A novel experience-based internet intervention for smoking cessation : feasibility randomised controlled trial

The iPEx programme presents independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research funding scheme (RP-PG-0608-10147). The views expressed in this paper are those of the authors, representing iPEx, and not necessarily those of the NHS, the NIHR or the Department of Health.Peer reviewedPublisher PD

Effectiveness and cost-effectiveness of a fully self-guided internet-based intervention for sub-clinical social anxiety symptoms : protocol for a randomised controlled trial

Design and objective: This paper describes the protocol for a large-scale pragmatic, randomised controlled trial and economic evaluation to investigate the effectiveness and cost-effectiveness of the self-directed E-Couch social anxiety module versus a waiting list control condition, for reducing sub-clinical social anxiety symptoms in the general population. Study population: Community-based adults (aged 18+) with social anxiety symptoms that do not meet the criteria for social anxiety disorder recruited via a direct-to-consumer advertisement on national websites. Intervention and control: Intervention is the self-guided E-Couch social anxiety module. Control group participants are placed on a waiting list to receive the intervention at the end of the trial. Both groups receive email and text message reminders. Outcome measures: The primary outcome will be change in self-reported social anxiety score using the Social Phobia Inventory (SPIN). Secondary outcomes will be the changes in the following self-report measures: Brief Fear of Negative Evaluation scale (BFNE-S); depression (CES-D); mental wellbeing (SWEMWEBS); health status (SF36); use of health services; safety events; and adherence, retention, and attrition rates. All measures will be administered at baseline, 6 weeks, and 3, 6 and 12 months. Analysis: A mixed effects model will be used to analyse the effect of the intervention on the primary and secondary outcomes (intention to treat analysis). Secondary analyses will explore moderators and mediators of effect. A prospective economic evaluation, conducted from a NHS and social care perspective, will provide estimates of cost utility and cost-effectiveness. An interview study will be conducted with 20 participants to explore issues including acceptability, adherence, retention and attrition

Effectiveness and cost-effectiveness of a self-guided internet intervention for social anxiety symptoms in a general population sample : randomized controlled trial

Background: Many people are accessing digital self-help for mental health problems, often with little evidence of effectiveness.Social anxiety is one of the most common sources of mental distress in the population and many people with symptoms do not seek help for what represents a significant public health problem. Objective: Two group randomized controlled trial conducted in England between 11th May 2016 and 27th June 2018. Adults with social anxiety symptoms who were not receiving treatment for social anxiety were recruited using online advertisements. All participants had unrestricted access to usual care and were randomized in a 1:1 ratio to either a web-based unguided self-help intervention based on cognitive-behavioural principles, or to a waiting list control group. All outcomes were collected through self-report online questionnaires. The primary outcome was the change in 17-item self-report Social Phobia Inventory (SPIN-17) score from baseline to 6 weeks using a linear mixed-effect model that used data from all timepoints (6 weeks, 3, 6, 12 months). Methods: Two group randomized controlled trial conducted in England between 11th May 2016 and 27th June 2018. Adults with social anxiety symptoms who were not receiving treatment for social anxiety were recruited using online advertisements. All participants had unrestricted access to usual care and were randomized in a 1:1 ratio to either a web-based unguided self-help intervention based on cognitive-behavioural principles, or to a waiting list control group. All outcomes were collected through self-report online questionnaires. The primary outcome was the change in 17-item self-report Social Phobia Inventory (SPIN-17) score from baseline to 6 weeks using a linear mixed-effect model that used data from all timepoints (6 weeks, 3, 6, 12 months). Results: 2212 participants were randomized. Six were excluded from analyses as ineligible. Of the 2116 eligible randomized participants (mean age 37 years, 80% women), 70.1% (1484/2116) had follow-up data available for analysis, and 56.9% (1205/2116) had data on the primary outcome, although attrition was higher in the intervention arm. At 6 weeks the mean (95% CI, P value) adjusted difference in change in SPIN-17 score in the intervention group compared to control, was -1.94 (-3.13 to -0.75, P=0.0014), a standardised mean difference effect size of 0.2. The improvement was maintained at 12 months. Given the high drop-out, sensitivity analyses explored missing data assumptions and were consistent with the primary analysis finding. The economic evaluation demonstrated cost-effectiveness with a small health status benefit and a reduction in health service utilisation. Conclusions: For people with social anxiety symptoms who are not receiving other forms of help, this study suggests that an online self-help tool based on cognitive behavioural principles can provide a small improvement in social anxiety symptoms compared with no intervention, although drop-out rates were high. Clinical Trial: ClinicalTrials.gov NCT02451878. https://clinicaltrials.gov/ct2/show/NCT0245187

An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): a pragmatic, parallel-group, randomised controlled trial

Background The obesity epidemic has major public health consequences. Expert dietetic and behavioural counselling with intensive follow-up is effective, but resource requirements severely restrict widespread implementation in primary care, where most patients are managed. We aimed to estimate the effectiveness and cost-effectiveness of an internet-based behavioural intervention (POWeR+) combined with brief practice nurse support in primary care. Methods We did this pragmatic, parallel-group, randomised controlled trial at 56 primary care practices in central and south England. Eligible adults aged 18 years or older with a BMI of 30 kg/m2 or more (or ≥28 kg/m2 with hypertension, hypercholesterolaemia, or diabetes) registered online with POWeR+—a 24 session, web-based, weight management intervention lasting 6 months. After registration, the website automatically randomly assigned patients (1:1:1), via computer-generated random numbers, to receive evidence-based dietetic advice to swap foods for similar, but healthier, choices and increase fruit and vegetable intake, in addition to 6 monthly nurse follow-up (control group); web-based intervention and face-to-face nurse support (POWeR+Face-to-face [POWeR+F]; up to seven nurse contacts over 6 months); or web-based intervention and remote nurse support (POWeR+Remote [POWeR+R]; up to five emails or brief phone calls over 6 months). Participants and investigators were masked to group allocation at the point of randomisation; masking of participants was not possible after randomisation. The primary outcome was weight loss averaged over 12 months. We did a secondary analysis of weight to measure maintenance of 5% weight loss at months 6 and 12. We modelled the cost-effectiveness of each intervention. We did analysis by intention to treat, with multiple imputation for missing data. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN21244703. Findings Between Jan 30, 2013, and March 20, 2014, 818 participants were randomly assigned to the control group (n=279), the POWeR+F group (n=269), or the POWeR+R group (n=270). Weight loss averaged over 12 months was recorded in 666 (81%) participants. The control group lost almost 3 kg over 12 months (crude mean weight: baseline 104·38 kg [SD 21·11; n=279], 6 months 101·91 kg [19·35; n=136], 12 months 101·74 kg [19·57; n=227]). The primary imputed analysis showed that compared with the control group, patients in the POWeR+F group achieved an additional weight reduction of 1·5 kg (95% CI 0·6–2·4; p=0·001) averaged over 12 months, and patients in the POWeR+R group achieved an additional 1·3 kg (0·34–2·2; p=0·007). 21% of patients in the control group had maintained a clinically important 5% weight reduction at month 12, compared with 29% of patients in the POWeR+F group (risk ratio 1·56, 0·96–2·51; p=0·070) and 32% of patients in the POWeR+R group (1·82, 1·31–2·74; p=0·004). The incremental overall cost to the health service per kg weight lost with the POWeR+ interventions versus the control strategy was £18 (95% CI −129 to 195) for POWeR+F and –£25 (−268 to 157) for POWeR+R; the probability of being cost-effective at a threshold of £100 per kg lost was 88% and 98%, respectively. No adverse events were reported. Interpretation Weight loss can be maintained in some individuals by use of novel written material with occasional brief nurse follow-up. However, more people can maintain clinically important weight reductions with a web-based behavioural program and brief remote follow-up, with no increase in health service costs. Future research should assess the extent to which clinically important weight loss can be maintained beyond 1 year

Effectiveness and cost-effectiveness of a fully self-guided internet-based intervention for sub-clinical social anxiety symptoms: Protocol for a randomised controlled trial

DESIGN AND OBJECTIVE: This paper describes the protocol for a large-scale pragmatic, randomised controlled trial and economic evaluation to investigate the effectiveness and cost-effectiveness of the self-directed E-Couch social anxiety module versus a waiting list control condition, for reducing sub-clinical social anxiety symptoms in the general population. STUDY POPULATION: Community-based adults (aged 18þ) with social anxiety symptoms that do not meet the criteria for social anxiety disorder recruited via a direct-to-consumer advertisement on national websites. INTERVENTION AND CONTROL: Intervention is the self-guided E-Couch social anxiety module. Control group participants are placed on a waiting list to receive the intervention at the end of the trial. Both groups receive email and text message reminders. OUTCOME MEASURES: The primary outcome will be change in self-reported social anxiety score using the Social Phobia Inventory (SPIN). Secondary outcomes will be the changes in the following self-report measures: Brief Fear of Negative Evaluation scale (BFNE-S); depression (CES-D); mental wellbeing (SWEMWEBS); health status (SF36); use of health services; safety events; and adherence, retention, and attrition rates. All measures will be administered at baseline, 6 weeks, and 3, 6 and 12 months. ANALYSIS: A mixed effects model will be used to analyse the effect of the intervention on the primary and secondary outcomes (intention to treat analysis). Secondary analyses will explore moderators and mediators of effect. A prospective economic evaluation, conducted from a NHS and social care perspective, will provide estimates of cost utility and costeffectiveness. An interview study will be conducted with 20 participants to explore issues including acceptability, adherence, retention and attrition.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the MQ charity under its PsyIMPACT funding call (www.joinMQ.org). KG is supported by NHMRC Fellowship 1059620. The ongoing delivery of E-Couch is enabled by funding from the Australian Commonwealth Department of Health. HA was funded by a NIHR National School for Primary Care Research Fellowship (up to September 2015). LL and YY are funded by the NIHR Oxford Biomedical Research Centre (Oxford BRC)

Protocol for a double-blind placebo controlled trial to evaluate the efficacy of probiotics in reducing antibiotics for infection in care home residents - the Probiotics to Reduce Infections iN CarE home reSidentS (PRINCESS) Trial

INTRODUCTION:Care home residents are at increased risk of infections and antibiotic prescription. Reduced antibiotic use from fewer infections would improve quality of life. The Probiotics to Reduce Infections iN CarE home residents (PRINCESS) trial aims to determine the efficacy and investigate mechanisms of daily probiotics on antibiotic use and incidence of infections in care home residents. METHODS AND ANALYSIS:PRINCESS is a double-blind, individually randomised, placebo-controlled trial that will assess the effect of a daily oral probiotic combination of Lactobacillus rhamnosus, GG (LGG) and Bifidobacterium animalis subsp. lactis, BB-12 (BB-12) on cumulative antibiotic administration days (CAADs) (primary outcome) for infection in up to 330 care home residents aged and#8805;65 years over up to 12and#8201;months. Secondary outcomes include: Infection: Total number of days of antibiotic administration for each infection type (respiratory tract infection, urinary tract infection, gastrointestinal infection, unexplained fever and other); number, site, duration of infection; estimation of incidence and duration of diarrhoea and antibiotic-associated diarrhoea; Stool microbiology: Clostridium difficile infection; Gram-negative Enterobacteriaceae and vancomycin-resistant enterococci; LGG and BB-12. Oral microbiology: Candida spp. Health and well-being: Self and/or proxy health-related quality of life EQ5D (5and#8201;L); self-and/or proxy-reported ICEpop CAPability measure for older people. Hospitalisations: number and duration of all-cause hospital stays. Mortality: deaths. Mechanistic immunology outcomes: influenza vaccine efficacy (haemagglutination inhibition assay and antibody titres); full blood count and immune cell phenotypes, plasma cytokines and chemokines; cytokine and chemokine response in whole blood stimulated ex vivo by toll-like receptor 2 and 4 agonists; monocyte and neutrophil phagocytosis of Escherichia coli; serum vitamin D. ETHICS AND DISSEMINATION:Ethics approval is from the Wales Research Ethics Committee 3. Findings will be disseminated through peer-reviewed journals and conferences; results will be of interest to patient and policy stakeholders

Effect of probiotic use on antibiotic administration among care home residents: a randomized clinical trial

Importance: probiotics are frequently used by residents in care homes (residential homes or nursing homes that provide residents with 24-hour support for personal care or nursing care), although the evidence on whether probiotics prevent infections and reduce antibiotic use in these settings is limited.Objectives: to determine whether a daily oral probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 compared to placebo reduces antibiotic administration in care home residents. Design, setting and participants: placebo-controlled randomized trial of 310 care home residents aged 65 years and older recruited from 23 care homes in the UK between December 2016 and May 2018, with last follow up on 31st October 2018. Interventions: study participants were assigned to receive a daily capsule containing a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 (total cell count per capsule 1.3x1010 - 1.6x1010) (n=155), or daily matched placebo (n=155), for up to one year. Main outcome measures: the primary outcome was cumulative antibiotic administration days for all cause infections measured from randomization for up to one year.Results: among 310 randomized care home residents (mean age 85.3 years; 66.8% women), 195 (62.9%) remained alive and completed the trial. Participant diary data (daily data including study product use, antibiotic administration, and signs of infection) were available for 97.4% randomized to placebo and 98.7% randomized to the probiotic group. Care home residents randomized to the probiotic group had a mean cumulative systemic antibiotic administration days of 12.9 days (95% CI: 0 to 18.05), and those randomized to placebo, 12.0 days (95% CI: 0 to 16.95) (absolute difference = 0.9 days, 95% CI: -3.25 to 5.05 days; adjusted incidence rate ratio = 1.13, 95% CI: 0.79 to 1.63, P=.50). A total of 120 care home residents experienced 283 adverse events, including 78 (58.6%) hospitalizations in the placebo group and 94 (62.7%) in probiotic group. There were 32 deaths (20.6%) in the placebo group and 33 (21.3%) in the probiotic group..Conclusions and relevance: among care home residents in the UK, a daily dose of a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 did not significantly reduce antibiotic administration for all-cause infections. These findings do not support the use of probiotics in this setting.Trial registration: the trial is registered with the ISRCTN, Registry number ISRCTN16392920. <br/

Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial

Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients

Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial

Introduction Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing.Methods and analysis The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation.Ethics and dissemination This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal.Trial registration ISRCTN20579216