Antibiotic Stewardship in Suspected Neutropenic Fever (ASTERIC Trial): a Multi-centre, Type 1 Hybrid Effectiveness-implementation, Stepped-wedge, Randomised Controlled Trial

Executive Summary

Background: Neutropenic Fever (NF), or febrile neutropenia, occurs in patients with early stage and metastatic solid tumours, non-leukaemic haematological cancers and acute leukaemia. It has a crude mortality rate of 3 to 18%. In Hong Kong, and in line with international guidelines, the target time from ED registration to ultra-broad spectrum antibiotic (UBSA) administration (door-to-antibiotic time, DTA time) is one hour disregarding the absolute neutrophil count (ANC). However, over 80% patients presenting to hospital with suspected NF (sNF) do not have NF and do not require UBSAs. Thus there is a need for evidence for a safe role for early treatments in patients with sNF to reduce unnecessary use of antibiotics.

Protocol, Eligibility and Randomisation: This protocol describes the ASTERIC Trial, a pragmatic, multi-centre, type 1, hybrid effectiveness-implementation, stepped-wedge, before and after, cluster randomised controlled trial with variable baseline and follow up periods. Hospitals will be randomised to start dates comparing usual standard of care (SoC) (Period 1, before) with a new antibiotic stewardship protocol (Period 2, after). Hospitals, not patients, are randomised to variable start dates. The evidence for starting early UBSAs in patients with NF is well-established. What is unclear is how to optimise personalised care and the start times of UBSA when the majority of sNF patients do not have NF, there are delays to receiving an ANC report, and a proportion of patients might not need hospital admission.

Study design: a multi-centre, hybrid type 1 effectiveness-implementation trial which is an appropriate study design to evaluate the real-world effectiveness of an antibiotic stewardship protocol; and the barriers to and facilitators of its implementation in the ED setting.

Settings: Eight hospitals in Hong Kong with patient involvement 24/7.

Outcomes: The Trial has two co-primary outcomes 1) mean total dose of UBSAs prescribed in 7 days and censored at 30 days from the time of randomisation; 2) safety (defined as the proportion of patients with a SAE), censored at 30 days from the time of randomisation.

This multifaceted trial addresses three broad domains of implementation according to Proctor's conceptual framework and taxonomy which incorporates the RE-AIM framework, namely: Service Outcomes; Implementation Outcomes and Client outcomes. Simplicity on the frontline: Patient enrolment and other front-line trial procedures will be streamlined. Informed consent is brief and simple and required for follow-up. Follow-up information may be ascertained by contacting participants in person, by phone or electronically, or by review of medical records and databases.

Data to be collected: Information will be collected on the patient, age, sex, major co-morbidity, sNF symptom onset date and severity, as well as any contraindications to study treatments. Follow-up information includes antibiotics - name, dose and duration; SAEs; mortality; sepsis; length of hospital stay; cost-effectiveness; patient satisfaction.

Numbers: 648 patients (324 patients in each group) adult patients with sNF ≥38.3ºC and Modified Early Warning Score ≤6 within 24 hours of ED registration.

Benefit to Healthcare/Expected results: Study results will inform health policy with improvement in hospital services in treating stable sNF evidenced by improved personalised, safe antibiotic stewardship, early antibiotic de-escalation, early discharge, and reduced costs and length of stay. The ASTERIC protocol safely reduces the type, duration and dose of antibiotics.