A model-based cost-utility analysis of an automated notification system for deteriorating patients on general wards.

BACKGROUND: Delayed response to clinical deterioration of hospital inpatients is common. Deployment of an electronic automated advisory vital signs monitoring and notification system to signal clinical deterioration is associated with significant improvements in clinical outcomes but there is no evidence on the cost-effectiveness compared with routine monitoring, in the National Health Service (NHS) in the United Kingdom (UK). METHODS: A decision analytic model was developed to estimate the cost-effectiveness of an electronic automated advisory notification system versus standard care, in adults admitted to a district general hospital. Analyses considered: (1) the cost-effectiveness of the technology based on secondary analysis of patient level data of 3787 inpatients in a before-and-after study; and (2) the cost-utility (cost per quality-adjusted life-year (QALY)) over a lifetime horizon, extrapolated using published data. Analysis was conducted from the perspective of the NHS. Uncertainty in the model was assessed using a range of sensitivity analyses. RESULTS: The study population had a mean age of 68 years, 48% male, with a median inpatient stay of 6 days. Expected life expectancy at discharge was assumed to be 17.74 years. (1) Cost-effectiveness analysis: The automated notification system was more effective (-0.027 reduction in mean events per patient) and provided a cost saving of -£12.17 (-182.07 to 154.80) per patient admission. (2) Cost-utility analysis: Over a lifetime horizon the automated notification system was dominant, demonstrating a positive incremental QALY gain (0.0287 QALYs, equivalent to ~10 days of perfect health) and a cost saving of £55.35. At a threshold of £20,000 per QALY, the probability of automated monitoring being cost-effective in the NHS was 81%. Increased use of cableless sensors may reduce cost-savings, however, the intervention remains cost-effective at 100% usage (ICER: £3,107/QALY). Stratified cost-effectiveness analysis by age, National Early Warning Score (NEWS) on admission, and primary diagnosis indicated the automated notification system was cost-effective for most strategies and that use representative of the patient population studied was the most cost-saving strategy. CONCLUSION: Automated notification system for adult patients admitted to general wards appears to be a cost-effective use in the NHS; adopting this technology could be good use of scarce resources with significance for patient safety.

The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Service users' preferences and feasibility - which alternative care pathway for adult ambulance users achieves the optimal balance? Workshops for the COLLABORATE project.

INTRODUCTION: Adults presenting to the ambulance service for diagnosed epilepsy are often transported to emergency departments (EDs) despite no clinical need. An alternative care pathway (CP) could allow paramedics to divert them from ED and instigate ambulatory care improvements. To identify the most promising CP configuration for subsequent testing, the COLLABORATE project surveyed people with epilepsy and family/friends who had recently used the English ambulance service to elicit preferences for 288 CP configurations for different seizures. This allowed CPs to be ranked according to alignment with service users' preferences. However, as well as being acceptable to users, a CP must be feasible. We thus engaged with paramedics, epilepsy specialists and commissioners to identify the optimal configuration. METHODS: Three Knowledge Exchange workshops completed. Participants considered COLLABORATE's evidence on service users' preferences for the different configurations. Nominal group techniques elicited views on the feasibility of users' preferences according to APEASE criteria. Workshop groups specified the configuration/s considered optimum. Qualitative data was analysed thematically. Utility to users of the specified CP configurations estimated using the COLLABORATE preference survey data. RESULTS: Twenty-seven participants found service users' preferences broadly feasible and outlined delivery recommendations. They identified enough commonality in preferences for different seizures to propose a single CP. Its configuration comprised: 1) patients staying where they were; 2) paramedics having access to medical records; 3) care episodes lasting <6 h; 4) paramedics receiving specialist advice on the day; 5) patient's GP being notified; and 6) a follow-up appointment being arranged with an epilepsy specialist. Preference data indicated higher utility for this configuration compared to current care. DISCUSSION: Stakeholders are of the view that the CP configuration favoured by service users could be NHS feasible. It should be developed and evaluated.

Developing an alternative care pathway for emergency ambulance responses for adults with epilepsy: A Discrete Choice Experiment to understand which configuration service users prefer. Part of the COLLABORATE project.

INTRODUCTION: To identify service users' preferences for an alternative care pathway for adults with epilepsy presenting to the ambulance service. METHODS: Extensive formative work (qualitative, survey and knowledge exchange) informed the design of a stated preference discrete choice experiment (DCE). This hypothetical survey was hosted online and consisted of 12 binary choices of alternative care pathways described in terms of: the paramedic's access to medical records/ 'care plan', what happens next (described in terms of conveyance), time, availability of epilepsy specialists today, general practitioner (GP) notification and future contact with epilepsy specialists. DCE scenarios were described as: (i) typical seizure at home. (ii) typical seizure in public, (iii) atypical seizure. Respondents were recruited by a regional English ambulance service and by national public adverts. Participants were randomised to complete 2 of the 3 DCEs. RESULTS: People with epilepsy (PWE; n = 427) and friends/family (n = 167) who completed the survey were representative of the target population. PWE preferred paramedics to have access to medical records, non-conveyance, to avoid lengthy episodes of care, availability of epilepsy specialists today, GP notification, and contact with epilepsy specialists within 2-3 weeks. Significant others (close family members or friends) preferred PWE experiencing an atypical seizure to be conveyed to an Urgent Treatment Centre and preferred shorter times. Optimal configuration of services from service users' perspective far out ranked current practice (rank 230/288 possible configurations). DISCUSSION: Preferences differ to current practice but have minimal variation by seizure type or stakeholder. Further work on feasibility of these pathways in England, and potentially beyond, is required.

Patient-Led Urate Self-Monitoring to Improve Clinical Outcomes in People With Gout: A Feasibility Study.

OBJECTIVE: Self-monitored point-of-care urate-measuring devices are an underexplored strategy to improve adherence to urate-lowering therapy and clinical outcomes in gout. This study observed patient-led urate self-monitoring practice and assessed its influence on allopurinol adherence, urate control, and health-related quality of life. METHODS: People with gout (n = 31) and prescribed allopurinol self-monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (<0.36 mmol/L) was determined. Health-related quality of life was measured using a survey (EuroQoL EQ-5D-5L). Gout flares were recorded. Two-tailed Spearman correlation and the Wilcoxon matched-pairs signed-rank test (P < 0.05) were used for statistical comparisons. RESULTS: Most participants were male (94%) and had urate concentrations below the target (74%) at baseline. Overall, seven participants demonstrated repeated periods of "missed doses" (two or fewer allopurinol doses missed consecutively) and "drug holidays" (three or more missed doses). Most participants (94%) persisted with allopurinol. Time spent within the target urate concentration increased 1.3-fold (from 79% to 100%; P = 0.346), and the incidence of gout flares decreased 1.6-fold (from 8 to 5; P = 0.25) in the final quarter compared to that in the first quarter of the study. Health-related quality of life was reduced for participants reporting at least one gout flare (median utility values 0.9309 vs 0.9563, P = 0.04). CONCLUSION: Patient-led urate self-monitoring may support the maintenance of allopurinol adherence and improve urate control, thus reducing the incidence of gout flares. Further research on patient-led urate self-monitoring in a randomized controlled study is warranted.

Supporting people with type 2 diabetes in effective use of their medicine through mobile health technology integrated with clinical care (SuMMiT-D pilot): results of a feasibility randomised trial.

BACKGROUND: The purpose of this 6-month intervention pilot feasibility randomised trial was to test sending brief messages using mobile phones to promote self-management through taking medication as prescribed to people with type 2 diabetes. This was to inform the design and conduct of a future large-scale United Kingdom-based clinical trial and establish the feasibility of recruitment, the technology used, follow-up, and data collection. METHODS: A multicentre individually randomised, controlled parallel group trial in primary care, recruiting adults (≥ 35 years) with type 2 diabetes in England. Consenting participants were randomly allocated to receive short message system text messages up to four times a week, or usual care, for a period of 6 months; messages contained behavioural change techniques targeting medication use. The primary outcome was the rate of recruitment to randomisation of participants to the trial with a planned rate of 22 participants randomised per month. The study also aimed to establish the feasibility of follow-up at 6 months, with an aim of retaining more than 80% of participants. Data, including patient-reported measures, were collected at baseline and the end of the 6-month follow-up period, and a notes review was completed at 24 months. RESULTS: The trial took place between 26 November 2018 and 30 September 2019. In total 209 participants were randomly allocated to intervention (n = 103) or usual care (n = 106). The maximum rate of monthly recruitment to the trial was 60-80 participants per month. In total, 12,734 messages were sent to participants. Of these messages, 47 were identified as having failed to be sent by the service provider. Participants sent 2,864 messages to the automated messaging system. Baseline data from medical records were available for > 90% of participants with the exception of cholesterol (78.9%). At 6 months, a further HbA1c measurement was reported for 67% of participants. In total medical record data were available at 6 months for 207 (99.0%) of participants and completed self-report data were available for 177 (84.7%) of participants. CONCLUSION: The feasibility of a large-scale randomised evaluation of brief message intervention for people with type 2 diabetes appears to be high using this efficient design. Failure rate of sending messages is low, rapid recruitment was achieved among people with type 2 diabetes, clinical data is available on participants from routine medical records and self-report of economic measures was acceptable. TRIAL REGISTRATION: ISCTRN ISRCTN13404264. Registered on 10 October 2018.

Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60-120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8-24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8-168 (i.e., weeks 2-24; range: 0-161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0-161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24-161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05-1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively-most commonly rapidly-resolving (mild-moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group-none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] -1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00-0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

BACKGROUND: There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting ß2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. RESULTS: Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. CONCLUSIONS: Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

Costs of orphan medicinal products: longitudinal analysis of expenditure in Wales.

BACKGROUND: The Orphan Regulation ((EC) No 141/2000) has successfully redirected private and public investment towards previously neglected areas through incentives, regulatory obligations and rewards. However, the growth in the number of licensed orphan medicinal products (OMPs) has led to concerns about increased costs. The aims were to investigate the trend in the costs of OMPs to the National Health Service in Wales, to attribute costs of medicines within and outside periods of marketing exclusivity, and estimate the contribution of individual medicines to the overall costs of OMPs. METHODS: Expenditure on OMPs in Wales was analysed between the 2014/15 and 2019/20 financial years using data on prescriptions dispensed in primary care, secondary care, and specialised commissioned services. OMP spend was calculated as a proportion of total medicines expenditure, whether it was incurred during, or outside the marketing exclusivity period (MEP), and by therapeutic area and medicine. RESULTS: Overall spend on OMPs and all medicines increased from £32 m to £82 m, and from £1,030 m to £1,198 m, respectively, with the proportion of spend on OMPs more than doubling from 3.1% to 6.9% per annum. Average year-on-year growth in the costs of OMPs was 21%, compared to 2% for other medicines. Costs following MEP expiry contributed significantly to overall OMP costs, increasing from £8 m to £30 m, corresponding to an increase from 24% to 37%. Treatments for 'malignant disease and immunosuppression', 'nutrition and blood' and the 'respiratory system' accounted for 90% of all OMP spend. Half of total OMP annual expenditure was on just 4 medicines in 2014/15, increasing to 8 in 2019/20. CONCLUSIONS: Both the number of OMPs and the amount spent on OMPs in Wales has increased over time, possibly as a consequence of favourable licensing conditions, permissive health technology assessment policies and dedicated funding.

Appropriate design and reporting of superiority, equivalence and non-inferiority clinical trials incorporating a benefit-risk assessment: the BRAINS study including expert workshop.

Background: Randomised controlled trials are designed to assess the superiority, equivalence or non-inferiority of a new health technology, but which trial design should be used is not always obvious in practice. In particular, when using equivalence or non-inferiority designs, multiple outcomes of interest may be important for the success of a trial, despite the fact that usually only a single primary outcome is used to design the trial. Benefit-risk methods are used in the regulatory clinical trial setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but are not regularly implemented in publicly funded trials. Objectives: The aim of the project is to aid the design of clinical trials with multiple outcomes of interest by defining when each trial design is appropriate to use and identifying when to use benefit-risk methods to assess outcome trade-offs (qualitatively or quantitatively) in a publicly funded trial setting. Methods: A range of methods was used to elicit expert opinion to answer the project objectives, including a web-based survey of relevant researchers, a rapid review of current literature and a 2-day consensus workshop of experts (in 2019). Results: We created a list of 19 factors to aid researchers in selecting the most appropriate trial design, containing the following overarching sections: population, intervention, comparator, outcomes, feasibility and perspectives. Six key reasons that indicate a benefit-risk method should be considered within a trial were identified: (1) when the success of the trial depends on more than one outcome; (2) when important outcomes within the trial are in competing directions (i.e. a health technology is better for one outcome, but worse for another); (3) to allow patient preferences to be included and directly influence trial results; (4) to provide transparency on subjective recommendations from a trial; (5) to provide consistency in the approach to presenting results from a trial; and (6) to synthesise multiple outcomes into a single metric. Further information was provided to support the use of benefit-risk methods in appropriate circumstances, including the following: methods identified from the review were collated into different groupings and described to aid the selection of a method; potential implementation of methods throughout the trial process were provided and discussed (with examples); and general considerations were described for those using benefit-risk methods. Finally, a checklist of five pieces of information that should be present when reporting benefit-risk methods was defined, with two additional items specifically for reporting the results. Conclusions: These recommendations will assist research teams in selecting which trial design to use and deciding whether or not a benefit-risk method could be included to ensure research questions are answered appropriately. Additional information is provided to support consistent use and clear reporting of benefit-risk methods in the future. The recommendations can also be used by funding committees to confirm that appropriate considerations of the trial design have been made. Limitations: This research was limited in scope and should be considered in conjunction with other trial design methodologies to assess appropriateness. In addition, further research is needed to provide concrete information about which benefit-risk methods are best to use in publicly funded trials, along with recommendations that are specific to each method. Study registration: The rapid review is registered as PROSPERO CRD42019144882. Funding: Funded by the Medical Research Council UK and the National Institute for Health and Care Research as part of the Medical Research Council-National Institute for Health and Care Research Methodology Research programme.

Randomised controlled trials are considered the best way to gather evidence about potential NHS treatments. They can be designed from different perspectives depending whether the aim is to show that a new treatment is better than, equal to or no worse than the current best available treatment. The selection of this design relates to the single most important outcome; however, often multiple outcomes can be affected by a treatment. For example, a new treatment may improve disease management but increase side effects. Patients want a treatment to work but not at the price of poor quality of life; therefore, a trade-off must be made, and the recommended treatment depends on this trade-off. Benefit­risk methods can assess the trade-off between multiple outcomes and can include patient preference. These methods could improve the way that decisions are made about treatments in the NHS, but there is currently limited research about the use of these methods in publicly funded trials. The aim of this report is to improve the design of clinical trials by helping researchers to select the most appropriate trial design and to decide when to include a benefit­risk method. The recommendations were created using the opinions of experts within the field and consisted of a survey, review of the literature and a workshop. The project created a list of 19 factors that can assist researchers to select the most appropriate trial design. Furthermore, six key areas were identified in which researchers may consider including a benefit­risk method within a trial. Finally, if a benefit­risk assessment is being used, a checklist of items has been created that identifies the information important to include in reports. This report is, however, limited in its applicability and further research should extend this work, as well as provide more detail on individual methods that are available.

We need to talk about values: a proposed framework for the articulation of normative reasoning in health technology assessment.

It is acknowledged that health technology assessment (HTA) is an inherently value-based activity that makes use of normative reasoning alongside empirical evidence. But the language used to conceptualise and articulate HTA's normative aspects is demonstrably unnuanced, imprecise, and inconsistently employed, undermining transparency and preventing proper scrutiny of the rationales on which decisions are based. This paper - developed through a cross-disciplinary collaboration of 24 researchers with expertise in healthcare priority-setting - seeks to address this problem by offering a clear definition of key terms and distinguishing between the types of normative commitment invoked during HTA, thus providing a novel conceptual framework for the articulation of reasoning. Through application to a hypothetical case, it is illustrated how this framework can operate as a practical tool through which HTA practitioners and policymakers can enhance the transparency and coherence of their decision-making, while enabling others to hold them more easily to account. The framework is offered as a starting point for further discussion amongst those with a desire to enhance the legitimacy and fairness of HTA by facilitating practical public reasoning, in which decisions are made on behalf of the public, in public view, through a chain of reasoning that withstands ethical scrutiny.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.

A framework for understanding sources of bias in medication adherence research.

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty-three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research.

Spanish translation of the ABC taxonomy for medication adherence.

BACKGROUND: The Ascertaining Barriers to Compliance (ABC) taxonomy was developed aiming at systematizing definitions and operationalizations of medication adherence. Its translation is crucial to improve the generalizability, application and comparison of study findings. OBJECTIVE: To provide a consensus translation of the ABC taxonomy from English to Spanish. METHODS: A two-phased approach was used, according to the Preferred Methods for the Translation of the ABC Taxonomy for Medication Adherence. Two literature reviews were conducted: to identify Spanish synonyms and definitions of the ABC taxonomy, and to identify a panel of Spanish-speaking experts in medication adherence. A Delphi survey was designed based on the synonyms and definitions found. The experts previously identified were invited to participate in the Delphi. A consensus of ≥85% was established for the first round. A moderate consensus (50-75%), a consensus (75-95%) or a strong consensus (>95%) were considered to be necessary in the second round. RESULTS: Forty potential synonyms of the ABC taxonomy terms were identified from a total of 270 papers. The response rate during the first Delphi round was 32% (63/197) and in the second round 86% (54/63). A strong consensus was reached for the term "inicio del tratamiento" (96%) and consensus for the term "implementación" (83%). A moderate consensus was obtained for "adherencia a la medicación" (70%), "interrupción del tratamiento" (52%), "manejo de la adherencia" (54%) and "disciplinas relacionadas con la adherencia" (74%). No consensus was reached for the term persistence. Five out of the seven definitions reached a consensus in the first round, and two definitions a moderate consensus after the second round. CONCLUSION: The adoption of the Spanish taxonomy will increase transparency, comparability and transferability of results in the field of medication adherence. This may facilitate benchmarking of adherence strategies between Spanish-speaking researchers and practitioners, and other language speakers.

Value of improving patient safety: health economic considerations for rapid response systems-a rapid review of the literature and expert round table.

OBJECTIVES: Failure to rescue deteriorating patients in hospital is a well-researched topic. We aimed to explore the impact of safer care on health economic considerations for clinicians, providers and policymakers. DESIGN: We undertook a rapid review of the available literature and convened a round table of international specialists in the field including experts on health economics and value-based healthcare to better understand health economics of clinical deterioration and impact of systems to reduce failure to rescue. RESULTS: Only a limited number of publications have examined the health economic impact of failure to rescue. Literature examining this topic lacked detail and we identified no publications on long-term cost outside the hospital following a deterioration event. The recent pandemic has added limited literature on prevention of deterioration in the patients' home.Cost-effectiveness and cost-efficiency are dependent on broader system effects of adverse events. We suggest including the care needs beyond the hospital and loss of income of patients and/or their informal carers as well as sickness of healthcare staff exposed to serious adverse events in the analysis of adverse events. They are likely to have a larger health economic impact than the direct attributable cost of the hospital admission of the patient suffering the adverse event. Premorbid status of a patient is a major confounder for health economic considerations. CONCLUSION: In order to optimise health at the population level, we must limit long-term effects of adverse events through improvement of our ability to rapidly recognise and respond to acute illness and worsening chronic illness both in the home and the hospital.

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS.

AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E: a protocol for a randomised controlled trial comparing an online behavioural sleep intervention with standard care in children with Rolandic epilepsy.

INTRODUCTION: Sleep and epilepsy have an established bidirectional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but was delivered via face-to-face educational sessions with parents, which are costly and non-scalable to population level. The Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E trial addresses this problem by comparing clinical and cost-effectiveness in children with Rolandic epilepsy between standard care (SC) and SC augmented with a novel, tailored parent-led CASTLE Online Sleep Intervention (COSI) that incorporates evidence-based behavioural components. METHODS AND ANALYSES: CASTLE Sleep-E is a UK-based, multicentre, open-label, active concurrent control, randomised, parallel-group, pragmatic superiority trial. A total of 110 children with Rolandic epilepsy will be recruited in outpatient clinics and allocated 1:1 to SC or SC augmented with COSI (SC+COSI). Primary clinical outcome is parent-reported sleep problem score (Children's Sleep Habits Questionnaire). Primary health economic outcome is the incremental cost-effectiveness ratio (National Health Service and Personal Social Services perspective, Child Health Utility 9D Instrument). Parents and children (≥7 years) can opt into qualitative interviews and activities to share their experiences and perceptions of trial participation and managing sleep with Rolandic epilepsy. ETHICS AND DISSEMINATION: The CASTLE Sleep-E protocol was approved by the Health Research Authority East Midlands (HRA)-Nottingham 1 Research Ethics Committee (reference: 21/EM/0205). Trial results will be disseminated to scientific audiences, families, professional groups, managers, commissioners and policymakers. Pseudo-anonymised individual patient data will be made available after dissemination on reasonable request. TRIAL REGISTRATION NUMBER: ISRCTN13202325.

The impact of parent treatment preference and other factors on recruitment: lessons learned from a paediatric epilepsy randomised controlled trial.

BACKGROUND: In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity MAIN BODY: In this paper, we critically reflect upon the factors which impacted recruitment to the pilot phase of a phase IV unblinded, randomised controlled 3×2 factorial trial examining the effectiveness of two antiseizure medications (ASMs) and a sleep behaviour intervention in children with Rolandic epilepsy. We consider the processes established to support recruitment, public and patient involvement and engagement (PPIE), site induction, our oversight of recruitment targets and figures, and the actions we took to help us understand why we failed to recruit sufficient children to continue to the substantive trial phase. The key lessons learned were about parent preference, children's involvement and collaboration in decision-making, potential and alternative trial designs, and elicitation of stated preferences pre-trial design. Despite pre-funding PPIE during the trial design phase, we failed to anticipate the scale of parental treatment preference for or against antiseizure medication (ASMs) and consequent unwillingness to be randomised. Future studies should ensure more detailed and in-depth consultation to ascertain parent and/or patient preferences. More intense engagement with parents and children exploring their ideas about treatment preferences could, perhaps, have helped predict some recruitment issues. Infrequent seizures or screening children close to natural remission were possible explanations for non-consent. It is possible some clinicians were unintentionally unable to convey clinical equipoise influencing parental decision against participation. We wanted children to be involved in decisions about trial participation. However, despite having tailored written and video information to explain the trial to children we do not know whether these materials were viewed in each consent conversation or how much input children had towards parents' decisions to participate. Novel methods such as parent/patient preference trials and/or discrete choice experiments may be the way forward. CONCLUSION: The importance of diligent consultation, the consideration of novel methods such as parent/patient preference trials and/or discrete choice experiments in studies examining the effectiveness of ASMs versus no-ASMs cannot be overemphasised even in the presence of widespread clinician equipoise.