PROcalcitonin and NEWS evaluation for Timely identification of sepsis and Optimal use of antibiotics in the Emergency Department (PRONTO)

BACKGROUND: Sepsis is acknowledged as a medical emergency and early antibiotic use with broad spectrum antimicrobial coverage is central to management. The early clinical diagnosis of sepsis lacks specificity leading to over treatment with antibiotics and increases the adverse consequences of their use. Procalcitonin (PCT) is a biomarker of sepsis, which if used in conjunction with National Early Warning Score (NEWS), may improve the specificity of early clinical assessment and reduce unhelpful antibiotic prescribing in suspected sepsis. AIM: To assess whether the addition of PCT measurement to NEWS scoring leads to a reduction in antibiotic initiation with at least no increase in 28-day mortality compared to NEWS scoring alone in the management of patients seen in the Emergency Department (ED) with suspected sepsis. Secondary research aims will be the assessment of a) feasibility, b) cost-effectiveness and c) acceptability to patients and their family. DESIGN: Prospective, individually randomised, open, two-arm group sequential RCT with internal pilot study across 10 centres. PHASE 1: An internal pilot study to assess recruitment rates, adherence to intervention, feasibility of individual randomisation, attrition rates, and the proportion of patients in whom we are able to measure both co-primary outcomes. Also a qualitative process evaluation which aims to improve the trial conduct in Phase 2. Defined stop-go criteria. PHASE 2: Full RCT, with a planned interim analysis after 50% of the patients provide primary outcome data. SETTING: Adult emergency care settings. TARGET POPULATION: Adults and adolescents =16 years old. HEALTH TECHNOLOGIES BEING ASSESSED: The addition of point of care testing for PCT to NEWS scoring compared to current standard of care using NEWS alone. OUTCOMES: Co-primary outcomes: IV antibiotics initiation at 3 hours (superiority end point) and mortality at 28 days (non-inferiority). A positive conclusion will be both a decrease in IV antibiotic duration AND non-inferiority in mortality. Secondary outcomes include total duration of antibiotics, type of antibiotic, readmissions, antibiotic associated side effects, health Utility (EQ-5D/5L) at 90 days. SAMPLE SIZE: Assuming a baseline 28 day mortality of 15% and a conservative non-inferiority margin of 2.5%, a one-sided significance level of 0.05 and 90% power and 5% drop out we will need 7372 participants. This will give 90% power to detect antibiotic initiation decrease from 90 to 87.6%. The group-sequential design will increase the total maximum sample size by just over 4% to 7676 (inflated for 5% dropout). Recruitment will take place over 24 months. Follow up will be to 28 days and 90 days. ECONOMIC EVALUATION: We will apply NHS and societal perspective to address the decision making in health system and on the society costs respectively. We will follow the intention-to-treat of the primary clinical effectiveness and safety analyses, and will include cost-saved per unit investment, cost-effectiveness analysis expressed as GBP per life year saved/per QALY gained, and cost-benefit analysis by comparing net cost of benefits between arms. QUALITATIVE ANALYSIS: We will interview clinicians, patients and carers (including in cases of participant death) to assess feasibility and acceptability of the PCT enhanced process. Ethnographic observation of trial-in-action will be carried out in 5 participating sites during 3 day periods.