Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.

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.

Does a screening checklist for complex health and social care needs have potential clinical usefulness for predicting unplanned hospital readmissions in intensive care survivors: development and prospective cohort study.

OBJECTIVES: Intensive care (ICU) survivors are at high risk of long-term physical and psychosocial problems. Unplanned hospital readmission rates are high, but the best way to triage patients for interventions is uncertain. We aimed to develop and evaluate a screening checklist to help predict subsequent readmissions or deaths. DESIGN: A checklist for complex health and social care needs (CHSCNs) was developed based on previous research, comprising six items: multimorbidity; polypharmacy; frequent previous hospitalisations; mental health issues; fragile social circumstances and impaired activities of daily living. Patients were considered to have CHSCNs if two or more were present. We prospectively screened all ICU discharges for CHSCNs for 12 months. SETTING: ICU, Royal Infirmary, Edinburgh, UK. PARTICIPANTS: ICU survivors over a 12-month period (1 June 2018 and 31 May 2019). INTERVENTIONS: None. OUTCOME MEASURE: Readmission or death in the community within 3 months postindex hospital discharge. RESULTS: Of 1174 ICU survivors, 937 were discharged alive from the hospital. Of these 253 (27%) were classified as having CHSCNs. In total 28% (266/937) patients were readmitted (N=238) or died (N=28) within 3 months. Among CHSCNs patients 45% (n=115) patients were readmitted (N=105) or died (N=10). Patients without CHSCNs had a 22% readmission (N=133) or death (N=18) rate. The checklist had: sensitivity 43% (95% CI 37% to 49%), specificity 79% (95% CI 76% to 82%), positive predictive value 45% (95% CI 41% to 51%), and negative predictive value 78% (95% CI 76% to 80%). Relative risk of readmission/death for patients with CHSCNs was 2.06 (95% CI 1.69 to 2.50), indicating a pretest to post-test probability change of 28%-45%. The checklist demonstrated high inter-rater reliability (percentage agreement ≥87% for all domains; overall kappa, 0.84). CONCLUSIONS: Early evaluation of a screening checklist for CHSCNs at ICU discharge suggests potential clinical usefulness, but this requires further evaluation as part of a care pathway.

Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.

A two-arm parallel-group individually randomised prison pilot study of a male remand alcohol intervention for self-efficacy enhancement: the APPRAISE study protocol.

INTRODUCTION: The prevalence of at-risk drinking is far higher among those in contact with the criminal justice system (73%) than the general population (35%). However, there is little evidence on the effectiveness of alcohol brief interventions (ABIs) in reducing risky drinking among those in the criminal justice system, including the prison system and, in particular, those on remand. Building on earlier work, A two-arm parallel group individually randomised Prison Pilot study of a male Remand Alcohol Intervention for Self-efficacy Enhancement (APPRAISE) is a pilot study designed to assess the feasibility and acceptability of an ABI, delivered to male prisoners on remand. The findings of APPRAISE should provide the information required to design a future definitive randomised controlled trial (RCT). METHODS AND ANALYSIS: APPRAISE will use mixed methods, with two linked phases, across two prisons in the UK, recruiting 180 adult men on remand: 90 from Scotland and 90 from England. Phase I will involve a two-arm, parallel-group, individually randomised pilot study. The pilot evaluation will provide data on the likely impact of A two-arm parallel group individually randomised Prison Pilot study of a male Remand Alcohol Intervention for Self-efficacy Enhancement (APPRAISE), which will be used to inform a future definitive multicentre RCT. Phase II will be a process evaluation assessing how the ABI has been implemented to explore the change mechanisms underpinning the ABI (figure 1) and to assess the context within which the ABI is delivered. ETHICS AND DISSEMINATION: The APPRAISE protocol has been approved by the East of Scotland Research Ethics Committee (19/ES/0068), National Offender Management System (2019-240), Health Board Research and Development (2019/0268), Scottish Prison Service research and ethics committee, and by the University of Edinburgh's internal ethics department. The findings will be disseminated via peer-reviewed journal publications, presentations at local, national and international conferences, infographics and shared with relevant stakeholders through meetings and events. TRIAL REGISTRATION NUMBER: ISRCTN27417180.