Editor's Choice - Comparison of Open Surgery and Endovascular Techniques for Juxtarenal and Complex Neck Aortic Aneurysms: The UK COMPlex AneurySm Study (UK-COMPASS) - Peri-operative and Midterm Outcomes.

OBJECTIVE: Treatment of juxtarenal and complex neck abdominal aortic aneurysms (AAAs) is now commonly by endovascular rather than open surgical repair (OSR). Published comparisons show poor validity and scientific precision. UK-COMPASS is a comparative cohort study of endovascular treatments vs. OSR for patients with an AAA unsuitable for standard on label endovascular aneurysm repair (EVAR). METHODS: All procedures for AAA in England (November 2017 to October 2019) were identified, AAA anatomy assessed in a Corelab, peri-operative risk scores determined, and propensity scoring used to identify patients suitable for either endovascular treatment or OSR. Patients were stratified by aneurysm neck length (0 - 4 mm, 5 - 9 mm, or ≥ 10 mm) and operative risk; the highest quartile was considered high risk and the remainder standard risk. Death was the primary outcome measure. Endovascular treatments included fenestrated EVAR (FEVAR) and off label standard EVAR (± adjuncts). RESULTS: Among 8 994 patients, 2 757 had AAAs that were juxtarenal, short neck, or complex neck in morphology. Propensity score stratification and adjustment method comparisons included 1 916 patients. Widespread off label use of standard EVAR devices was noted (35.6% of patients). The adjusted peri-operative mortality rate was 2.9%, lower for EVAR (1.2%; p = .001) and FEVAR (2.2%; p = .001) than OSR (4.5%). In standard risk patients with a 0 - 4 mm neck, the mortality rate was 7.4% following OSR and 2.3% following FEVAR. Differences were smaller for patients with a neck length ≥ 5 mm: 2.1% OSR vs. 1.0% FEVAR. At 3.5 years of follow up, the overall mortality rate was 20.7% in the whole study population, higher following FEVAR (27.6%) and EVAR (25.2%) than after OSR (14.2%). However, in the 0 - 4 mm neck subgroup, overall survival remained equivalent. The aneurysm related mortality rate was equivalent between treatments, but re-intervention was more common after EVAR and FEVAR than OSR. CONCLUSION: FEVAR proves notably safer than OSR in the peri-operative period for juxtarenal aneurysms (0 - 4 mm neck length), with comparable midterm survival. For patients with short neck (5 - 9 mm) and complex neck (≥ 10 mm) AAAs, overall survival was worse in endovascularly treated patients compared with OSR despite relative peri-operative safety. This warrants further research and a re-appraisal of the current clinical application of endovascular strategies, particularly in patients with poor general survival outlook owing to comorbidity and age.

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.

Treatment Adherence in a Randomized Controlled Trial of Pirfenidone in HFpEF: Determinants and Impact on Efficacy.

OBJECTIVES: Medication adherence in patients with heart failure with preserved ejection fraction is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial. METHODS AND RESULTS: Adherence was evaluated through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis. Complete adherence data were available in 54 of 80 participants completing the trial. Mean adherence to study medication was 94.7% and 96.9% in the pirfenidone and placebo groups, respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (-0.004%; 95% confidence interval: -0.007% to -0.001%; P = 0.007). Associations with adherence included older age, higher symptom burden, lower body weight, and smaller right ventricular size. CONCLUSION: Adherence to study medication in the PIROUETTE trial was very high among patients for whom complete adherence data were available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required.

A mixed method, phase 2 clinical evaluation of a novel device to treat postpartum haemorrhage.

BACKGROUND: We evaluated the safety, efficacy, and acceptability of a new device designed to facilitate uterine compression in women with postpartum haemorrhage (PPH). METHODS: A prospective, phase two clinical device trial with concurrent qualitative study, conducted in a UK consultant obstetric unit. The device was used in addition to standard care in women unresponsive to initial oxytocin therapy. The primary effectiveness outcome was additional blood loss of over 1000mls, whilst safety was assessed through adverse events. Interviews assessed device feasibility and acceptability, and were analysed using framework analysis. RESULTS: We recruited 57 women with clinical PPH after vaginal birth; 67% were primiparous and 47% had undergone operative birth. All but two (96%) had atony as a cause of the haemorrhage; in addition, 30% also had bleeding from lacerations and 11% had retained tissue. After device use, only one woman had additional blood loss over 1000mls, although 3 women (7%) needed a Bakri balloon and 14% received a blood transfusion. All but one clinician felt that the device was easy to use. Clinicians stated that the device assisted management in 85% of cases. All 56 women who responded stated that if they bled in a future birth they would want the device to be used again. There were no serious adverse events related to the device. However, 3 events were judged as 'possibly' being caused by the device - 2 minor vaginal grazes and one postnatal episiotomy infection and breakdown. Lax vaginal tissue complicated the use of the device in three women. In 47 interviews, participants, birth partners, clinician users and attending midwives viewed the device positively. Clinicians found it useful as a way of stopping blood loss and as an aid to diagnose the source of bleeding. CONCLUSIONS: The PPH Butterfly may provide a rapid, acceptable and effective treatment for postpartum haemorrhage. Clinical Trial Registration prospective with ISRCTN15452399 11/09/2017 (www.isrctn.com/ISRCTN15452399).

Use of an Online Forum for Relatives of People With Psychosis and Bipolar Disorder: Mixed Methods Study.

BACKGROUND: Relatives of people with psychosis or bipolar disorder experience high levels of distress but are typically not offered the support they need. Online peer forums may offer a solution, but knowledge about who uses them, how, and why is limited. This study reported on online forum use during the Relatives Education and Coping Toolkit (REACT) trial. OBJECTIVE: We aimed to report who used the forum and why; how sociodemographic factors are associated with participation; the relationship among frequency, type of use, and outcomes; and how the forum was used. METHODS: The relationships between key sociodemographic characteristics, levels of forum use, and distress were statistically analyzed. We used thematic and semantic analyses to understand the reasons for relatives joining the forum and the key topics initiated by them. We also used the University Centre for Computer Corpus Research on Language Semantic Analysis System to compare how relatives and REACT supporters (moderators) used the forum. RESULTS: A total of 348 participants with full forum use data from REACT were included in this study. The forum was accessed by 59.4% (207/348) of the relatives across the entire age range, with no significant associations between sociodemographic factors and forum participation, or between level or type of use and relatives' distress levels. Relatives joined the forum primarily to find people in similar circumstances, express concerns, and talk about stressful events. Relatives were most concerned about recent events, negative emotions linked to caring, experiences of conflict or threat, and concerns about suicide. These posts underscored both the challenges the relatives were facing and the fact that they felt safe sharing them in this context. CONCLUSIONS: Although only a proportion of REACT participants engaged actively with its forum, they were widely distributed across age and other sociodemographic groupings. Relatives used the forum for information, support, and guidance and to offer detailed information about their experiences. The topics raised highlighted the burden carried by relatives and the potential value of easy-access, moderated, peer-supported forums in helping relatives to manage the challenges they faced.

Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure with Preserved Ejection Fraction.

Myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume (ECV), is associated with adverse outcome in heart failure with preserved ejection fraction, but the mechanisms by which myocardial fibrosis exerts this deleterious effect are unclear. We performed mediation analyses of data from the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial to determine whether myocardial fibrotic regression causes changes in cardiovascular function and functional status following antifibrotic therapy. Regression of myocardial fibrosis correlated with improvements in 6-min walk test and KCCQ clinical summary score. The only outcome variable that demonstrated a treatment effect was an increase in left ventricular ejection fraction (LVEF). The estimated average causal mediation effects of myocardial ECV, absolute myocardial extracellular matrix volume and absolute myocardial cellular volume on LVEF were 6.1%, 21.5% and 13.7%, respectively, none of which was significant and therefore not mediated by myocardial fibrosis. (PIROUETTE; NCT02932566).

Characteristics Associated With Growth Differentiation Factor 15 in Heart Failure With Preserved Ejection Fraction and the Impact of Pirfenidone.

Background Growth differentiation factor 15 (GDF-15) is elevated in heart failure with preserved ejection fraction and is associated with adverse outcome, but its relationship with myocardial fibrosis and other characteristics remains unclear. We sought to evaluate the effect of pirfenidone, a novel antifibrotic agent, on GDF-15 in heart failure with preserved ejection fraction and identify characteristics that associate with GDF-15 and with change in GDF-15 over 1 year. Methods and Results Among patients enrolled (n=107) in the PIROUETTE (Pirfenidone in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, GDF-15 was measured at baseline and at prespecified time points in patients randomized (n=94) to pirfenidone or placebo. The response of GDF-15 to pirfenidone and the association with baseline patient characteristics were evaluated. Pirfenidone had no impact on circulating GDF-15 at any time point during the 52-week trial period. In multivariable analysis, male sex, diabetes, higher circulating levels of N-terminal pro-B-type natriuretic peptide, lower renal function, and shorter 6-minute walk test distance at baseline were associated with baseline log-GDF-15. Impaired global longitudinal strain at baseline was the strongest predictor of increased GDF-15 over 52 weeks. Conclusions In patients with heart failure with preserved ejection fraction, circulating levels of GDF-15 were unaffected by treatment with pirfenidone and do not appear to be determined by myocardial fibrosis. Circulating GDF-15 was associated with a spectrum of important heart failure characteristics and it may represent a marker of overall physiological disruption. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02932566; Unique identifier: NCT02932566.

Predictors of myocardial fibrosis and response to anti-fibrotic therapy in heart failure with preserved ejection fraction.

Myocardial fibrosis, measured using magnetic resonance extracellular volume (ECV), associates with adverse outcome in heart failure with preserved ejection fraction (HFpEF). In the PIROUETTE (The Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, the novel anti-fibrotic agent pirfenidone reduced myocardial fibrosis. We sought to identify baseline characteristics that associate with myocardial fibrotic burden, the change in myocardial fibrosis over a year, and predict response to pirfenidone in patients with HFpEF. Amongst patients enrolled in the PIROUETTE trial (n = 107), linear regression models were used to assess the relationship between baseline variables and baseline myocardial ECV, with change in myocardial ECV adjusting for treatment allocation, and to identify variables that modified the pirfenidone treatment effect. Body mass index, left atrial reservoir strain, haemoglobin and aortic distensibility were associated with baseline ECV in stepwise modelling, and systolic blood pressure, and log N-terminal pro B-type natriuretic peptide were associated with baseline ECV in clinically-guided modelling. QRS duration, left ventricular mass and presence of an infarct at baseline were associated with an increase in ECV from baseline to week 52. Whilst QRS duration, presence of an infarct, global longitudinal strain and left atrial strain modified the treatment effect of pirfenidone when considered individually, no variable modified treatment effect on multivariable modelling. Baseline characteristics were identified that associate with myocardial fibrosis and predict change in myocardial fibrosis. No variables that independently modify the treatment effect of pirfenidone were identified (PIROUETTE, NCT02932566).

Increased transparency was required when reporting imputation of primary outcome data in clinical trials.

OBJECTIVES: The aim of this study is to explore the transparency of reporting primary outcome data within randomized controlled trials in the presence of missing data. STUDY DESIGN AND SETTING: A cohort examination of randomized controlled trials published in the four major medical journals (NEJM, JAMA, BMJ, Lancet) in 2013 and the first quarter of 2018. Data were extracted on reporting quality, the number of randomized participants, and the number of participants included within the primary outcome analysis with observed or imputed data. RESULTS: Ninety-one of 159 (57%) studies analyzed from 2013 and 19 of 46 (41%) from 2018 included imputed data within the primary outcome analysis. Of these, only 13 of 91 (14%) studies from 2013 and 1 of 19 (5%) studies from 2018 explicitly reported the number of imputed values in the CONSORT diagram. Results' tables included levels of imputed data in 12 of 91 (13%) studies in 2013 and 4 of 19 (21%) in 2018. Consequently, identification of imputed data was a time-consuming task requiring extensive cross-referencing of all manuscript elements. CONCLUSION: Imputed primary outcome data are poorly reported. Participant flow diagrams frequently reported participant status which does not necessarily correlate to availability of data. We recommended that the number of imputed values are explicitly reported within CONSORT flow diagrams to increase transparency.

Protocol for DexEnceph: a randomised controlled trial of dexamethasone therapy in adults with herpes simplex virus encephalitis.

INTRODUCTION: Herpes simplex virus (HSV) encephalitis is a rare severe form of brain inflammation that commonly leaves survivors and their families with devastating long-term consequences. The virus particularly targets the temporal lobe of the brain causing debilitating problems in memory, especially verbal memory. It is postulated that immunomodulation with the corticosteroid, dexamethasone, could improve outcomes by reducing brain swelling. However, there are concerns (so far not observed) that such immunosuppression might facilitate increased viral replication with resultant worsening of disease. A previous trail closed early because of slow recruitment. METHOD: DexEnceph is a pragmatic multicentre, randomised, controlled, open-label, observer-blind trial to determine whether adults with HSV encephalitis who receive dexamethasone alongside standard antiviral treatment with aciclovir for have improved clinical outcomes compared with those who receive standard treatment alone. Overall, 90 patients with HSV encephalitis are being recruited from a target of 45 recruiting sites; patients are randomised 1:1 to the dexamethasone or control arms of the study. The primary outcome measured is verbal memory as assessed by the Weschler Memory Scale fourth edition Auditory Memory Index at 26 weeks after randomisation. Secondary outcomes are measured up to 72 weeks include additional neuropsychological, clinical and functional outcomes as well as comparison of neuroimaging findings. Patient safety monitoring occurs throughout and includes the detection of HSV DNA in cerebrospinal fluid 2 weeks after randomisation, which is indicative of ongoing viral replication. Innovative methods are being used to ensure recrutiment targets are met for this rare disease. DISCUSSION: DexEnceph aims to be the first completed randomised controlled trial of corticosteroid therapy in HSV encephalitis. The results will provide evidence for future practice in managing adults with the condition and has the potential to improve outcomes . ETHICS AND DISSEMINATION: The trial has ethical approval from the UK National Research Ethics Committee (Liverpool Central, REF: 15/NW/0545, 10 August 2015). Protocol V.2.1, July 2019. The results will be published and presented as soon as possible on completion. TRIAL REGISTRATION NUMBERS: ISRCTN11774734, EUDRACT 2015-001609-16.

Adding a fourth rater to three had little impact in pre-linguistic outcome classification.

The consequence of differing levels of agreement across raters is rarely studied. Subsequently, knowledge is limited on how number of raters affects the outcome. The present study aimed to examine the impact on pre-linguistic outcome classifications of 12-month-old infants when using four raters compared to three. Thirty experienced Speech and Language Therapists (SLTs) from five countries assessed 20 minute video recordings of four 12-month-old infants during a play session with a parent. One recording was assessed twice. A naturalistic listening method in real time was used. This involved: (1) assessing, each syllable as canonical or non-canonical, and (2) following the recording, assessing if the infant was babbling canonically and listing the syllables the infant produced with command. The impact that four raters had on outcome, compared to three, was explored by classifying the outcome based on all possible combinations of three raters and determining the frequency that the outcome assessment changed when a fourth assessor was added. Results revealed that adding a fourth rater had a minimal impact on canonical babbling ratio assessment. Presence/absence of canonical babbling and size of consonant inventory showed a negligible impact on three out of four recordings, whereas the size of syllable inventory and presence/absence of canonical babbling was minimally affected in one recording by adding a fourth rater. In conclusion, adding a forth rater in assessment of pre-linguistic utterances in 12-month-old infants with naturalistic assessment in real time does not affect outcome classifications considerably. Thus, using three raters, as opposed to four, is recommended.

National survey of feasibility of NIV trials for management of children with bronchiolitis.

BACKGROUND: Bronchiolitis is a major cause of admission to hospital in children. Non-invasive ventilation (NIV) support with continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) oxygen is routinely used for infants in the UK with bronchiolitis. OBJECTIVE: To establish UK paediatric practice regarding management of bronchiolitis, and to explore issues pertinent to the design of a potential future randomised controlled trial of NIV. DESIGN: Screening logs were completed in hospitals in England capturing information on paediatric bronchiolitis admissions. An online national survey of clinical practice was disseminated to healthcare professionals (HCPs) across the UK to ascertain current management strategies. RESULTS: Screening logs captured data on 393 infants from 8 hospitals. Reasons for admission were most commonly respiratory distress and/or poor fluid intake. Oxygen was administered for 54% of admissions. Respiratory (CPAP and HFNC) and non-respiratory support administered varied considerably. The national survey was completed by 111 HCPs from 76 hospitals. Data were obtained on criteria used to commence and wean NIV, responsibilities for altering NIV settings, minimum training requirements for staff managing a child on NIV, and numbers of trained staff. Most centres were interested in and capable of running a trial of NIV, even out of normal office hours. CONCLUSIONS: Respiratory and non-respiratory management of bronchiolitis in UK centres varies widely. A trial of HFNC oxygen therapy in this group of patients is feasible and HCPs would be willing to randomise patients into such a trial. Future work should focus on defining trial eligibility criteria.

Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study.

BACKGROUND: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity. METHODS: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics. FINDINGS: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047). INTERPRETATION: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation. FUNDING: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT.

BACKGROUND: Relatives caring for people with severe mental health problems find information and emotional support hard to access. Online support for self-management offers a potential solution. OBJECTIVE: The objective was to determine the clinical effectiveness and cost-effectiveness of an online supported self-management tool for relatives: the Relatives' Education And Coping Toolkit (REACT). DESIGN AND SETTING: This was a primarily online (UK), single-blind, randomised controlled trial, comparing REACT plus a resource directory and treatment as usual with the resource directory and treatment as usual only, by measuring user distress and other well-being measures at baseline and at 12 and 24 weeks. PARTICIPANTS: A total of 800 relatives of people with severe mental health problems across the UK took part; relatives who were aged ≥ 16 years, were experiencing high levels of distress, had access to the internet and were actively seeking help were recruited. INTERVENTION: REACT comprised 12 psychoeducation modules, peer support through a group forum, confidential messaging and a comprehensive resource directory of national support. Trained relatives moderated the forum and responded to messages. MAIN OUTCOME MEASURE: The main outcome was the level of participants' distress, as measured by the General Health Questionnaire-28 items. RESULTS: Various online and offline strategies, including social media, directed potential participants to the website. Participants were randomised to one of two arms: REACT plus the resource directory (n = 399) or the resource directory only (n = 401). Retention at 24 weeks was 75% (REACT arm, n = 292; resource directory-only arm, n = 307). The mean scores for the General Health Questionnaire-28 items reduced substantially across both arms over 24 weeks, from 40.2 (standard deviation 14.3) to 30.5 (standard deviation 15.6), with no significant difference between arms (mean difference -1.39, 95% confidence interval -3.60 to 0.83; p = 0.22). At 12 weeks, the General Health Questionnaire-28 items scores were lower in the REACT arm than in the resource directory-only arm (-2.08, 95% confidence interval -4.14 to -0.03; p = 0.027), but this finding is likely to be of limited clinical significance. Accounting for missing data, which were associated with higher distress in the REACT arm (0.33, 95% confidence interval -0.27 to 0.93; p = 0.279), in a longitudinal model, there was no significant difference between arms over 24 weeks (-0.56, 95% confidence interval -2.34 to 1.22; p = 0.51). REACT cost £142.95 per participant to design and deliver (£62.27 for delivery only), compared with £0.84 for the resource directory only. A health economic analysis of NHS, health and Personal Social Services outcomes found that REACT has higher costs (£286.77), slightly better General Health Questionnaire-28 items scores (incremental General Health Questionnaire-28 items score adjusted for baseline, age and gender: -1.152, 95% confidence interval -3.370 to 1.065) and slightly lower quality-adjusted life-year gains than the resource directory only; none of these differences was statistically significant. The median time spent online was 50.8 minutes (interquartile range 12.4-172.1 minutes) for REACT, with no significant association with outcome. Participants reported finding REACT a safe, confidential environment (96%) and reported feeling supported by the forum (89%) and the REACT supporters (86%). No serious adverse events were reported. LIMITATIONS: The sample comprised predominantly white British females, 25% of participants were lost to follow-up and dropout in the REACT arm was not random. CONCLUSIONS: An online self-management support toolkit with a moderated group forum is acceptable to relatives and, compared with face-to-face programmes, offers inexpensive, safe delivery of National Institute for Health and Care Excellence-recommended support to engage relatives as peers in care delivery. However, currently, REACT plus the resource directory is no more effective at reducing relatives' distress than the resource directory only. FUTURE WORK: Further research in improving the effectiveness of online carer support interventions is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72019945. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 32. See the NIHR Journals Library website for further project information.

Relatives of people with severe mental health problems need better access to information and emotional support. The Relatives' Education And Coping Toolkit (REACT) is a website designed to do this. It includes lots of information presented in text and video, an online forum for relatives to share knowledge and experience, a messaging system where they can ask questions in confidence and a comprehensive directory of contact details for national organisations offering relevant support. Trained relatives support the forum and messaging. In the UK, we recruited 800 relatives of people with severe mental health problems: all were aged ≥ 16 years, had high levels of distress, had access to the internet and wanted help. We divided them into two equal groups: one group received REACT (including the resource directory), whereas the other group received the resource directory only. To ensure that there were no differences between groups at the start, relatives were allocated to the two groups randomly, so they had an equal chance of being in either group. We followed up with both groups at 12 and 24 weeks, and received data from approximately three-quarters of the participants. This trial found that REACT was acceptable, safe and inexpensive to deliver (£62.27 per relative), compared with face-to-face interventions, and that relatives using it felt well supported. However, once we accounted for missing data (relatives who dropped out of the trial or did not complete the follow-up questionnaires), there were no significant differences between the groups. There was no evidence that REACT increased relatives' quality of life or saved money for the NHS.

Methodological Challenges in Web-Based Trials: Update and Insights From the Relatives Education and Coping Toolkit Trial.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2017-016965.

Lay-therapist-delivered, low-intensity, psychosocial intervention for refugees and asylum seekers (PROSPER): protocol for a pilot randomised controlled trial.

BACKGROUND: Asylum seekers and refugees (AS&Rs) experience impaired mental health and wellbeing, related to stresses in their country of origin, experiences in transit and reception on arrival, including significant barriers to accessing mainstream services. Their contact with health care is often crisis-driven and mediated through non-governmental organisations (NGOs). Problem Management Plus (PM+) is a psychosocial intervention recommended by the World Health Organisation to address distress experienced by adults affected by humanitarian crises. We are investigating its application for the first time in a high-income country. METHODS: In a pilot randomised controlled trial (RCT), PM+ will be delivered to AS&Rs in contact with NGOs in Liverpool City Region, UK by lay therapists who have lived experience of forced migration. Following systematic review and stakeholder engagement, PM+ has been adapted to the local context, and lay therapists have been trained in its delivery. We will assess the feasibility of conducting a three-arm RCT of five 90-min sessions of PM+, delivered individually or in groups by lay therapists to AS&Rs experiencing emotional distress and functional impairment, compared with each other and with usual support offered by local NGOs. Distress and impairment at baseline will be measured by the Hospital Anxiety and Depression Scale (HADS) and the WHO Disability Assessment Schedule (WHO-DAS). We aim to recruit 105 participants, 35 per arm. Primary health outcomes are anxiety and depressive symptoms at 3 months, measured by HADS. Secondary outcomes include subjective wellbeing, functional status, progress on identified problems, presence of post-traumatic stress disorder and depressive disorder and service usage. Longer-term impact will be assessed at 6 months post baseline, on the same parameters. We will assess the feasibility of conducting a full RCT in relation to the following elements: recruitment and retention of lay therapists and study participants; fidelity of delivery of PM+; and suitability of the study measures, including any linguistic or cultural barriers. DISCUSSION: We will use these findings to specify the parameters for a full RCT to test the effectiveness and cost-effectiveness of PM+ in reducing emotional distress and health inequalities, and improving functional ability and wellbeing, amongst asylum seekers and refugees. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN15214107. Registered on 10 September 2019.

Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial.

BACKGROUND: The Relatives Education And Coping Toolkit (REACT) is an online supported self-management toolkit for relatives of people with psychosis or bipolar designed to improve access to NICE recommended information and emotional support. AIMS: Our aim was to determine clinical and cost-effectiveness of REACT including a Resource Directory (RD), versus RD-only. METHODS: A primarily online, observer-blind randomised controlled trial comparing REACT (including RD) with RD only (registration ISRCTN72019945). Participants were UK relatives aged > = 16, with high distress (assessed using the GHQ-28), and actively help-seeking, individually randomised, and assessed online. Primary outcome was relatives' distress (GHQ-28) at 24 weeks. Secondary outcomes were wellbeing, support, costs and user feedback. RESULTS: We recruited 800 relatives (REACT = 399; RD only = 401) with high distress at baseline (GHQ-28 REACT mean 40.3, SD 14.6; RD only mean 40.0, SD 14.0). Median time spent online on REACT was 50.8 min (IQR 12.4-172.1) versus 0.5 min (IQR 0-1.6) on RD only. Retention to primary follow-up (24 weeks) was 75% (REACT n = 292 (73.2%); RD-only n = 307 (76.6%)). Distress decreased in both groups by 24 weeks, with no significant difference between the two groups (- 1.39, 95% CI -3.60, 0.83, p = 0.22). Estimated cost of delivering REACT was £62.27 per person and users reported finding it safe, acceptable and convenient. There were no adverse events or reported side effects. CONCLUSIONS: REACT is an inexpensive, acceptable, and safe way to deliver NICE-recommended support for relatives. However, for highly distressed relatives it is no more effective in reducing distress (GHQ-28) than a comprehensive online resource directory. TRIAL REGISTRATION: ISRCTN72019945 prospectively registered 19/11/2015.

Author Correction: A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis.

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87-1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.

A review of current practice in the design and assessment of internal pilots in UK NIHR clinical trials.

BACKGROUND: Internal pilots provide useful information which can help to optimise the running of the main trial. Although some recommendations exist in the literature for the design of internal pilots, little is known about current practice in terms of the specification and also the assessment of progression criteria. The aim of the review is to provide an overview of current practice. METHODS: A cohort of clinical trials with an internal pilot, funded by the National Institute for Health Research (NIHR), Health Technology Assessment programme (HTA), extracted in 2017 was reviewed. Data were extracted from: project descriptions; summary of changes from the first stage; feedback about the full application; monitoring notes; progress report history and protocols, for information about the design and assessment of internal pilots. RESULTS: Fifty-seven studies were reviewed. An internal pilot was first proposed in the early stages of the trial in the majority of cases. Target number for recruitment, rate of randomisation, retention/primary outcome ascertainment rate, rate of treatment adherence and consent rate were included as progression criteria. All but one study was permitted to continue to the main trial; however, 25% did not strictly meet the progression criteria. Changes were made to the design of the main trial for 25% of studies, mainly in terms of conduct of recruitment. CONCLUSIONS: This review provides insight into the process of designing and assessing internal pilots. Progression criteria are sometimes not met; however, committees involved in the reviewing process will recommend continuation to the main trial, usually accompanied by a second review or close monitoring. Recommendations are made to optimise the process.