Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial.

INTRODUCTION: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes. METHODS AND ANALYSIS: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored. ETHICS AND DISSEMINATION: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement. TRIAL REGISTRATION NUMBER: NCT03653832.

Socioeconomic status in adulthood of children with and without a history of seizures: A retrospective cohort study.

OBJECTIVE: Compare adulthood socioeconomic status for children with and without a history of seizures. METHODS: Retrospective cohort study using Aberdeen Children of the Nineteen Fifties (ACONF) data comprising children born 1950-1956 attending primary school 1962-1964, with follow-up data collected in 2001. Adulthood socioeconomic status was based on registrar general measure of occupational social class and categorised as high or low. We adjusted for potentially confounding variables including childhood socioeconomic status, behavioural issues (Rutter A/B scores), biological sex, school test scores, educational attainment, parental engagement with education, peer-status in school, and alcohol use in adulthood. A multivariate binary logistic regression was performed to estimate the adjusted association between children with a history of seizures of any type (for example febrile seizures, or provoked seizures of any other etiology or seizures in the context of epilepsy) or severity and adult socioeconomic status. Multiple imputation using the Monte-Carlo-Markov-Chain method accounted for missing data. RESULTS: Pooled estimates (N = 2,208) comparing children with a history of seizures (n = 81) and children without a history of seizures (n = 2,127) found no differences between these cohorts in terms of adulthood socioeconomic status in both unadjusted (Odds Ratio (OR) 1.45 [95 % CI 0.71-2.96], p = 0.31) and adjusted (1.02 [0.46, 2.24], p = 0.96) analyses. Compared to males, females were at increased odds of having a lower socioeconomic status in adulthood (1.56 [1.13-2.17], p = 0.01).Compared to those with low educational attainment, those with moderate (0.32 [0.21, 0.48], p < 0.001) and high (0.12 [0.07, 0.20], p < 0.001) educational attainment were at reduced odds of having a lower socioeconomic status in adulthood. CONCLUSION: Cognitive problems in childhood (using educational attainment and scores on primary school tests proxy markers for cognition) rather than a history of seizures per se, were associated with lower SES in a population of adults born 1950-56 in Aberdeen. This relationship may be different depending on the time in history and nation/region of study. Given the changes in health, education and social support in the management of children with seizures over time, it would be of interest to investigate outcomes in a contemporary cohort. Such studies should ideally have validated diagnoses of seizures, details on seizure characteristics such as seizure type and severity, and a large sample size using national data.

Comparison of neurodevelopmental, educational and adult socioeconomic outcomes in offspring of women with and without epilepsy: A systematic review and meta-analysis.

BACKGROUND: Adequate pre-pregnancy counselling and education planning are essential to improve outcomes for offspring of women with epilepsy (OWWE). The current systematic review and meta-analysis aimed to compare outcomes for OWWE and offspring of women without epilepsy (OWWoE). METHODS: We conducted a systematic review and meta-analysis. We searched MEDLINE, EMBASE, CINAHL, PsycINFO (database inception-1st January 2023), OpenGrey, GoogleScholar, and hand-searched journals and reference lists of included studies to identify eligible studies. We placed no language restrictions and included observational studies concerning OWWE and OWWoE. We followed the PRIMSA checklist for abstracting data. The Newcastle-Ottawa Scale for risk of bias assessment was conducted independently by two authors with mediation by a third. We report pooled unadjusted odds ratios (OR) or mean differences (MD) with 95% confidence intervals (95CI) from random (I2>50%) or fixed (I2<50%) effects meta-analyses. Outcomes of interest included offspring autism, attention deficit/hyperactive disorder, intellectual disability, epilepsy, developmental disorder, intelligence, educational, and adulthood socioeconomic outcomes. RESULTS: Of 10,928 articles identified, we included 21 in meta-analyses. OWWE had increased odds of autism (2 articles, 4,502,098 offspring) OR [95CI] 1·67 [1·54, 1·82], attention-deficit/hyperactivity disorder (3 articles, 957,581 offspring) 1·59 [1·44, 1·76], intellectual disability (2 articles, 4,501,786 children) 2·37 [2·13, 2·65], having special educational needs (3 articles, 1,308,919 children) 2·60 [1·07, 6·34]. OWWE had worse mean scores for full-scale intelligence (5 articles, 989 children) -6·05 [-10·31, -1·79]. No studies were identified that investigated adulthood socioeconomic outcomes. CONCLUSIONS: Increased odds of poor outcomes are higher with greater anti-seizure medication burden including neurodevelopmental and educational outcomes. In fact, these two outcomes seem to be worse in OWWE compared to OWWoE, even if there was no ASM exposure during pregnancy, but further work is needed to take into account potential confounding factors.

Protocol of a randomised trial of teriparatide followed by zoledronic acid to reduce fracture risk in adults with osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) is a rare genetic disease associated with multiple fractures throughout life. It is often treated with osteoporosis medications but their effectiveness at preventing fractures is unknown. The Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid trial will determine if therapy with teriparatide (TPTD) followed by zoledronic acid (ZA) can reduce the risk of clinical fractures in OI. METHODS AND ANALYSIS: Individuals aged ≥18 years with a clinical diagnosis of OI are eligible to take part. At baseline, participants will undergo a spine X-ray, and have bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip. Information on previous fractures and previous bone targeted treatments will be collected. Questionnaires will be completed to assess pain and other aspects of health-related quality of life (HRQoL). Participants will be randomised to receive a 2-year course of TPTD injections 20 µg daily followed by a single intravenous infusion of 5 mg ZA, or to receive standard care, which will exclude the use of bone anabolic drugs. Participants will be followed up annually, have a repeat DXA at 2 years and at the end of study. Spine X-rays will be repeated at the end of study. The duration of follow-up will range between 2 and 8 years. The primary endpoint will be new clinical fractures confirmed by X-ray or other imaging. Secondary endpoints will include participant reported fractures, BMD and changes in pain and HRQoL. ETHICS AND DISSEMINATION: The study received ethical approval in December 2016. Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results will inform clinical practice by determining if TPTD/ZA can reduce the risk of fractures in OI compared with standard care. TRIAL REGISTRATION NUMBER: ISRCTN15313991.

Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments.

BACKGROUND: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). PURPOSE: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. STUDY-TYPE: Longitudinal. POPULATION: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. FIELD STRENGTH/SEQUENCE: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. ASSESSMENT: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. STATISTICAL TESTS: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. RESULTS: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (ß = -0.21); in the riluzole arm, GM Glx (ß = -0.25) and Glx/tCr (ß = -0.29) were reduced. Baseline tNAA(ß = 0.22) and tNAA/tCr (ß = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. DATA CONCLUSION: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Evaluation of Digitalisation in Healthcare and the Quantification of the "Unmeasurable".

Evaluating healthcare digitalisation, where technology implementation and adoption transforms existing socio-organisational processes, presents various challenges for outcome assessments. Populations are diverse, interventions are complex and evolving over time, meaningful comparisons are difficult as outcomes vary between settings, and outcomes take a long time to materialise and stabilise. Digitalisation may also have unanticipated impacts. We here discuss the limitations of evaluating the digitalisation of healthcare, and describe how qualitative and quantitative approaches can complement each other to facilitate investment and implementation decisions. In doing so, we argue how existing approaches have focused on measuring what is easily measurable and elevating poorly chosen values to inform investment decisions. Limited attention has been paid to understanding processes that are not easily measured even though these can have significant implications for contextual transferability, sustainability and scale-up of interventions. We use what is commonly known as the McNamara Fallacy to structure our discussions. We conclude with recommendations on how we envisage the development of mixed methods approaches going forward in order to address shortcomings.

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study.

BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review.

OBJECTIVE: To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items. STUDY DESIGN AND SETTING: Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items. RESULTS: After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1-6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7-9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11-14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15-16); and informing trial participants about using surrogate end points (item 17). CONCLUSION: The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials-SURROGATE and Consolidated Standards of Reporting Trials-SURROGATE extensions.

Comparison of Perinatal Outcomes for Women With and Without Epilepsy: A Systematic Review and Meta-analysis.

Importance: Pregnant women who have epilepsy need adequate engagement, information, and pregnancy planning and management to improve pregnancy outcomes. Objective: To investigate perinatal outcomes in women with epilepsy compared with women without epilepsy. Data Sources: Ovid MEDLINE, Embase, CINAHL, and PsycINFO were searched with no language or date restrictions (database inception through December 6, 2022). Searches also included OpenGrey and Google Scholar and manual searching in journals and reference lists of included studies. Study Selection: All observational studies comparing women with and without epilepsy were included. Data Extraction and Synthesis: The PRISMA checklist was used for abstracting data and the Newcastle-Ottawa Scale for risk-of-bias assessment. Data extraction and risk-of-bias assessment were done independently by 2 authors with mediation conducted independently by a third author. Pooled unadjusted odds ratios (OR) or mean differences were reported with 95% CI from random-effects (I2 heterogeneity statistic >50%) or fixed-effects (I2 < 50%) meta-analyses. Main Outcomes and Measures: Maternal, fetal, and neonatal complications. Results: Of 8313 articles identified, 76 were included in the meta-analyses. Women with epilepsy had increased odds of miscarriage (12 articles, 25 478 pregnancies; OR, 1.62; 95% CI, 1.15-2.29), stillbirth (20 articles, 28 134 229 pregnancies; OR, 1.37; 95% CI, 1.29-1.47), preterm birth (37 articles, 29 268 866 pregnancies; OR, 1.41; 95% CI, 1.32-1.51) and maternal death (4 articles, 23 288 083 pregnancies; OR, 5.00; 95% CI, 1.38-18.04). Neonates born to women with epilepsy had increased odds of congenital conditions (29 articles, 24 238 334 pregnancies; OR, 1.88; 95% CI, 1.66-2.12), neonatal intensive care unit admission (8 articles, 1 204 428 pregnancies; OR, 1.99; 95% CI, 1.58-2.51), and neonatal or infant death (13 articles, 1 426 692 pregnancies; OR, 1.87; 95% CI, 1.56-2.24). The increased odds of poor outcomes was increased with greater use of antiseizure medication. Conclusions and Relevance: This systematic review and meta-analysis found that women with epilepsy have worse perinatal outcomes compared with women without epilepsy. Women with epilepsy should receive pregnancy counseling from an epilepsy specialist who can also optimize their antiseizure medication regimen before and during pregnancy.

Multicentre open label randomised controlled trial of immediate enhanced ambulatory ECG monitoring versus standard monitoring in acute unexplained syncope patients: the ASPIRED study.

INTRODUCTION: Diagnosing underlying arrhythmia in emergency department (ED) syncope patients is difficult. There is a evidence that diagnostic yield for detecting underlying arrhythmia is highest when cardiac monitoring devices are applied early, ideally at the index visit. This strategy has the potential to change current syncope management from low diagnostic yield Holter to higher yield ambulatory monitoring, reduce episodes of syncope, reduce risk of recurrence and its potential serious consequences, reduce hospital admissions, reduce overall health costs and increase quality of life by allowing earlier diagnosis, treatment and exclusion of clinically important arrhythmias. METHODS AND ANALYSES: This is a UK open prospective parallel group multicentre randomised controlled trial of an immediate 14-day ambulatory patch heart monitor vs standard care in 2234 patients presenting acutely with unexplained syncope. Our patient focused primary endpoint will be number of episodes of syncope at 1 year. Health economic evaluation will estimate the incremental cost per syncope episode avoided and quality-adjusted life year gained. ETHICS AND DISSEMINATION: Informed consent for participation will be sought. The ASPIRED trial received a favourable ethical opinion from South East Scotland Research Ethics Committee 01 (21/SS/0073). Results will be disseminated via scientific publication, lay summary and visual abstract. TRIAL REGISTRATION NUMBER: ISRCTN 10278811.

Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART).

BACKGROUND: MND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival. METHODS: Initially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022. DISCUSSION: In developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects. TRIAL REGISTRATION: EudraCT Number, 2019-000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smart ClinicalTrials.gov, NCT04302870 . Registered 10 March 2020.

A complex ePrescribing-based Anti-Microbial Stewardship (ePAMS+) intervention for hospitals combining technological and behavioural components: protocol for a feasibility trial.

BACKGROUND: Antimicrobial resistance is a leading global public health threat, with inappropriate use of antimicrobials in healthcare contributing to its development. Given this urgent need, we developed a complex ePrescribing-based Anti-Microbial Stewardship intervention (ePAMS+). METHODS: ePAMS+ includes educational and organisational behavioural elements, plus guideline-based clinical decision support to aid optimal antimicrobial use in hospital inpatients. ePAMS+ particularly focuses on prompt initiation of antimicrobials, followed by early review once test results are available to facilitate informed decision-making on stopping or switching where appropriate. A mixed-methods feasibility trial of ePAMS+ will take place in two NHS acute hospital care organisations. Qualitative staff interviews and observation of practice will respectively gather staff views on the technical component of ePAMS+ and information on their use of ePAMS+ in routine work. Focus groups will elicit staff and patient views on ePAMS+; one-to-one interviews will discuss antimicrobial stewardship with staff and will record patient experiences of receiving antibiotics and their thoughts on inappropriate prescribing. Qualitative data will be analysed thematically. Fidelity Index development will enable enactment of ePAMS+ to be measured objectively in a subsequent trial assessing the effectiveness of ePAMS+. Quantitative data collection will determine the feasibility of extracting data and deriving key summaries of antimicrobial prescribing; we will quantify variability in the primary outcome, number of antibiotic defined daily doses, to inform the future larger-scale trial design. DISCUSSION: This trial is essential to determine the feasibility of implementing the ePAMS+ intervention and measuring relevant outcomes, prior to evaluating its clinical and cost-effectiveness in a full scale hybrid cluster-randomised stepped-wedge clinical trial. Findings will be shared with study sites and with qualitative research participants and will be published in peer-reviewed journals and presented at academic conferences. TRIAL REGISTRATION: The qualitative and Fidelity Index research were approved by the Health and Research Authority and the North of Scotland Research Ethics Service (ref: 19/NS/0174). The feasibility trial and quantitative analysis (protocol v1.0, 15 December 2021) were approved by the London South East Research Ethics Committee (ref: 22/LO/0204) and registered with ISRCTN ( ISRCTN 13429325 ) on 24 March 2022.

Protocol for the development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: SPIRIT-SURROGATE and CONSORT-SURROGATE.

INTRODUCTION: Randomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome. METHODS AND ANALYSIS: The project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases. ETHICS AND DISSEMINATION: The study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums.

Practical guidance for planning resources required to support publicly-funded adaptive clinical trials.

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: An exploratory post-hoc investigation.

BACKGROUND: The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis. METHODS: Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined. RESULTS: The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data. CONCLUSIONS: Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs.

Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.

INTRODUCTION: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine. METHODS AND ANALYSIS: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments. ETHICS AND DISSEMINATION: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants. TRIAL REGISTRATION NUMBERS: European Clinical Trials Registry (2019-000099-41); NCT04302870.

Informed decision-making: Statistical methodology for surrogacy evaluation and its role in licensing and reimbursement assessments.

The desire, by patients and society, for faster access to therapies has driven a long tradition of the use of surrogate endpoints in the evaluation of pharmaceuticals and, more recently, biologics and other innovative medical technologies. The consequent need for statistical validation of potential surrogate outcome measures is a prime example on the theme of statistical support for decision-making in health technology assessment (HTA). Following the pioneering methodology based on hypothesis testing that Prentice presented in 1989, a host of further methods, both frequentist and Bayesian, have been developed to enable the value of a putative surrogate outcome to be determined. This rich methodological seam has generated practical methods for surrogate evaluation, the most recent of which are based on the principles of information theory and bring together ideas from the causal effects and causal association paradigms. Following our synopsis of statistical methods, we then consider how regulatory authorities (on licensing) and payer and HTA agencies (on reimbursement) use clinical trial evidence based on surrogate outcomes. We review existing HTA surrogate outcome evaluative frameworks. We conclude with recommendations for further steps: (1) prioritisation by regulators and payers of the application of formal surrogate outcome evaluative frameworks, (2) application of formal Bayesian decision-analytic methods to support reimbursement decisions, and (3) greater utilization of conditional surrogate-based licensing and reimbursement approvals, with subsequent reassessment of treatments in confirmatory trials based on final patient-relevant outcomes.