's co-primary outcomes of eczema and food allergy were similar in IPD meta-analysis (eczema RR 1.03, 95% CI 0.81, 1.31; I2 41%, 7 studies 3075 participants), and aggregate meta-analysis (eczema RR 1.01 95% CI 0.77, 1.33; I2 53%, 7 studies, 3089 participants). In aggregate meta-analysis the statistical heterogeneity could not be explained but using IPD it was explained by one trial which used a different, bathing intervention. For IPD meta-analysis, risk of bias was assessed as lower and more adverse event data were available compared with aggregate meta-analysis. This resulted in higher certainty of evidence, especially for adverse events. IPD meta-analysis enabled analysis of treatment interactions by age and hereditary eczema risk; and analysis of the effect of treatment adherence using pooled complier-adjusted-causal-effect analysis, none of which was possible in aggregate meta-analysis. CONCLUSIONS: For this systematic review, IPD did not significantly change primary outcome risk ratios compared with aggregate data meta-analysis. However, certainty of evidence, safety out

Journal article

Cornelius V, 2021, Improving the analysis of adverse event in randomised controlled trials, Journal of Clinical Epidemiology, ISSN: 0895-4356

Journal article

Partington G, Cro S, Mason A, Phillips R, Cornelius Vet al., 2021, Design and analysis features used in small population and rare disease trials: A targeted review., Journal of Clinical Epidemiology, Vol: 144, Pages: 93-101, ISSN: 0895-4356

OBJECTIVE: Frequentist trials in Rare disease/small population trials often require unfeasibly large sample size to detect minimum clinically important differences. A targeted review was performed investigating what design and analysis methods these trials use when facing restricted recruitment. STUDY DESIGN AND SETTING: Targeted Review searching EMBASE and MEDLINE for Phase II-IV RCTs reporting 'rare' disease or 'small population' within title or abstract, since 2009. RESULTS: A total of 6,128 articles were screened with 64 trials eligible (4 Bayesian, 60 frequentist trials). Frequentists trials had planned power ranging 72-90% (median: 80%) but reported recruiting a mean of 6.6% below the planned sample size (n=38) [median 0%, IQR (-5%, 5%)], most used standard type 1 error (52 used 5% and 1 used 1%), and the average standardised effect was high (0.7) with 50% missing their assumed level. Of the 4 Bayesian trials, 3 used informed priors, 2 and 1 trials performed sensitivity analysis for the impact of priors on design and analysis respectively. Historical data, expert consensus, or both were used to construct informative priors. Bayesian trials required 30%-2400% less participants than using frequentist frameworks. CONCLUSION: Bayesian trials required lower sample size through use of informative priors. Most frequentists didn't achieve their target sample size. Bayesian methods offer promising solutions for such trials but are underutilised.

Journal article

Munro APS, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, Dodd K, Enever Y, Gokani K, Goodman AL, Green CA, Harndahl L, Haughney J, Hicks A, van der Klaauw AA, Kwok J, Libri V, Llewelyn MJ, McGregor AC, Minassian AM, Moore P, Mughal M, Mujadidi YF, Murira J, Osanlou O, Osanlou R, Owens DR, Pacurar M, Palfreeman A, Pan D, Rampling T, Regan K, Saich S, Salkeld J, Saralaya D, Sharma S, Sheridan R, Sturdy A, Thomson EC, Todd S, Twelves C, Read RC, Charlton S, Hallis B, Ramsay M, Andrews N, Nguyen-Van-Tam JS, Snape MD, Liu X, Faust SN, COV-BOOST study groupet al., 2021, Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial, The Lancet, Vol: 398, ISSN: 0140-6736

BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June

Journal article

Ue KL, Hunter H, Cornelius V, Yung CC, Thomas I, Tsilochristou O, Siew LQ, Till Set al., 2021, Preliminary results of a phase II trial of peanut oral immunotherapy in adults, Publisher: WILEY, Pages: 1655-1656, ISSN: 0954-7894

Conference paper

Clark I, Wallman P, Cornelius V, Taylor Det al., 2021, Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: A 2-year naturalistic follow-up study, EUROPEAN PSYCHIATRY, Vol: 64, ISSN: 0924-9338

Journal article

Gimeno H, Polatajko HJ, Cornelius V, Lin J-P, Brown RGet al., 2021, Rehabilitation in childhood-onset hyperkinetic movement disorders including dystonia: Treatment change in outcomes across the ICF and feasibility of outcomes for full trial evaluation, EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, Vol: 33, Pages: 159-167, ISSN: 1090-3798

Journal article

Chis Ster A, Phillips R, Sauzet O, Cornelius Vet al., 2021, Improving analysis practice of continuous adverse event outcomes in randomised controlled trials – a distributional approach, Trials, Vol: 22, ISSN: 1745-6215

BackgroundRandomised controlled trials (RCTs) provide valuable information for developing harm profiles but current analysis practices to detect between-group differences are suboptimal. Drug trials routinely screen continuous clinical and biological data to monitor participant harm. These outcomes are regularly dichotomised into abnormal/normal values for analysis. Despite the simplicity gained for clinical interpretation, it is well established that dichotomising outcomes results in a considerable reduction in information and thus statistical power. We propose an automated procedure for the routine implementation of the distributional method for the dichotomisation of continuous outcomes proposed by Peacock and Sauzet, which retains the precision of the comparison of means.MethodsWe explored the use of a distributional approach to compare differences in proportions based on the comparison of means which retains the power of the latter. We applied this approach to the screening of clinical and biological data as a means to detect ‘signals’ for potential adverse drug reactions (ADRs). Signals can then be followed-up in further confirmatory studies. Three distributional methods suitable for different types of distributions are described. We propose the use of an automated approach using the observed data to select the most appropriate distribution as an analysis strategy in a RCT setting for multiple continuous outcomes. We illustrate this approach using data from three RCTs assessing the efficacy of mepolizumab in asthma or COPD. Published reference ranges were used to define the proportions of participants with abnormal values for a subset of 10 blood tests. The between-group distributional and empirical differences in proportions were estimated for each blood test and compared.ResultsWithin trials, the distributions varied across the 10 outcomes demonstrating value in a practical approach to selecting the distributional method in the context of multipl

Journal article

Lammons W, Moss R, Battersby C, Cornelius V, Babalis D, Modi Net al., 2021, Incorporating parent, former patient, and clinician perspectives in the design of a national UK double-cluster, randomised controlled trial addressing uncertainties in preterm nutrition, BMJ Paediatrics Open, Vol: 5, ISSN: 2399-9772

Background: Comparative effectiveness randomised controlled trials are powerful tools to resolve uncertainties in existing treatments and care processes. We sought parent and patient perspectives on the design of a planned national, double-cluster randomised controlled trial (COLLABORATE) to resolve two longstanding uncertainties in preterm nutrition.Methods: We used qualitative focus groups and interviews with parents, former patients and clinicians. We followed the Consolidated Criteria for Reporting Qualitative Research checklist and conducted framework analysis, a specific methodology within thematic analysis.Results: We identified support for the trial’s methodology and vision, and elicited themes illustrating parents’ emotional needs in relation to clinical research. These were: relieving the pressure on mothers to breastfeed; opt-out consent as reducing parent stress; the desire for research to be a partnership between clinicians, parents and researchers; the value of presenting trial information in a collaborative tone; and in a format that allows assimilation by parents at their own pace. We identified anxiety and cognitive dissonance among some clinicians in which they recognised the uncertainties that justify the trial but felt unable to participate because of their strongly held views.Conclusions: The early involvement of parents and former patients identified the centrality of parents’ emotional needs in the design of comparative effectiveness research. These insights have been incorporated into trial enrolment processes and information provided to participants. Specific outputs were a two-sided leaflet providing very brief as well as more detailed information, and use of language that parents perceive as inclusive and participatory. Further work is warranted to support clinicians to address personal biases that inhibit trial participation.

Journal article

Tan P-T, Cro S, Van Vogt E, Szigeti M, Cornelius Vet al., 2021, A review of the use of controlled multiple imputation in randomised controlled trials with missing outcome data, BMC Medical Research Methodology, Vol: 21, ISSN: 1471-2288

Background:Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs.Methods:A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared.Results:A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based (n = 9) or reference-based approach (n = 7). Controlled MI was mostly used in sensitivity analysis (n = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using con

Journal article

Vergis N, Phillips R, Cornelius V, Katsarou A, Youngstein T, Cook L, Willicombe M, Pilay C, Shturova T, Almonte M, Charania A, Turner R, Kon OM, Cooke G, Thursz M, Cherlin S, Wason J, Milojkovic D, Innes AJ, Cooper Net al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215

OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C

Journal article

Li C, Chen K, Cornelius V, Tomeny E, Wang Y, Yang X, Yuan X, Qin R, Yu D, Wu Z, Wang D, Chen Tet al., 2021, Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese population: A cost-effectiveness modeling study, PLoS Medicine, Vol: 18, Pages: 1-14, ISSN: 1549-1277

BackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of <120 mm Hg compared with a SBP goal of <140 mm Hg. Our study aimed to assess the applicability of SPRINT to Chinese adults. Additionally, we sought to predict the medical and economic implications of this intensive SBP treatment among those meeting SPRINT eligibility.Methods and findingsWe used nationally representative baseline data from the China Health and Retirement Longitudinal Study (CHARLS) (2011–2012) to estimate the prevalence and number of Chinese adults aged 45 years and older who meet SPRINT criteria. A validated microsimulation model was employed to project costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPRINT-eligible adults, under 2 alternative treatment strategies (SBP goal of <120 mm Hg [intensive treatment] and SBP goal of <140 mm Hg [standard treatment]). Overall, 22.2% met the SPRINT criteria, representing 116.2 (95% CI 107.5 to 124.8) million people in China. Of these, 66.4%, representing 77.2 (95% CI 69.3 to 85.0) million, were not being treated for hypertension, and 22.9%, representing 26.6 (95% CI 22.4 to 30.7) million, had a SBP between 130 and 139 mm Hg, yet were not taking antihypertensive medication. We estimated that over 5 years, compared to standard treatment, intensive treatment would reduce heart failure incidence by 0.84 (95% CI 0.42 to 1.25) million cases, reduce CVD deaths by 2.03 (95% CI 1.44 to 2.63) million cases, and save 3.84 (95% CI 1.53 to 6.34) million life-years. Estimated reductions of 0.069 (95% CI −0.28, 0.42) million myocardial infarction cases and 0.36 (95% CI −0.10, 0.82) million stroke cases were not statistically significant. Furthermore, over a lifetime, moving from standard to intensive treatment increased the mean QALYs from 9.51 to 9.87 (an increment of 0.38 [95% CI 0.13

Journal article

Kelleher MM, Cro S, Van Vogt E, Cornelius V, Lodrup Carlsen KC, Ove Skjerven H, Rehbinder EM, Lowe A, Dissanayake E, Shimojo N, Yonezawa K, Ohya Y, Yamamoto-Hanada K, Morita K, Cork M, Cooke A, Simpson EL, McClanahan D, Weidinger S, Schmitt J, Axon E, Tran L, Surber C, Askie LM, Duley L, Chalmers JR, Williams HC, Boyle RJet al., 2021, Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis, Clinical and Experimental Allergy, Vol: 51, Pages: 402-418, ISSN: 0954-7894

ObjectiveEczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.DesignA prospectively planned individual participant data meta‐analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.Data sourcesCochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.Eligibility criteria for selected studiesIncluded studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.ResultsOf the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta‐analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3–12 months. Skincare interventions probably do not change risk of eczema by age 1–3 years (RR 1.03, 95% CI 0.81, 1.31; I2=41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1–3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2=0%; moderate certainty; 2728 participants, 6 trials).ConclusionRegular emollients during infancy probably do not prevent eczema and probably increase local skin infections.

Journal article

Kelleher MM, Cro S, Cornelius V, Lodrup Carlsen KC, Skjerven HO, Rehbinder EM, Lowe AJ, Dissanayake E, Shimojo N, Yonezawa K, Ohya Y, Yamamoto-Hanada K, Morita K, Axon E, Surber C, Cork M, Cooke A, Tran L, Van Vogt E, Schmitt J, Weidinger S, McClanahan D, Simpson E, Duley L, Askie LM, Chalmers JR, Williams HC, Boyle RJet al., 2021, Skin care interventions in infants for preventing eczema and food allergy., Cochrane Database of Systematic Reviews, Vol: 2021, Pages: 1-165, ISSN: 1469-493X

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together 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 in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess 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 searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included 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 ana

Journal article

Gimeno H, Polatajko HJ, Lin J-P, Cornelius V, Brown RGet al., 2021, Cognitive strategy training in childhood-onset movement disorders: replication across therapists, Frontiers in Pediatrics, Vol: 8, Pages: 1-22, ISSN: 2296-2360

Objective: To explore preliminary effectiveness of the Cognitive Orientation to daily Occupational Performance (CO-OP) Approach in improving outcomes in childhood-onset hyperkinetic movement disorders (HMDs) including dyskinetic cerebral palsy following deep brain stimulation (DBS) across UK clinical occupational therapists.Methods: Randomized, multiple-baseline, Single Case Experimental Design N-of-1 trial with replications across participants. Five self-selected goals were identified: three goals were worked on during CO-OP and two goals were left untreated and used to assess skills transfer. Participants were between 6 and 21 years and had received DBS surgery with baseline Manual Ability Classification System (MACS) levels I–IV. Participants were randomized to typical or extended baseline (2 vs. 6 weeks), followed by 10 weekly individual CO-OP sessions. The primary outcome was functional performance measured by the Performance Quality Rating Scale-Individualized (PQRS-I), assessed before, during, and following treatment. Outcome assessors were blinded to baseline allocation, session number, and assessment time. A non-overlapping index, Tau-U, was used to measure effect size.Results: Of the 12 participants recruited, 10 commenced and completed treatment. In total, 63% of trained goals improved with effect sizes 0.66–1.00 (“moderate” to “large” effect), seen for all children in at least one goal. Skills transfer was found in 37% of the untrained goals in six participants.Conclusions: Cognitive strategy use improved participant-selected functional goals in childhood-onset HMD, more than just practice during baseline. Preliminary effectiveness is shown when the intervention is delivered in clinical practice by different therapists in routine clinical settings.

Journal article

Sin J, Elkes J, Batchelor R, Henderson C, Gillard S, Woodham LA, Chen T, Aden A, Cornelius Vet al., 2021, Mental health and caregiving experiences of family carers supporting people with psychosis, Epidemiology and Psychiatric Sciences, Vol: 30, Pages: 1-9, ISSN: 2045-7979

Background: Family carers supporting an individual with psychosis often experience distress associated with caregiving responsibility. However, scarce research evidence exists investigating mental health morbidities in carers of people with psychosis. Methods: We conducted an online cross-sectional study with adult carers supporting a relative or close friend with psychosis in England. We collected participants’ demographic and health outcome data, including wellbeing (primary outcome) using Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). We explored the relationships between carers’ characteristics for each outcome in turn, using linear regression. We compared carers’ wellbeing with Health Survey England (HSE 2016) general population data using a meta-analysis.Findings: Between March 2018 and February 2020, 407 carers across England provided study data. Carers had a mean WEMWBS score of 42∙2 (SD 9∙21), and their overall weighted pooled WEMWBS score was 7∙3 (95% CI -8∙6 to -6∙0, p<0∙01) lower than the HSE sample, indicating carers have poorer mental wellbeing by more than double the minimum clinically important difference of 3 points on WEMWBS. Among all caring relationships, partners had poorer wellbeing compared to parents with lower WEMWBS score (-6∙8, -16∙9 to 3∙3, p=0∙03). Single or lone carers had significantly poorer wellbeing (-3∙6, -5∙6 to -1∙5, p<0∙01) than those who were cohabiting.Interpretation: Carers of people with psychosis have poorer mental health than non-carers; partners and lone carers most at risk of poor outcomes. Future large-scale prospective studies are needed to develop a predictive model for healthcare clinicians to use and to inform tailored intervention development.Funding Statement: NIHR Post-Doctoral Research Fellowship.Declaration of Interests: All authors have no conflicts of interests to declare.Ethics Approval Statement: The RCT has been reviewed and approved by South Central – Oxford C Research Et

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