John Norrie

Realising the full potential of data-enabled trials in the UK: a call for action

Publisher: BMJ

Date: 06-2021

DOI: 10.1136/BMJOPEN-2020-043906

Abstract: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up. The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for ‘data-enabled clinical trials’. Showcasing successful ex les and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility recruitment conduct/follow-up collecting benefits/harms and analysis/interpretation. Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a ‘route map’ to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution. EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysi

Publisher: Public Library of Science (PLoS)

Date: 06-07-2021

DOI: 10.1371/JOURNAL.PMED.1003686

Abstract: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Pregnant women included in the analyses were 22 +0 to 34 +6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an in idual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016 1,783 women mean age 29.7 years median BMI 24.8 kg/m 2 67.6% White 11.7% smokers 51.8% nulliparous 10.4% with multiple pregnancy 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018 2,924 women mean age 28.2 years median BMI 25.4 kg/m 2 88.2% White 21% smokers 35.2% nulliparous 3.5% with multiple pregnancy 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R 2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R 2 of 36% (95% CI: 34% to 38%). Recalibration of the model’s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than “treat all” or “treat none” strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry ( ISRCTN 41598423 ) and NIHR Portfolio (CPMS: 31277).

A Digital Intervention to Improve Mental Health and Interpersonal Resilience in Young People Who Have Experienced Technology-Assisted Sexual Abuse: Protocol for a Nonrandomized Feasibility Clinical Tr

Publisher: JMIR Publications Inc.

Date: 25-06-2022

DOI: 10.2196/PREPRINTS.40539

Abstract: o evidence-based support has been offered to young people (YP) who have experienced technology-assisted sexual abuse (TASA). Interventions aimed at improving mentalization (the ability to understand the mental states of oneself and others) are increasingly being applied to treat YP with various clinical issues. Digital technology use among YP is now common. A digital intervention aimed at improving mentalization in YP who have experienced TASA may reduce the risk of revictimization and future harm and make YP more resilient and able to manage distress that might result from TASA experiences. n this paper, we describe a protocol for determining the feasibility of the i-Minds trial and the acceptability, safety, and usability of the digital intervention (the i i-Minds /i app) and explore how to best integrate i-Minds into existing routine care pathways. his is a mixed methods nonrandomized study aimed to determine the feasibility, acceptability, safety, and usability of the intervention. Participants aged between 12 and 18 years who report distress associated with TASA exposure will be recruited from the United Kingdom from the National Health Service (NHS) Trust Child and Adolescent Mental Health Services, sexual assault referral centers, and a web-based e-therapy provider. All participants will receive the i-Minds app for 6 weeks. Coproduced with YP and a range of stakeholders, the i-Minds app focuses on 4 main topics: mentalization, TASA and its impact, emotional and mental health, and trauma. A daily prompt will encourage YP to use the app, which is designed to be used in a stand-alone manner alongside routine care. We will follow participants up after the intervention and conduct interviews with stakeholders to explore the acceptability of the app and trial procedures and identify areas for improvement. Informed by the normalization process theory, we will examine barriers and enablers relevant to the future integration of the intervention into existing care pathways, including traditional clinic-based NHS and NHS e-therapy providers. his study was approved by the Research Ethics Board of Scotland. We expect data to be collected from up to 60 YP. We expect to conduct approximately 20 qualitative interviews with participants and 20 health care professionals who referred YP to the study. The results of this study have been submitted for publication. his study will provide preliminary evidence on the feasibility of recruiting YP to a trial of this nature and on the acceptability, safety, and usability of the i-Minds app, including how to best integrate it into existing routine care. The findings will inform the decision to proceed with a powered efficacy trial. nternational Standard Randomised Controlled Trial Number Registry (ISRCTN) ISRCTN43130832 www.isrctn.com/ISRCTN43130832 ERR1-10.2196/40539

Text message intervention to reduce frequency of binge drinking among disadvantaged men: the TRAM RCT

Publisher: National Institute for Health and Care Research

Date: 06-2018

DOI: 10.3310/PHR06060

Abstract: Socially disadvantaged men are more likely to binge drink frequently and to experience high levels of alcohol-related harm. To test the effectiveness and cost-effectiveness of a text message intervention in reducing the frequency of binge drinking among disadvantaged men. A four-centre, parallel-group, pragmatic, in idually randomised controlled trial was conducted. Randomisation was carried out using a secure remote web-based system. It was stratified by participating centre and recruitment method and restricted using block sizes of randomly varying lengths. The study was conducted in the community. Members of the public helped to develop the study methods. Participants were men aged 25–44 years who had ≥ 2 episodes of binge drinking ( 8 units of alcohol in a single session) in the preceding 28 days. Men were recruited from areas of high deprivation. An empirically and theoretically based text message intervention was delivered by 112 interactive text messages over a 12-week period. The control group received an attentional control comprising 89 text messages on general health. The primary outcome measure was the proportion of men consuming 8 units of alcohol on ≥ 3 occasions (in the previous 28 days) at 12 months post intervention. The recruitment target of 798 was exceeded and 825 men were randomised. Retention was high and similar in the intervention (84.9%) and control (86.5%) groups. Most men in the intervention group engaged enthusiastically with the text messages: almost all (92%) replied to text messages and over two-thirds (67%) replied more than 10 times. The intervention was estimated to have had a modest, statistically non-significant effect on the primary outcome at the 12-month follow-up [odds ratio 0.79, 95% confidence interval (CI) 0.57 to 1.08]. This corresponds to a net reduction of 5.7% in regular binge drinking. Five secondary outcomes showed small non-significant and inconsistent effects on alcohol consumption, with one suggesting a positive effect and four suggesting an adverse effect. Both the short- and the long-term cost per quality-adjusted life-year (QALY) analysis suggested that the brief intervention was dominated by a ‘do-nothing’ option. The intervention’s impacts on patterns of alcohol consumption, QALYs and downstream costs were inconsistent and uncertain. The study used an active control that, combined with the recruitment procedures and baseline assessments, could have biased the treatment effect towards the null. The measurement of alcohol consumption relied on self-reported drinking. The trial has demonstrated that it is possible to recruit and retain large numbers of socially disadvantaged men in a research study. The text messages delivered a complex theoretically and empirically based intervention that fostered enthusiastic engagement with the key components of the behaviour change sequence. The intervention produced a modest, statistically non-significant effect on the primary outcome, with wide CIs. Further research is needed to reduce uncertainty about the treatment effect. The methods developed for this study provide a platform for the design and testing of interventions to reduce inequalities in health. A future trial could reduce the uncertainty around the treatment effect of the intervention. Current Controlled Trials ISRCTN07695192. This study was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research Vol. 6, No. 6. See NIHR Journals Library website for further information.

A Theranostic Cellulose Nanocrystal‐Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma

Publisher: Wiley

Date: 18-03-2021

DOI: 10.1002/SMLL.202007705

Treatment guided by fractional exhaled nitric oxide in addition to standard care in 6- to 15-year-olds with asthma: the RAACENO RCT

Publisher: National Institute for Health and Care Research

Date: 05-2022

DOI: 10.3310/AWOI5587

Abstract: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. The trial took place in 35 hospitals and seven primary care practices in the UK. Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent- atient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. This trial was registered as ISRCTN67875351. This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation Vol. 9, No. 4. See the NIHR Journals Library website for further project information.

Early Signs Monitoring to Prevent Relapse in Psychosis and Promote Well-Being, Engagement, and Recovery: Protocol for a Feasibility Cluster Randomized Controlled Trial Harnessing Mobile Phone Technolo

Publisher: JMIR Publications Inc.

Date: 17-06-2019

DOI: 10.2196/PREPRINTS.15058

Abstract: elapse in schizophrenia is a major cause of distress and disability and is predicted by changes in symptoms such as anxiety, depression, and suspiciousness (early warning signs [EWSs]). These can be used as the basis for timely interventions to prevent relapse. However, there is considerable uncertainty regarding the implementation of EWS interventions. his study was designed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) against treatment as usual (TAU). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, safety, and outcome signals of a digital health intervention as an adjunct to usual care that is deliverable in the UK National Health Service and Australian community mental health service (CMHS) settings. We will assess the feasibility of candidate primary outcomes, candidate secondary outcomes, and candidate mechanisms for a definitive trial. e will randomize CMHSs to EMPOWER or TAU. We aim to recruit up to 120 service user participants from 8 CMHSs and follow them for 12 months. Eligible service users will (1) be aged 16 years and above, (2) be in contact with local CMHSs, (3) have either been admitted to a psychiatric inpatient service or received crisis intervention at least once in the previous 2 years for a relapse, and (4) have an International Classification of Diseases-10 diagnosis of a schizophrenia-related disorder. Service users will also be invited to nominate a carer to participate. We will identify the feasibility of the main trial in terms of recruitment and retention to the study and the acceptability, usability, safety, and outcome signals of the EMPOWER intervention. EMPOWER is a mobile phone app that enables the monitoring of well-being and possible EWSs of relapse on a daily basis. An algorithm calculates changes in well-being based on participants’ own baseline to enable tailoring of well-being messaging and clinical triage of possible EWSs. Use of the app is blended with ongoing peer support. ecruitment to the trial began September 2018, and follow-up of participants was completed in July 2019. Data collection is continuing. The database was locked in July 2019, followed by analysis and disclosing of group allocation. he knowledge gained from the study will inform the design of a definitive trial including finalizing the delivery of our digital health intervention, s le size estimation, methods to ensure successful identification, consent, randomization, and follow-up of participants, and the primary and secondary outcomes. The trial will also inform the final health economic model to be applied in the main trial. nternational Standard Randomized Controlled Trial Number (ISRCTN): 99559262 isrctn.com/ISRCTN99559262

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study

Publisher: National Institute for Health and Care Research

Date: 09-2021

DOI: 10.3310/HTA25520

Abstract: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an in idual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Pregnant women at 22 +0 –34 +6 weeks’ gestation with signs and symptoms of preterm labour. Quantitative fetal fibronectin. Spontaneous preterm birth within 7 days. The in idual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. 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. 25, No. 52. See the NIHR Journals Library website for further project information.

Tibial nerve stimulation compared with sham to reduce incontinence in care home residents: ELECTRIC RCT

Publisher: National Institute for Health and Care Research

Date: 06-2021

DOI: 10.3310/HTA25410

Abstract: Urinary incontinence is prevalent in nursing and residential care homes, and has a profound impact on residents’ dignity and quality of life. Treatment options are limited in these care contexts and care homes predominantly use absorbent pads to contain incontinence, rather than actively treat it. Transcutaneous posterior tibial nerve stimulation is a non-invasive, safe, low-cost intervention that is effective in reducing urinary incontinence in adults. To determine the clinical effectiveness of transcutaneous posterior tibial nerve stimulation to treat urinary incontinence in care home residents and to determine the associated costs of the treatment. A multicentre, pragmatic, participant and outcome assessor-blind, randomised placebo-controlled trial. A total of 37 UK residential and nursing care homes. Care home residents with at least weekly urinary incontinence that is contained using absorbent pads and who are able to use a toilet/toilet aid with or without assistance. Residents were randomised (1 : 1) to receive 12 30-minute sessions of transcutaneous posterior tibial nerve stimulation or sham stimulation over a 6-week period. Primary outcome – change in volume of urine leaked over a 24-hour period at 6 weeks. Secondary outcomes – number of pads used, Perception of Bladder Condition, toileting skills, quality of life and resource use. A total of 408 residents were randomised (transcutaneous posterior tibial nerve stimulation, n = 197 sham stimulation, n = 209) two exclusions occurred post randomisation. Primary outcome data were available for 345 (85%) residents (transcutaneous posterior tibial nerve stimulation, n = 167 sham stimulation, n = 178). Adherence to the intervention protocol was as follows: 78% of the transcutaneous posterior tibial nerve stimulation group and 71% of the sham group received the correct stimulation. Primary intention-to-treat adjusted analysis indicated a mean change of –5 ml (standard deviation 362 ml) urine leakage from baseline in the transcutaneous posterior tibial nerve stimulation group and –66 ml (standard deviation 394 ml) urine leakage in the sham group, which was a statistically significant, but not clinically important, between-group difference of 68-ml urine leakage (95% confidence interval 0 to 136 ml p = 0.05) in favour of the sham group. Sensitivity analysis supported the primary analysis. No meaningful differences were detected in any of the secondary outcomes. No serious adverse events related to transcutaneous posterior tibial nerve stimulation were reported. Economic evaluation assessed the resources used. The training and support costs for the staff to deliver the intervention were estimated at £121.03 per staff member. Estimated costs for delivery of transcutaneous posterior tibial nerve stimulation during the trial were £81.20 per participant. No significant difference was found between participants’ scores over time, or between transcutaneous posterior tibial nerve stimulation and sham groups at any time point, for resident or proxy quality-of-life measures. The ELECTRIC (ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes) trial showed, in the care home context (with a high proportion of residents with poor cognitive capacity and limited independent mobility), that transcutaneous posterior tibial nerve stimulation was not effective in reducing urinary incontinence. No economic case for transcutaneous posterior tibial nerve stimulation was made by the cost–consequences analysis however, the positive reception of learning about urinary incontinence for care home staff supports a case for routine education in this care context. Completing 24-hour pad collections was challenging for care home staff, resulting in some missing primary outcome data. Research should investigate transcutaneous posterior tibial nerve stimulation in residents with urgency urinary incontinence to determine whether or not targeted stimulation is effective. Research should evaluate the effects of continence training for staff on continence care in care homes. Current Controlled Trials ISRCTN98415244 and ClinicalTrials.gov NCT03248362. 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. 25, No. 41. See the NIHR Journals Library website for further project information.

Early Signs Monitoring to Prevent Relapse in Psychosis and Promote Well-Being, Engagement, and Recovery: Protocol for a Feasibility Cluster Randomized Controlled Trial Harnessing Mobile Phone Technolo

Publisher: JMIR Publications Inc.

Date: 09-01-2020

DOI: 10.2196/15058

Abstract: Relapse in schizophrenia is a major cause of distress and disability and is predicted by changes in symptoms such as anxiety, depression, and suspiciousness (early warning signs [EWSs]). These can be used as the basis for timely interventions to prevent relapse. However, there is considerable uncertainty regarding the implementation of EWS interventions. This study was designed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) against treatment as usual (TAU). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, safety, and outcome signals of a digital health intervention as an adjunct to usual care that is deliverable in the UK National Health Service and Australian community mental health service (CMHS) settings. We will assess the feasibility of candidate primary outcomes, candidate secondary outcomes, and candidate mechanisms for a definitive trial. We will randomize CMHSs to EMPOWER or TAU. We aim to recruit up to 120 service user participants from 8 CMHSs and follow them for 12 months. Eligible service users will (1) be aged 16 years and above, (2) be in contact with local CMHSs, (3) have either been admitted to a psychiatric inpatient service or received crisis intervention at least once in the previous 2 years for a relapse, and (4) have an International Classification of Diseases-10 diagnosis of a schizophrenia-related disorder. Service users will also be invited to nominate a carer to participate. We will identify the feasibility of the main trial in terms of recruitment and retention to the study and the acceptability, usability, safety, and outcome signals of the EMPOWER intervention. EMPOWER is a mobile phone app that enables the monitoring of well-being and possible EWSs of relapse on a daily basis. An algorithm calculates changes in well-being based on participants’ own baseline to enable tailoring of well-being messaging and clinical triage of possible EWSs. Use of the app is blended with ongoing peer support. Recruitment to the trial began September 2018, and follow-up of participants was completed in July 2019. Data collection is continuing. The database was locked in July 2019, followed by analysis and disclosing of group allocation. The knowledge gained from the study will inform the design of a definitive trial including finalizing the delivery of our digital health intervention, s le size estimation, methods to ensure successful identification, consent, randomization, and follow-up of participants, and the primary and secondary outcomes. The trial will also inform the final health economic model to be applied in the main trial. International Standard Randomized Controlled Trial Number (ISRCTN): 99559262 isrctn.com/ISRCTN99559262 DERR1-10.2196/15058

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception: the Bridge-it RCT

Publisher: National Institute for Health and Care Research

Date: 05-2021

DOI: 10.3310/HTA25270

Abstract: Unless women start effective contraception after using emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies that are unable to provide ongoing contraception (apart from barrier methods which have high failure rates). This means that women need an appointment with a general practitioner or at a sexual and reproductive health clinic. We conducted a pragmatic cluster randomised cohort crossover trial to determine whether or not pharmacist provision of a bridging supply of a progestogen-only pill plus the invitation to attend a sexual and reproductive health clinic resulted in increased subsequent use of effective contraception (hormonal or intrauterine). Twenty-nine pharmacies in three UK cities recruited women receiving emergency contraception (levonorgestrel). In the intervention, women received a 3-month supply of the progestogen-only pill (75 µg of desogestrel) plus a card that provided rapid access to a local sexual and reproductive health clinic. In the control arm, pharmacists advised women to attend their usual contraceptive provider. The primary outcome was reported use of an effective contraception (hormonal and intrauterine methods) at 4 months. Process evaluation was also conducted to inform any future implementation. The study took place December 2017 and June 2019 and recruited 636 women to the intervention ( n = 316) and control groups ( n = 320). There were no statistically significant differences in demographic characteristics between the groups. Four-month follow-up data were available for 406 participants: 63% (198/315) of the control group and 65% (208/318) of the intervention group. The proportion of participants reporting use of effective contraception was 20.1% greater (95% confidence interval 5.2% to 35.0%) in the intervention group (58.4%, 95% confidence interval 48.6% to 68.2%) than in the control group (40.5%, 95% confidence interval 29.7% to 51.3%) (adjusted for recruitment period, treatment arm and centre p = 0.011). The proportion of women using effective contraception remained statistically significantly larger, when adjusted for age, current sexual relationship and history of past use of effective contraception, and was robust to the missing data. There were no serious adverse events. Provision of a bridging supply of the progestogen-only pill with emergency contraception from a pharmacist and the invitation to a sexual and reproductive health clinic resulted in a significant increase in self-reported subsequent use of effective contraception. This simple intervention has the potential to prevent more unintended pregnancies for women after emergency contraception. Current Controlled Trials ISRCTN70616901. 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. 25, No. 27. See the NIHR Journals Library website for further project information.

A Digital Intervention to Improve Mental Health and Interpersonal Resilience in Young People Who Have Experienced Technology-Assisted Sexual Abuse: Protocol for a Nonrandomized Feasibility Clinical Tr

Publisher: JMIR Publications Inc.

Date: 21-03-2023

DOI: 10.2196/40539

Abstract: No evidence-based support has been offered to young people (YP) who have experienced technology-assisted sexual abuse (TASA). Interventions aimed at improving mentalization (the ability to understand the mental states of oneself and others) are increasingly being applied to treat YP with various clinical issues. Digital technology use among YP is now common. A digital intervention aimed at improving mentalization in YP who have experienced TASA may reduce the risk of revictimization and future harm and make YP more resilient and able to manage distress that might result from TASA experiences. In this paper, we describe a protocol for determining the feasibility of the i-Minds trial and the acceptability, safety, and usability of the digital intervention (the i-Minds app) and explore how to best integrate i-Minds into existing routine care pathways. This is a mixed methods nonrandomized study aimed to determine the feasibility, acceptability, safety, and usability of the intervention. Participants aged between 12 and 18 years who report distress associated with TASA exposure will be recruited from the United Kingdom from the National Health Service (NHS) Trust Child and Adolescent Mental Health Services, sexual assault referral centers, and a web-based e-therapy provider. All participants will receive the i-Minds app for 6 weeks. Coproduced with YP and a range of stakeholders, the i-Minds app focuses on 4 main topics: mentalization, TASA and its impact, emotional and mental health, and trauma. A daily prompt will encourage YP to use the app, which is designed to be used in a stand-alone manner alongside routine care. We will follow participants up after the intervention and conduct interviews with stakeholders to explore the acceptability of the app and trial procedures and identify areas for improvement. Informed by the normalization process theory, we will examine barriers and enablers relevant to the future integration of the intervention into existing care pathways, including traditional clinic-based NHS and NHS e-therapy providers. This study was approved by the Research Ethics Board of Scotland. We expect data to be collected from up to 60 YP. We expect to conduct approximately 20 qualitative interviews with participants and 20 health care professionals who referred YP to the study. The results of this study have been submitted for publication. This study will provide preliminary evidence on the feasibility of recruiting YP to a trial of this nature and on the acceptability, safety, and usability of the i-Minds app, including how to best integrate it into existing routine care. The findings will inform the decision to proceed with a powered efficacy trial. International Standard Randomised Controlled Trial Number Registry (ISRCTN) ISRCTN43130832 www.isrctn.com/ISRCTN43130832 DERR1-10.2196/40539

Digital smartphone intervention to recognise and manage early warning signs in schizophrenia to prevent relapse: the EMPOWER feasibility cluster RCT

Publisher: National Institute for Health and Care Research

Date: 05-2022

DOI: 10.3310/HLZE0479

Abstract: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse. How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse? A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up. Glasgow, UK, and Melbourne, Australia. Service users were aged 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user. The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted. The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse. We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement ( 33%). The median time to discontinuation of 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference –4.29, 95% confidence interval –7.29 to –1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained. This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness. A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible. A main trial with a s le size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3–0.4). This trial is registered as ISRCTN99559262. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Radiolabeled Molecular Imaging Probes for the In Vivo Evaluation of Cellulose Nanocrystals for Biomedical Applications

Publisher: American Chemical Society (ACS)

Date: 11-2019

DOI: 10.1021/ACS.BIOMAC.8B01313

The University Of Edinburgh

Location: United Kingdom of Great Britain and Northern Ireland

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University Of Alabama At Birmingham

Location: United States of America

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University Of Helsinki

Location: Finland

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Hunter College

Location: United States of America

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