Title: PROcalcitonin and NEWS evaluation for Timely identification of sepsis and Optimal use of antibiotics in the Emergency Department (PRONTO)
Funder: Department of Health and Social Care

Abstract: THE PROBLEM_x000D_ Sepsis is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes early recognition, prompt antibiotics and fluids into a vein (intravenous/IV). Currently, clinicians assess severity in patients in the Emergency Department (ED) with a scoring system based on simple to measure observations: the National Early Warning Score (NEWS). NEWS helps clinicians identify the sickest patients. It is not specific and tends to over-diagnose sepsis leading to over prescribing of antibiotics, and promoting antimicrobial resistance. It is the best we have and currently used in over 70% of English hospitals. Adults with suspected sepsis fall into one of three categories: a) those looking ill needing urgent IV antibiotics and fluids within 1 hour, b) those that are unwell, but will not come to harm if IV antibiotics are not administered within 1 hour, allowing time for further assessment prior to starting antibiotics within 3 hours, c) those not critically unwell who may or may not need IV antibiotics. Procalcitonin (PCT), a blood test not widely used in the NHS, helps to identify bacterial infection. The National Institute for Health and Care Excellence (NICE) recommended further research on PCT testing in EDs for guiding antibiotic use in people with suspected sepsis._x000D_ _x000D_ AIM OF THE RESEARCH_x000D_ The primary aim is to compare PCT- supported assessment with standard care of suspected sepsis in adults presenting to the ED, and measure whether this approach reduces prescriptions of antibiotics without increasing mortality by decreasing uncertainty in the group who may not need IV antibiotics urgently within 1 hour, or not need antibiotics at all._x000D_ _x000D_ WHAT WILL BE DONE?_x000D_ The evaluation will be done via a randomised controlled trial in ten hospitals. Adult patients with suspected sepsis presenting to the ED will be randomly assigned to current standard of care or PCT- supported care. In the PCT arm, a bedside test (taking 20 minutes) is performed plus the NEWS assessment. Depending on the result of the PCT plus the NEWS, patients will receive IV antibiotics and fluids within the current recommended time frame depending on severity (see study flow chart). Doctors and patients will know what treatment arm they are in. Doctors remain free to use antibiotics outside the study guidelines using their clinical judgement in any of the risk groups. The key outcome measures will be whether IV antibiotics are started, and death within 28 days. An analysis will be done to understand how well clinicians follow the recommendations, ease of use of the additional test in a busy ED, and its cost effectiveness. A sample of patients interviewed at 90 days follow up will assess experiences of care._x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ The UK Sepsis Trust (UKST) were consulted. This application includes JC as a patient representative, sepsis survivor and UKST volunteer. JC contributed to all parts of the study proposal. A sepsis patient focus group has been involved in a wider consultation on the study design, patient acceptability, patient perceptions of antibiotic therapy in sepsis management and the risks of antimicrobial resistance._x000D_ _x000D_ HOW WILL IT BENEFIT PATIENTS?_x000D_ If the study shows that PCT-supported assessment is superior to current practice, then it will lead to better outcomes in sepsis, improved care and a reduction in inappropriate antibiotics prescriptions.

Lay abstract: 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._x000D_ 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._x000D_ DESIGN: Prospective, individually randomised, open, two-arm group sequential RCT with internal pilot study across 10 centres._x000D_ 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._x000D_ PHASE 2: Full RCT, with a planned interim analysis after 50% of the patients provide primary outcome data._x000D_ SETTING: Adult emergency care settings._x000D_ TARGET POPULATION: Adults and adolescents =16 years old._x000D_ 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._x000D_ 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. _x000D_ 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. _x000D_ 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._x000D_ 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.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM