Every year, thousands of ICU patients in the UK are given antifungal drugs for suspected *Candida* infections—but many receive the drugs longer than necessary, risking side effects, drug interactions, and fuelling antimicrobial resistance. This trial tests whether a simple diagnostic algorithm, combining two rapid blood biomarkers (beta-D-glucan and *Candida* DNA), can safely allow doctors to stop those drugs earlier. The problem is clear: overtreatment harms patients, costs the NHS, and accelerates drug resistance. Current standard care lacks a reliable, rapid way to rule out infection, so clinicians err on the side of caution. The A-Stop 2 trial will randomise 1,226 adults across up to 50 NHS ICUs to either the biomarker-guided algorithm or standard care, measuring both treatment duration and 28-day survival to ensure safety is not compromised. If the algorithm works, it could set a new standard of care—not just in the NHS but globally. Patients would face fewer adverse effects, the NHS would save on drug costs and bed days, and society would benefit from reduced antifungal resistance. The trial also includes a health economic analysis and a process evaluation to identify barriers to NHS implementation, ensuring the findings can translate directly into practice.
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RESEARCH QUESTION: In Intensive Care Unit (ICU) patients treated empirically for suspected Candida infection, does a diagnostic algorithm, based on biomarkers alongside standard care tests, safely reduce the number of days of antifungal treatment prescribed? BACKGROUND: This proposal aligns with the antimicrobial resistance (AMR) commissioning brief. The clinical problem is overuse of antifungal drugs in ICU patients. Overtreatment disadvantages patients (adverse effects, drug interactions), the NHS (cost of care) and wider society (increasing drug resistance). The recent HTA-funded A-Stop Study evaluated the accuracy of four rapid biomarker tests for Candida infection and developed an algorithm for stopping empirical treatment early based on combining two biomarkers. AIM: To determine the clinical- and cost-effectiveness of this biomarker-guided algorithm for early cessation of empirical antifungal treatment, compared to standard care, among adults in ICU. OBJECTIVES: (1) Conduct a multi-centre, allocation-concealed, open-label, individually randomised, parallel group trial to determine if the algorithm can reduce the number of days’ empirical antifungal treatment without causing patients harm, assessed using survival status at 28-days; (2) Embed an internal pilot study to confirm the trial’s feasibility; (3) Evaluate the cost-effectiveness of the algorithm; (4) Assess the process, clinical decision-making, and barriers/facilitators to implementation in the NHS. METHODS: Setting: Up to 50 NHS ICUs, covering diverse demographics/backgrounds to maximise inclusion and generalisability. Randomisation: Allocation concealed, randomisation (1:1 ratio), stratified by hospital site and SOFA score. Population: Adults started on empirical systemic antifungal therapy for suspected Candida infection. Health technologies being assessed: Diagnostic algorithm based on biomarkers (beta-D-glucan and Candida DNA) Comparator: Standard NHS care. Primary outcome: Total duration of antifungal treatment to 28 days (primary effectiveness); survival status at 28 days (primary safety). Secondary outcomes: Survival status at 90 days; proportion alive and discharged from hospital at 90 days; ICU and hospital length of stay; duration of initial antifungal treatment episode; suspected infection relapse/recurrence of infection requiring antifungal treatment (to day-28); adverse events; incremental cost per quality-adjusted life year gained (NHS/PSS perspective); barriers and facilitators to NHS implementation. Sample size: 1226 patients (90% power, 5% alpha, for detecting a 2-day difference in mean treatment duration; 5% withdrawals). TIMELINE: 60 months, comprising: 9-months set-up; 12-months internal pilot; 33-months further recruitment; 6-months final follow-up, data analysis, reporting and dissemination. ANTICIPATED IMPACT AND DISSEMINATION: The study will provide definitive evidence for the effectiveness of a biomarker-guided algorithm for stopping unnecessary empirical antifungal treatment. The findings will set a new standard of care for the NHS and globally. We will publish lay and professional summaries (in written, audible and infographic styles), promote these at public engagement events and develop patient facing website material / leaflets. We will disseminate to clinicians through peer-reviewed publications, podcasts, blogs, conference presentations and social media. We will engage policy makers through links with key organisations.
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