Imperial College London

Dr Rachel Phillips

Faculty of MedicineSchool of Public Health

Senior Lecturer in Medical Statistics and Clinical Trials
 
 
 
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Contact

 

+44 (0)20 7594 8802r.phillips

 
 
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Location

 

Stadium HouseWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

72 results found

Yoong J, Yuen KH, Molton JS, Ding Y, Cher BP, Chan M, Kalimuddin S, Oon J, Young B, Low J, Salada BMA, Lee TH, Wijaya LM, Fisher D, Izharuddin E, Wei Y, Phillips R, Moorakonda R, Lye DC, Archuleta Set al., 2023, Cost-minimization analysis of oral versus intravenous antibiotic treatment for Klebsiella pneumoniae liver abscess, Scientific Reports, Vol: 13, Pages: 1-7, ISSN: 2045-2322

A cost-minimization analysis was conducted for Klebsiella pneumoniae liver abscess (KLA) patients enrolled in a randomized controlled trial which found oral ciprofloxacin to be non-inferior to intravenous (IV) ceftriaxone in terms of clinical outcomes. Healthcare service utilization and cost data were obtained from medical records and estimated from self-reported patient surveys in a non-inferiority trial of oral ciprofloxacin versus IV ceftriaxone administered to 152 hospitalized adults with KLA in Singapore between November 2013 and October 2017. Total costs were evaluated by category and payer, and compared between oral and IV antibiotic groups over the trial period of 12 weeks. Among the subset of 139 patients for whom cost data were collected, average total cost over 12 weeks was $16,378 (95% CI, $14,620-$18,136) for the oral ciprofloxacin group and $20,569 (95% CI, $18,296-$22,842) for the IV ceftriaxone group, largely driven by lower average outpatient costs, as the average number of outpatient visits was halved for the oral ciprofloxacin group. There were no other statistically significant differences, either in inpatient costs or in other informal healthcare costs. Oral ciprofloxacin is less costly than IV ceftriaxone in the treatment of Klebsiella liver abscess, largely driven by reduced outpatient service costs.Trial registration: ClinicalTrials.gov Identifier NCT01723150 (7/11/2012).

Journal article

Junqueira DR, Zorzela L, Golder S, Loke Y, Gagnier JJ, Julious SA, Li T, Mayo-Wilson E, Pham B, Phillips R, Santaguida P, Scherer RW, Gøtzsche PC, Moher D, Ioannidis JPA, Vohra S, CONSORT Harms Groupet al., 2023, CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomized trials., Journal of Clinical Epidemiology, Vol: 158, Pages: 149-165, ISSN: 0895-4356

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper.

Journal article

Edwards MR, Forbes G, Walker N, Morton DG, Mythen MG, Murray D, Anderson I, Mihaylova B, Thomson A, Taylor M, Hollyman M, Phillips R, Young K, Kahan BC, Pearse RM, Grocott MPW, FLO-ELA investigatorset al., 2023, Fluid Optimisation in Emergency Laparotomy (FLO-ELA) Trial: study protocol for a multi-centre randomised trial of cardiac output-guided fluid therapy compared to usual care in patients undergoing major emergency gastrointestinal surgery, Trials, Vol: 24, ISSN: 1745-6215

INTRODUCTION: Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. METHODS: The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phas

Journal article

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

Journal article

Junqueira DR, Zorzela L, Golder S, Loke Y, Gagnier JJ, Julious SA, Li T, Mayo-Wilson E, Pham B, Phillips R, Santaguida P, Scherer RW, Gøtzsche PC, Moher D, Ioannidis JPA, Vohra S, CONSORT Harms Groupet al., 2023, CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomised trials., BMJ: British Medical Journal, Vol: 381, Pages: 1-15, ISSN: 0959-535X

Journal article

Rosan C, Dijk KA-V, Darwin Z, Babalis D, Cornelius V, Phillips R, Richards L, Wright H, Pilling S, Fearon P, Pizzo E, Fonagy Pet 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

Journal article

Kelleher MM, Phillips R, Brown SJ, Cro S, Cornelius V, Carlsen KCL, Skjerven HO, Rehbinder EM, Lowe AJ, Dissanayake E, Shimojo N, Yonezawa K, Ohya Y, Yamamoto-Hanada K, Morita K, Axon E, Cork M, Cooke A, Van Vogt E, Schmitt J, Weidinger S, McClanahan D, Simpson E, Duley L, Askie LM, Williams HC, Boyle RJet 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

Journal article

Paterson L, Lingford-Hughes A, Cro S, Phillips R, Mozgunov P, Paterson S, Nahar L, Barker D, Smith Cet al., 2022, FORWARDS-1; An adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment; a pharmacokinetic-pharmacodynamic study, Trials, Vol: 23, ISSN: 1745-6215

Background:Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone.Methods:Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodicall

Journal article

Paterson LM, Barker D, Cro S, Mozgunov P, Phillips R, Smith C, Nahar LK, Paterson S, Lingford-Hughes ARet al., 2022, FORWARDS-1; An adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment; a pharmacokinetic-pharmacodynamic study.

<jats:title>Abstract</jats:title> <jats:p>BackgroundTreatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid dependent individuals receiving methadone.MethodsOpiate dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or Type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60 or 90mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 hour later. Measures including oxygen saturation, transcutaneous CO<jats:sub>2</jats:sub>, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofe

Journal article

Monk-Cunliffe J, Borschmann R, Monk A, O'Mahoney J, Henderson C, Phillips R, Gibb J, Moran Pet al., 2022, Crisis interventions for adults with borderline personality disorder, Cochrane Database of Systematic Reviews, Vol: 2022, Pages: 1-57, ISSN: 1469-493X

BackgroundPeople diagnosed with borderline personality disorder (BPD) frequently present to healthcare services in crisis, often with suicidal thoughts or actions. Despite this, little is known about what constitutes effective management of acute crises in this population and what type of interventions are helpful at times of crisis. In this review, we will examine the efficacy of crisis interventions, defined as an immediate response by one or more individuals to the acute distress experienced by another individual, designed to ensure safety and recovery and lasting no longer than one month. This review is an update of a previous Cochrane Review examining the evidence for the effects of crisis interventions in adults diagnosed with BPD.ObjectivesTo assess the effects of crisis interventions in adults diagnosed with BPD in any setting.Search methodsWe searched CENTRAL, MEDLINE, Embase, nine other databases and three trials registers up to January 2022. We also checked reference lists, handsearched relevant journal archives and contacted experts in the field to identify any unpublished or ongoing studies.Selection criteriaRandomised controlled trials (RCTs) comparing crisis interventions with usual care, no intervention or waiting list, in adults of any age diagnosed with BPD.Data collection and analysisWe used standard methodological procedures expected by Cochrane.Main resultsWe included two studies with 213 participants.One study (88 participants) was a feasibility RCT conducted in the UK that examined the effects of joint crisis plans (JCPs) plus treatment as usual (TAU) compared to TAU alone in people diagnosed with BPD. The primary outcome was self‐harm. Participants had an average age of 36 years, and 81% were women. Government research councils funded the study. Risk of bias was unclear for blinding, but low in the other domains assessed. Evidence from this study suggested that there may be no difference between JCPs and TAU on deaths (risk ratio (RR) 0.91, 9

Journal article

Qureshi R, Chen X, Goerg C, Mayo-Wilson E, Dickinson S, Golzarri-Arroyo L, Hong H, Phillips R, Cornelius V, DeMarco MMA, Guallar E, Li Tet 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.

Journal article

Kelleher MM, Cro S, Phillips R, Williams HC, Lowe AJ, Boyle RJet al., 2022, Correspondence to " Emollients in infancy to prevent atopic dermatitis: A systematic review and meta-analysis", Allergy, Vol: 77, Pages: 1931-1933, ISSN: 0105-4538

Journal article

Castle EM, Dijk G, Asgari E, Shah S, Phillips R, Greenwood J, Bramham K, Chilcot J, Greenwood SAet al., 2022, The feasibility and user-experience of a digital health intervention designed to prevent weight gain in new kidney transplant recipients-the ExeRTiOn2 Trial, Frontiers in Nutrition, Vol: 9, ISSN: 2296-861X

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruit

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

Castle E, Dijk G, Shah S, Asgari E, Phillips R, Greenwood J, Bramham K, Chilcot J, Greenwood Set al., 2022, MO589: Exertion2 trial: THE weight gain prevention in renal transplant online study—a randomized controlled feasibility trial, 59th ERA Congress, Publisher: Oxford University Press, Pages: I433-I433, ISSN: 0931-0509

Conference paper

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

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

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

Charania AS, 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, 63rd ASH Annual Meeting and Exposition, Publisher: American Society of Hematology, Pages: 4200-4200, ISSN: 0006-4971

Conference paper

Junqueira D, Phillips R, Zorzela L, Golder S, Yoon L, Moher D, Ioannidis JPA, Vohra Set al., 2021, Commentary: Time to improve the reporting of harms in randomized controlled trials, Journal of Clinical Epidemiology, Vol: 136, Pages: 216-220, ISSN: 0895-4356

Journal article

Furukawa T, Levine S, Buntrock C, Ebert D, Gilbody S, Brabyn S, Kessler D, Kivi M, Björkelund C, Kleiboer A, van Straten A, Riper H, Montero-Marin J, Garcia- Campayo J, Phillips R, Scheider J, Cuijpers P, Karyotaki Eet al., 2021, How can we estimate QALYs based on PHQ-9 scores? Equipercentile linking analysis of PHQ-9 and EQ-5D, Evidence-Based Mental Health, Vol: 24, Pages: 97-101, ISSN: 1362-0347

Background Quality-adjusted life years (QALYs) are widely used to measure the impact of various diseases on both the quality and quantity of life and in their economic valuations. It will be clinically important and informative if we can estimate QALYs based on measurements of depression severity.Objective To construct a conversion table from the Patient Health Questionnaire-9 (PHQ-9), the most frequently used depression scale in recent years, to the Euro-Qol Five Dimensions Three Levels (EQ-5D-3L), one of the most commonly used instruments to assess QALYs.Methods We obtained individual participant data of randomised controlled trials of internet cognitive-behavioural therapy which had administered depression severity scales and the EQ-5D-3L at baseline and at end of treatment. Scores from depression scales were all converted into the PHQ-9 according to the validated algorithms. We used equipercentile linking to establish correspondences between the PHQ-9 and the EQ-5D-3L.Findings Individual-level data from five trials (total N=2457) were available. Subthreshold depression (PHQ-9 scores between 5 and 10) corresponded with EQ-5D-3L index values of 0.9–0.8, mild major depression (10–15) with 0.8–0.7, moderate depression (15–20) with 0.7–0.5 and severe depression (20 or higher) with 0.6–0.0. A five-point improvement in PHQ-9 corresponded approximately with an increase in EQ-5D-3L score by 0.03 and a ten-point improvement by approximately 0.25.Conclusions and Clinical Implications The conversion table between the PHQ-9 and the EQ-5D-3L scores will enable fine-grained assessment of burden of depression at its various levels of severity and of impacts of its various treatments.

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

Furukawa T, Suganuma A, Ostinelli E, Andersson G, Beevers C, Shumake J, Berger T, Willemijn Boele F, Buntrock C, Carlbring P, Choi I, Christensen H, Mackinnon A, Dahne J, Huibers M, Ebert D, Farrer L, Forand N, Strunk D, Ezawa I, Forsell E, Kaldo V, Geraedts A, Gilbody S, Littlewood E, Brabyn S, Hadjistavropoulos H, Schneider L, Johansson R, Kenter R, Kivi M, Björkelund C, Kleiboer A, Riper H, Philipp Klein J, Schröder J, Meyer B, Moritz S, Bücker L, Lintvedt O, Lundgren J, Milgrom J, Gemmill A, Mohr D, Montero-Marin J, Garcia-Campayo J, Nobis S, Zarski A-C, O'Moore K, Williams A, Newby J, Perini S, Phillips R, Schneider J, Pots W, Pugh N, Richards D, Rosso I, Rauch S, Sheeber L, Smith J, Spek V, Pop V, Burcin U, van Bastelaar K, van Luenen S, Garnefski N, Kraaij V, Vernmark K, Warmerdam L, van Straten A, Zagorscak P, Knaevelsrud C, Heinrich M, Miguel C, Cipriani A, Efthimiou O, Karyotaki E, Cuijpers Pet al., 2021, Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data, The Lancet Psychiatry, Vol: 8, Pages: 500-511, ISSN: 2215-0366

BackgroundInternet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom.MethodsWe did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683.FindingsWe identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD −1·83 [95% credible interval (CrI) −2·90 to −0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognosti

Journal article

Ram B, Chalkley A, van Sluijs E, Phillips R, Venkatraman T, Hargreaves D, Viner R, Saxena Set al., 2021, Impact of The daily Mile on children's physical and mental health and educational attainment in primary schools; iMprOVE cohort study protocol, BMJ Open, Vol: 11, ISSN: 2044-6055

Introduction: School-based active mile initiatives such as The Daily Mile (TDM) are widely promoted to address shortfalls in meeting physical activity recommendations. The iMprOVE Study aims to examine the impact of TDM on children’s physical and mental health and educational attainment throughout primary school.Methods and analysis: iMprOVE is a longitudinal quasi-experimental cohort study. We will send a survey to all state-funded primary schools in Greater London to identify participation in TDM. The survey responses will be used for non-random allocation to either the intervention group (Daily Mile schools) or to the control group (non-Daily Mile schools). We aim to recruit 3533 year 1 children (aged 5–6 years) from 77 primary schools and follow them up annually until the end of their primary school years. Data collection taking place at baseline (children in school year 1) and each primary school year thereafter includes device-based measures of moderate-to-vigorous physical activity (MVPA) and questionnaires to measure mental health (Strengths and Difficulties Questionnaire) and educational attainment (ratings from ‘below expected’ to ‘above expected levels’). The primary outcome is the mean change in MVPA minutes from baseline to year 6 during the school day among the intervention group compared with controls. We will use multilevel linear regression models adjusting for sociodemographic data and participation in TDM. The study is powered to detect a 10% (5.5 min) difference between the intervention and control group which would be considered clinically significant.Ethics and dissemination: Ethics has been approved from Imperial College Research Ethics Committee, reference 20IC6127. Key findings will be disseminated to the public through research networks, social, print and media broadcasts, community engagement opportunities and schools. We will work with policy-makers for direct application and impact of our findings.

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

Bartholomew R, Kerry-Barnard S, Beckley-Hoelscher N, Phillips R, Reid F, Fleming C, Lesniewska A, Yoward F, Oakeshott Pet al., 2021, Alcohol use, cigarette smoking, vaping and number of sexual partners: A cross-sectional study of sexually active, ethnically diverse, inner city adolescents, Health Expectations, Vol: 24, Pages: 1009-1014, ISSN: 1369-6513

ContextThere are few UK data on the prevalence and clustering of risky behaviours in ethnically diverse adolescents.ObjectivesTo investigate the prevalence of reported alcohol use, smoking and vaping, and explore whether these behaviours are associated with increased numbers of sexual partners.DesignQuestionnaire survey of ‘Test n Treat’ chlamydia screening trial participants.Setting and participantsSexually active students attending six London technical colleges completed confidential questionnaires and provided genitourinary samples.ResultsThe median age of the 509 participants was 17 years (IQR: 16‐18), 47% were male, 50% were of black ethnicity, 55% reported ≥2 sexual partners in the past year (67% of males and 45% of females) and 6.2% had chlamydia infection and 0.6% gonorrhoea. Almost half (48%) reported getting drunk in the past month, 33% smoked cigarettes and 7% had ever vaped.A larger percentage of students with ≥2 sexual partners than 0‐1 partners reported getting drunk in the past month (53.7%, 144/268% versus 42.2% 94/223, adjusted prevalence ratio: 1.33, 95% confidence interval: 1.11‐1.61) and smoking cigarettes (36.6%, 100/273% versus 30.2%, 67/222, 1.34 (1.05‐1.70)). By contrast, multiple sexual partners were not associated with vaping or chlamydia infection, but numbers were small.ConclusionsWe found high prevalences of risky behaviour and an association between multiple sexual partners and smoking and/or getting drunk. Findings support the introduction of compulsory sex and relationship education in UK secondary schools, including information about the adverse effects of alcohol and smoking.Public contributionParticipants helped with study design, conduct and interpretation.

Journal article

Vergis N, Phillips R, Cornelius V, Katsarou A, Youngstein T, Cook L, Willicombe M, Pillay C, Shturova T, Almonte M, Charania A, Turner R, Kon OM, Cooke G, Thursz M, Cherlin S, Wason J, Milojkovic D, Innes A, Cooper Net al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS)&nbsp;for Hospitalised Patients with Mild or Moderate COVID-19 Pneumonia: A Structured Summary of a Study Protocol for a Randomised Controlled Trial, Publisher: BioMed Central

<jats:title>Abstract</jats:title> <jats:p>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 desaturationDetermine 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.<jats:bold>Trial design</jats:bold>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.</jats:p>

Working paper

Karyotaki E, Efthimiou O, Miguel C, Bermpohl FMG, Furukawa TA, Cuijpers P, Riper H, Patel V, Mira A, Gemmil AW, Yeung AS, Lange A, Williams AD, Mackinnon A, Geraedts A, van Straten A, Meyer B, Björkelund C, Knaevelsrud C, Beevers CG, Botella C, Strunk DR, Mohr DC, Ebert DD, Kessler D, Richards D, Littlewood E, Forsell E, Feng F, Wang F, Andersson G, Hadjistavropoulos H, Christensen H, Ezawa ID, Choi I, Rosso IM, Klein JP, Shumake J, Garcia-Campayo J, Milgrom J, Smith J, Montero-Marin J, Newby JM, Bretón-López J, Schneider J, Vernmark K, Bücker L, Sheeber LB, Warmerdam L, Farrer L, Heinrich M, Huibers MJH, Kivi M, Kraepelien M, Forand NR, Pugh N, Lindefors N, Lintvedt O, Zagorscak P, Carlbring P, Phillips R, Johansson R, Kessler RC, Brabyn S, Perini S, Rauch SL, Gilbody S, Moritz S, Berger T, Pop V, Kaldo V, Spek V, Forsell Yet al., 2021, Internet-based cognitive behavioral therapy for depression, JAMA Psychiatry, ISSN: 2168-622X

Importance Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them.Objective To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information.Data Sources We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019.Study Selection Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization.Data Extraction and Synthesis We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression.Main Outcomes and Measures Patient Health Questionnaire–9 (PHQ-9) scores.Results Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, −0.8; 95% CI, −1.4 to −0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshol

Journal article

Cornelius V, Cro S, Phillips R, 2020, Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials, Trials, Vol: 21, ISSN: 1745-6215

BackgroundRandomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data.MethodsIn this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata.Results/case studyVisualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors’ conclusion. In the Parkinson’s disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary.ConclusionsVisualisations can better support investigators to assimilate large volumes of data and ena

Journal article

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