Annie Hawton

Purpose: Concerns have been raised about the sensitivity and responsiveness of the EQ-5D, one of the most commonly used preference-based health-related quality of life measures, in the context of multiple sclerosis (MS). In response to these concerns, a condition-specific preference-based measure, the Multiple Sclerosis Impact Scale Eight Dimensions (MSIS-8D), was developed. This research aimed to assess the psychometric and distributional properties of the MSIS-8D compared to the EQ-5D-3L, in people with MS. Methods: Analyses were undertaken using data from the UK MS Register. Both measures were compared in terms of acceptability (missing data), distributional properties (health state frequencies, health state density curves and indices), construct validity in relation to disability, mobility, fatigue, anxiety and depression (discriminative and convergent validity, using ANOVA, independent t-tests and Spearman correlations), and responsiveness to symptom onset and relapse (mean change scores, standardised response means, standardised effect sizes, paired t-tests). Results: The MSIS-8D exhibited superior distributional properties, while the EQ-5D-3L showed greater acceptability. Both measures demonstrated excellent construct validity. Neither measure appeared responsive to symptom onset, and only the MSIS-8D met all criteria for responsiveness when people moved from a non-relapse to a relapse state. Conclusion: Although the MSIS-8D appears to offer superior distributional properties and responsiveness compared to the EQ-5D-3L, the responsiveness of both measures in this analysis was limited. This adds weight to existing concerns about the ability of utility measures used in healthcare decision-making to fully capture treatment effects in MS.

Introduction: Cellulitis is a common bacterial skin infection causing significant pain, swelling, and impact on daily activities, frequently leading to emergency department presentations and hospital admissions. While antibiotics are the mainstay of treatment, they do not directly address inflammation, often resulting in persisting or worsening symptoms in the initial days. Corticosteroids, with their potent anti-inflammatory effects, have shown benefit in other acute infections but are not currently standard care for patients with cellulitis. This trial aims to determine if adjunctive oral dexamethasone can reduce pain and improve outcomes in adults with cellulitis presenting to UK urgent secondary care settings. Methods and analysis: This is a pragmatic, multicentre, double-blind, placebo-controlled, randomised, parallel group, phase 3 superiority trial, with an internal pilot and parallel health economic evaluation. Adult patients (≥16 years) with a clinical diagnosis of cellulitis (at any body site except the orbit) presenting to urgent secondary care will be screened for eligibility. 450 participants will be randomised (1:1) to receive either two 8 mg doses of oral dexamethasone or matched placebo, administered approximately 24 hours apart, in addition to standard antibiotic therapy. The primary outcome is total pain experienced over the first 3 days post-randomisation, calculated using the standardised area under the curve (AUC) from pain scores (Numerical Rating Scale 0-10) across up to seven timepoints. Secondary outcomes include health-related quality of life (EQ-5D-5L), patient global impression of improvement, analgesia and antibiotic usage, hospital (re)admissions, complications, unscheduled healthcare use, cellulitis recurrence, and cost-effectiveness at 90 days. The primary estimand will apply a treatment policy approach to intercurrent events. Ethics and dissemination: The trial has received ethical approval from South Central – Oxford B Research Ethics Committee (reference; 24/SC/0289) and will be conducted in compliance with GCP and applicable regulations. Informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed publications and conference presentations, and to patient groups and relevant clinical guideline committees. Trial registration: ISRCTN76873478. Current protocol version 5.0, 7th January 2025. Strengths and limitations of this study: This trial employs a robust double-blind, placebo-controlled design to minimise bias in assessing a subjective primary outcome (patient-reported pain). The pragmatic nature of the trial, recruiting from diverse urgent secondary care settings, with additional incentives to recruit from minoritised groups, aims to enhance the generalisability of findings to real-world clinical practice. Comprehensive follow-up to 90 days allows for assessment of both short-term symptom relief and longer-term impacts on healthcare utilisation and recurrence. The inclusion of a parallel health economic evaluation will provide crucial information on the cost-effectiveness of adjunctive dexamethasone. Potential variability in’usual care’ antibiotic regimens across sites, while reflecting real-world practice, is a possible limitation, which is accounted for in the pragmatic design.

Postpartum pelvic girdle pain (PGP), experienced by approximately 10% of women, is typically refractory to conservative management. Customised dynamic elastomeric fabric orthoses (DEFOs) are one novel option to address this. We assessed the feasibility and acceptability of a randomised controlled trial comparing a DEFO plus standardised advice/exercises (intervention) versus standardised advice/exercise alone (control). A multicentre randomised controlled feasibility trial with embedded qualitative study and economic evaluation. Participants were randomised to either intervention or control group. All received two remote physiotherapy sessions via videoconferencing separated by 14 days. Primary feasibility outcomes were related to the feasibility and acceptability of methods and interventions, recruitment, intervention fidelity, outcome measure performance and completion. The proposed primary outcome measure for the definitive trial was the Numerical Pain Rating Scale (NPRS) which assessed pain intensity fortnightly over 24 weeks. Secondary outcome measures assessed kinesiophobia, continence, function, health-related quality of life, depression and health/care resource use at baseline, 12 and 24 weeks. Adverse events were recorded. Pre-defined progression criteria were set to decide whether, and how, to proceed with a future definitive trial: (1) Target sample size (60 from 3 centres over a 7-month recruitment period), (2) outcome measure completion (> 60% at 24 weeks), (3) orthosis wear-time compliance (> 70% for 6 h/day) as measured by the Orthotimer, and (4) evidence suggesting efficacy. Of 180 participants sent information sheets, 40 were screened and 24 randomised. At 24 weeks, 95% completed NPRS and 89–95% the secondary outcome measures. Wear-time adherence appeared below the set target of 42 h per week. Outcomes were broadly comparable between groups. Recruitment was insufficient to estimate a signal of efficacy with confidence. Two intervention participants experienced Candida infections, considered possibly due to the DEFO. Trial procedures and interventions were acceptable to participants. Technical Orthotimer issues are resolvable through modification of recording parameters. Recruitment of participants was a major challenge. Work to understand how best to engage women in this research is needed before moving to a definitive trial. ISCRTN, ISRCTN67232113. Registered 08/05/2021, https://www.isrctn.com/ISRCTN67232113 . • What uncertainties existed regarding the feasibility? ➣ There is uncertainty regarding the feasibility of recruiting participants at a rate conducive to a definitive trial. • What are the key feasibility findings? ➣ Twenty-four participants were recruited over 7 months. Retention and complete NPRS data were available for analysis at final follow-up for 18 participants (75%). ➣ Overall, the trial procedures and interventions were perceived as acceptable by participants and clinicians. ➣ Overall recruitment was insufficient to estimate a signal of efficacy with confidence. ➣ Technical issues with the Orthotimer significantly impacted on adherence data collection. ➣ Progression criteria indicate that progression to a definitive trial in its current format is not recommended. • What are the implications of the feasibility findings for the design of the main study? ➣ Further research is required to best understand how to recruit women to a future study. ➣ A hybrid approach to intervention delivery may be preferable. ➣ Orthotimer reading intervals for capturing orthosis wear-time adherence require careful consideration. ➣ An internal pilot within a future definitive multicentre randomised controlled trial would add value.

Introduction: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. Methods and analysis: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0–6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate. The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression. Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. Ethics and dissemination: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration numbers: NCT03387670 ; ISRCTN82598726 .

Background: Early blood transfusion improves survival in patients with life-threatening bleeding, but the optimal transfusion strategy in the pre-hospital setting has yet to be established. Although there is some evidence of benefit with the use of whole blood, there have been no randomised controlled trials exploring the clinical and cost effectiveness of pre-hospital administration of whole blood versus component therapy for trauma patients with life-threatening bleeding. The aim of this trial is to determine whether pre-hospital leukocyte-depleted whole blood transfusion is better than standard care (blood component transfusion) in reducing the proportion of participants who experience death or massive transfusion at 24 h. Methods: This is a multi-centre, superiority, open-label, randomised controlled trial with internal pilot and within-trial cost-effectiveness analysis. Patients of any age will be eligible if they have suffered major traumatic haemorrhage and are attended by a participating air ambulance service. The primary outcome is the proportion of participants with traumatic haemorrhage who have died (all-cause mortality) or received massive transfusion in the first 24 h from randomisation. A number of secondary clinical, process, and safety endpoints will be collected and analysed. Cost (provision of whole blood, hospital, health, and wider care resource use) and outcome data will be synthesised to present incremental cost-effectiveness ratios for the trial primary outcome and cost per quality-adjusted life year at 90 days after injury. We plan to recruit 848 participants (a two-sided test with 85% power, 5% type I error, 1-1 allocation, and one interim analysis would require 602 participants—after allowing for 25% of participants in traumatic cardiac arrest and an additional 5% drop out, the sample size is 848). Discussion: The SWiFT trial will recruit 848 participants across at least ten air ambulances services in the UK. It will investigate the clinical and cost-effectiveness of whole blood transfusion versus component therapy in the management of patients with life-threatening bleeding in the pre-hospital setting. Trial registration: ISRCTN: 23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072, 21 Dec 2021.

Background and Objectives: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS. Methods: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics. Results: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS. Conclusion: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles.

Background: Parent carers of disabled children are at increased risk of physical and mental health problems. The Healthy Parent Carers (HPC) programme is a manualised peer‐led group‐based programme that aims to promote parent carer health and wellbeing. Previously, the programme had been delivered in person, with recruitment and delivery managed in a research context. This study explored implementation by two delivery partner organisations in the United Kingdom. Facilitator Training and Delivery Manuals were modified for online delivery using Zoom due to COVID‐19.Methods: The study methodology utilised the Replicating Effective Programs framework. A series of stakeholder workshops informed the development of the Implementation Logic Model and an Implementation Package. After delivering the programme, delivery partner organisations and facilitators participated in a workshop to discuss experiences of implementing the programme. A wider group of stakeholders, including commissioners, Parent Carer Forums and charity organisations representatives and researchers subsequently met to consider the sustainability and potential barriers to delivering the programme outside the research context.Results: This study explored implementation by two delivery partner organisations in the United Kingdom that were able to recruit facilitators, who we trained, and they recruited participants and delivered the programme to parent carers in different localities using Zoom. The co‐created Implementation Logic Model and Implementation Package were subsequently refined to enable the further roll‐out of the programme with other delivery partner organisations.Conclusions: This study provides insight and understanding of how the HPC programme can be implemented sustainably outside of the research context. Further research will evaluate the effectiveness of the programme and refine the implementation processes.Patient and Public Contribution: Parent carers, delivery partner organisation staff and service commissioners were consulted on the design, delivery and reporting of the research.

Background: New interventions for multiple sclerosis (MS) commonly require a demonstration of cost-effectiveness using health-related quality of life (HRQoL) utility values. The EQ-5D is the utility measure approved for use in the UK NHS funding decision-making. There are also MS-specific utility measures – e.g., MS Impact Scale Eight Dimensions (MSIS-8D) and MSIS-8D-Patient (MSIS-8D-P). Objectives: Provide EQ-5D, MSIS-8D and MSIS-8D-P utility values from a large UK MS cohort and investigate their association with demographic/clinical characteristics. Methods: UK MS Register data from 14,385 respondents (2011 to 2019) were analysed descriptively and using multivariable linear regression, with self-report Expanded Disability Status Scale (EDSS) scores. Results: The EQ-5D and MSIS-8D were both sensitive to differences in demographic/clinical characteristics. An inconsistency found in previous studies whereby mean EQ-5D values were higher for an EDSS score of 4 rather than 3 was not observed. Similar utility values were observed between MS types at each EDSS score. Regression showed EDSS score and age were associated with utility values from all three measures. Conclusions: This study provides generic and MS-specific utility values for a large UK MS sample, with the potential for use in cost-effectiveness analyses of treatments for MS.

Introduction An estimated 10% of women experience severe, chronic pelvic girdle pain post partum. This has significant physical, psychological and socioeconomic consequences. Typically, such pain is recalcitrant to conservative management; hence the need to identify effective management strategies. Customised Dynamic Elastomeric Fabric Orthoses may be an option to address this gap; designed to improve pain by providing support while optimising movement and function. Currently, no studies have evaluated the clinical and cost-effectiveness, or acceptability of these customised orthoses in postpartum women. Methods and analysis EMaPP is a pragmatic, multicentre randomised controlled feasibility trial with an embedded qualitative study and economic evaluation. Sixty participants with pregnancy-related severe pelvic girdle pain >3 months post partum will be recruited. Participants will be randomly allocated in a 1:1 ratio (stratified by centre and presence/absence of lumbo-pelvic pain pre pregnancy) to receive either standard care (standardised information and exercise) or intervention (orthosis plus standard care). All participants will be asked to complete a battery of self-report questionnaires (including pain, function, health-related quality of life and health and social care resource use), via a web-based application at baseline, 12 weeks and 24 weeks. Pain levels and medication usage will be reported fortnightly. Feasibility and acceptability of the trial procedures will be determined in terms of recruitment and retention rates, data completion rates and intervention adherence. Five clinicians and 10 participants will be interviewed to explore their experiences of the trial procedures and receiving the intervention. Ethics and dissemination This study was approved by: National Research Ethics Scheme (NRES Committee Health and Care Research Wales Research Ethics Committee (21/WM/0155) and University of Plymouth Faculty of Health Research Ethics and Integrity Committee (ref:2966). Results will be made available to participants, the funders, staff, general public and other researchers through a range of mechanisms. Trial status Currently recruiting. Trial registration number ISRCTN67232113.