Title: Early switch to oral antibiotic therapy in patients with low risk neutropenic sepsis (The EASI-SWITCH Trial)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: DESIGN: Randomised controlled, allocation-concealed, non-inferiority trial SETTING: 12 UK hospitals POPULATION: Hospitalised patients with fever and neutropenia after systemic anti-cancer therapy. INCLUSION CRITERIA: Age over 16 years; fever (temperature >38oC); neutropenia (neutrophil count <0.5x10^9/L); received intravenous antibiotics <24 hours; expected duration of neutropenia <7 days; low risk of complications using a validated clinical risk score (MASCC score >/= 21); adequate oral intake and oral medication; adequate renal and hepatic function; physician in charge of care willing to follow either the intervention or standard care protocol per randomisation, including not treating with colony stimulating factor (CSF). EXCLUSION CRITERIA: Acute leukaemia or haematopoietic stem cell transplant; hypotension; prior allergy, serious adverse reaction, or other contraindication to any study drug; treatment with fluoroquinolone or penicillin antibiotics in the preceding 14 days; enrolled with prior episode of neutropenic sepsis; colonised with an organism resistant to a study drug regimen; localising signs of severe infection (pneumonia, soft tissue/central-venous access device infection, purulent collection). HEALTH TECHNOLOGY: Switch from intravenous to oral antibiotic therapy (comprising ciprofloxacin and co-amoxiclav for 5 days) 12-24 hours after intravenous treatment commences. Compared to standard care, comprising intravenous piperacillin/tazobactam or meropenem, for at least 48 hours with subsequent discontinuation or switch to oral therapy at physician discretion. MEASUREMENT OF OUTCOMES: The primary outcome is treatment failure on day 14. This is an internationally-endorsed composite outcome, defined by any of: persistence or recurrence of fever (temperature >38oC) after 72hrs of starting intravenous antibiotic treatment; physician-directed escalation from protocol antibiotic treatment; re-admission to hospital (related to infection or antibiotic treatment); critical care admission; death. Secondary outcomes assessed on day 14 are: time to fever resolution; adverse events due to antibiotics; resource utilisation, including discharge readiness/length of hospitalisation; quality of life and cost-effectiveness. Readmission and death will also be assessed on day 28. SAMPLE SIZE: Based on a 15% failure rate for the standard care arm and a non-inferiority margin of 10%, at 90% power (1-sided 97.5% CI), 269 patients per arm are required. Accounting for up to a 5% dropout rate (based on smaller RCTs), and with inflation to allow for up to 10% crossover from control to intervention arm, gives 314 participants per arm (628 in total). PROJECT TIMETABLE AND RECRUITMENT RATE: Total duration - 45 months. Following 3 months’ set-up, an internal pilot will run for 6 months in 4 centres. Recruitment will proceed in all 12 centres over the subsequent 30 months at an average of 1.7 patients per centre per month. Trial closedown and report-writing will be completed in the final 6 months. TEAM EXPERTISE: We have expertise in delivery of clinical trials in cancer patients, treatment of complex infection and trial design/management. There is input from: physicians who care for patients with neutropenic sepsis; medical microbiologists; a patient representative; an experienced methodologist; and a UKCRC-registered clinical trials unit (including director, health economist and senior statistician).

Lay abstract: Neutropenic sepsis, or infection that develops in the setting of a low white blood cell count, is a potentially life-threatening complication of chemotherapy treatment in patients with cancer. As the amount of chemotherapy given in the UK has increased significantly in recent years the frequency of this complication has also increased. There is widespread recognition that this condition requires immediate hospital assessment and prompt antibiotic treatment to avoid serious complications, however, there is less agreement about how best to manage patients thereafter. Several bedside clinical risk scores have been developed which aim to categorise patients depending on their risk of complications. The ability to identify patients at low risk offers the opportunity to avoid unnecessary treatment and hospital stay which disadvantages both patients and the NHS. We propose a randomised trial of patients at low risk of complications, identified using a previously validated risk score, to evaluate whether changing from intravenous to oral antibiotics on the first day of treatment is clinically and cost-effective in comparison with standard longer duration intravenous antibiotics. In the intervention arm patients will switch from intravenous to oral antibiotics (comprising ciprofloxacin and co-amoxiclav) for five days, 12-24 hours after intravenous treatment commences. In the control arm, patients will receive standard care intravenous antibiotic (piperacillin/tazobactam or meropenem) for at least 48 hours with subsequent antibiotic continuation or switch to oral therapy at physician discretion. The primary outcome that we will use to assess effectiveness is failure of treatment and we will measure this on day 14 of follow-up. This will be defined by the presence of one of several clinical outcomes. With input from our patient representatives, we have included a range of undesirable outcomes that are all of importance to patients. The study will also evaluate the effect of the different treatments on: readmission to hospital; antibiotic side-effects; quality of life; utilisation of health care resources, including length of hospital stay; cost-effectiveness; and death within 28 days. A total of 628 patients will be needed to definitively demonstrate that the proposed treatment intervention is not significantly less effective than standard care. The main expected advantages of the intervention (patients’ quality of life and resource utilisation) will also be measured. The trial will begin with a 6 month pilot phase, enrolling patients in 4 hospitals, to demonstrate feasibility followed by expansion to 12 hospitals across the UK over the next 30 months. This will ensure the results are relevant to the wider UK population.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS;INFECTION