STRENGTHS AND LIMITATIONS OF THIS STUDY
This multicentre, hybrid type 1 effectiveness-implementation trial uses a stepped-wedge randomised design across eight hospitals to assess a real-world application of an antibiotic stewardship protocol.
The protocol incorporates both clinical outcomes and implementation metrics, including barriers and facilitators analysis across diverse emergency department settings.
The stepped-wedge design allows for sequential implementation while potentially introducing temporal confounding factors.
As an open-label trial, it may be subject to performance bias despite randomisation.
Variations in local hospital protocols and resources may affect the intervention across sites and complicate the analysis.
Introduction
Neutropenic fever (NF), or febrile neutropenia, is characterised by a high body temperature and low absolute neutrophil count (ANC) after myelosuppressive cancer treatment. 1 It occurs in patients with early-stage and metastatic solid tumours, non-leukaemic haematological cancers and acute leukaemia. 1 2 The crude mortality rate varies from 3% to 18%. 3 4 In the USA, each year, 7.83 per 1000 patients with cancer are hospitalised with NF. 4 The mean direct hospitalisation costs of managing NF vary from €3950 (about HKD$34 000) to US$19 110 (about HKD$150 000) per patient. 5 6
NF can have infectious and non-infectious causes. 7 Although 30–50% cases appear clinically to be infections, only 20–30% have microbiologically documented infections. 8 Bloodstream infections, bacterial translocations from the respiratory tract and perianal region, and central venous catheter-related infections are major sources. Fever may be the only manifestation of infection during neutropenia because the typical signs of inflammation are obscured. Neutropenia usually results from myelosuppressive cancer treatments, pre-engraftment phases of haematopoietic stem cell transplantation (HSCT), bone marrow failure and/or defective neutrophil maturation. 9
Local public emergency departments (EDs) have standard operating procedures and guidelines for managing NF (see figure 1 ). In line with international guidelines, the target time from ED registration to antibiotic administration (door-to-antibiotic time, DTA time) is 1-hour disregarding ANC. 10 11 The clinical pathways for suspected NF (sNF) expedites medical consultation, septic workup and early prescription of ultrabroad-spectrum antibiotics (UBSAs) such as meropenem or piperacillin/tazobactam. After implementing clinical pathways in local EDs, DTA times have shortened. 12
However, over 75–86% patients presenting to Queen Mary Hospital in Hong Kong with sNF have an ANC>1×10 9 /L, do not have NF, do not require UBSAs and possibly do not require hospital admission. 13 14 Widespread, inappropriate use of UBSAs may contribute to the emergence of antimicrobial resistance and multidrug resistance (MDR) strains. 15 Thus, there is a need for prudent, pragmatic, personalised antibiotic stewardship and appropriate de-escalation.
As patients with cancer are frequently prescribed antibiotics, they are more vulnerable to MDR and are in special need of antibiotic stewardship. 16 UBSAs are often started empirically in the ED for patients with sNF, assuming infection by drug-resistant bacteria. However, clinicians infrequently de-escalate once antibiotics have been started. Prolonged exposure to parenteral broad-spectrum antibiotic (BSA) imposes risks of nosocomial infection and injection site complications. There is also evidence that meeting the 1-hour target does not improve outcomes but that using appropriate antibiotic regimes does. 17
There is reasonable evidence that patients with NF presenting to hospital benefit from early UBSA/BSA treatment, and that patients with a high Multinational Association for Supportive Care in Cancer (MASCC) Risk Index do not need to be admitted to hospital. 10 The Infectious Diseases Society of America recommends oral empirical therapy for low-risk patients with NF with an MASCC score ≥21. For the Clinical Index of Stable Febrile Neutropenia, a score of 0, indicating low risk, is associated with a low risk of serious complications. 18 However, many healthcare settings have adopted a 1 hour limit on starting BSA/UBSA treatment and admit all patients (high and low risk) to hospital. As ANC results are not usually available within 1 hour, more than 80% sNF may be treated unnecessarily with inappropriate antibiotics. Consequently, there is a need for implementation studies to identify barriers and facilitators of care, and to optimise early management.
Evidence-based practices are slow to be implemented into routine care. 19 Implementation science supports translational medicine research to practice gaps. 20 , 23 It identifies barriers and facilitators to effective implementation and designs evolving strategies to achieve desired service, implementation and client outcomes.
A multicentre, hybrid type 1 effectiveness-implementation trial 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. Type 1 hybrid effectiveness-implementation trials test the effects of a clinical intervention on relevant outcomes while observing and gathering information on implementation. 21 This multifaceted trial addresses three broad domains of implementation according to Proctor’s conceptual framework and taxonomy which incorporates the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework, 22 23 namely Service Outcomes, Implementation Outcomes and Client Outcomes.
The ASTERIC trial is designed to address one primary question. In ED and hospitalised adult patients with cancer with sNF, does an antibiotic treatment protocol guided by early ANCs compared with standard of care (SoC) improve safe antibiotic stewardship in 7 days ? We hypothesise that in the ED and hospitalised adult patients with sNF, the ASTERIC protocol effectively and safely reduces the use of UBSAs compared with SoC alone (see figure 2 ). We aim first to investigate the effectiveness service outcome of the ASTERIC protocol to reduce the use of UBSAs in adult patients attending the ED and admitted to hospital with a clinical diagnosis of sNF over 7 days; and second to investigate the safety of the ASTERIC protocol to reduce SAEs in adult patients attending the ED and admitted to hospital with a clinical diagnosis of sNF over 30 days.
The ASTERIC trial asks a second question regarding implementation. In ED and hospitalised adult patients with cancer with sNF, what barriers and facilitators influence implementation of the ASTERIC interventions? Implementation science is multifaceted and highly complex. The trial seeks to answer other service, implementation and client outcome questions. The main secondary objectives are to investigate other service components, implementation components and the client component of the ASTERIC trial.
In ASTERIC , healthcare professionals receive a multifaceted stewardship intervention consisting of risk assessment tools, fast-track ANCs, a decision tool for patient management and antibiotic use, that is supported by an educational package and staff interaction programmes (ASTERIC intervention package, figure 3 , online supplemental file 3 ).
Methods and analysis
Trial design and setting
Effectiveness phase
This study is a pragmatic multicentre, type 1 hybrid effectiveness-implementation, stepped-wedge, randomised controlled trial ( figure 4 ). 24 Eligible hospitals will be randomly allocated to staggered start dates using a central, computer-generated systems in a stepped-wedge design by our data analyst to commence using the ASTERIC protocol between 3 and 10 months after starting the trial ( figure 5 ). This was a simple randomisation and the sequence was not concealed because hospitals needed to prepare in advance for the transition from phase 1 to phase 2. Importantly, the randomisation sequence determined the timing of each hospital’s transition, not the assignment of individual participants. Analyses will use generalised linear mixed models (random intercept for cluster; fixed effect for time), with prespecified site-level covariates to account for practice/case-mix differences.
The study will initially be conducted at eight hospitals in Hong Kong (Local Clinical Centres)—Gleneagles Hospital Hong Kong (GHK), North Lantau Hospital, Princess Margaret Hospital, Pamela Youde Nethersole Eastern Hospital, Queen Elizabeth Hospital, Queen Mary Hospital, Ruttonjee Hospital and United Christian Hospital. All are public or private hospitals. Patients will be recruited from the EDs or wards with subsequent follow-up in the medical wards, intensive care units and home after hospital discharge.
Key timeline dates
The study commenced patient recruitment on 14 February 2025 across all eight participating centres. By 6 June, 262 patients had been recruited in phase 1. The last subject recruitment is anticipated on 13 February 2026, with a 30-day follow-up until 15 March 2026. The study completion date, with Final Analysis/Reports, is anticipated on 13 February 2027.
Patient recruitment
Patients are involved in the post-recruitment stage. After obtaining informed consent, each recruited patient and participant will be assigned a study code, which is confidentially linked to patient identifiable number for data retrieval and follow-up.
Patient participants
Inclusion criteria for patient recruitment
All patients in the ED or admitted to medical wards who fulfil ALL of the following criteria will be eligible for the study:
≥18 years;
Tympanic temperature ≥38.3°C (or equivalent) within 24 hours before ED registration;
Last chemotherapy or targeted therapy within 6 weeks for any solid tumour, or in any period following therapies against leukaemia, lymphoma, myelodysplastic syndrome, aplastic anaemia, multiple myeloma or recipient of HSCT.
Exclusion criteria for patient recruitment
The decision on how far to apply or deviate from a protocol rests with the clinicians. Patients would only be excluded from follow-up if they are unable or unwilling to provide informed consent for data access. Online supplemental appendix 1a shows an example of the patient information and consent form in English. Different ethics bodies have required minor variations.
Staff participants
Inclusion criteria for staff recruitment
Three doctors and three nurses will be recruited based on their willingness, availability and senior staff approval.
Exclusion criteria for staff recruitment
There are no exclusion criteria for staff recruitment. The decision for staff to participate and withdraw will not affect the workplace evaluation. Online supplemental appendix 1b shows an example of the patient information and consent form in English.
Trial Arm 1 (before implementation): existing hospital NF protocol+SoC
Standard care is defined as the daily practice of physicians in evaluating and treating patients with sNF. During the SoC period, physicians will assess the patients based on history, physical examination, laboratory tests, chest radiography or other imaging studies and will offer treatment based on clinical expertise and local or international guidelines. The Centre for Health Protection Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy guideline provides appropriate antibiotic prescription. 25 Figure 1 provides generic information about the NF protocols for patients with NF. However, as ANC results are not usually available within 1 hour of triage, 10 all patients with sNF tend to receive UBSAs.
Trial Arm 2 (after): ASTERIC protocol+SoC
The ASTERIC protocol seeks to introduce locally developed protocols around a multifaceted stewardship intervention consisting of four items: (1) risk assessment tools, (2) fast-track ANCs, (3) a decision tool for patient management and antibiotic use supported by (4) an educational package.
The evidence for using antibiotics in this trial is well-established. However, the evidence for the need to start UBSAs within an hour of ED arrival prior to an ANC result is absent. There is currently no evidence-based guidelines for the urgent initiation of antibiotics administered in the ED for adult patients with sNF, as there are concerns regarding safety. ASTERIC will also evaluate and address barriers to and facilitators of a fast-track ANC service coupled with prudent and timely antibiotic stewardship. Figure 2 shows the ASTERIC protocol.
Administration of protocols and other treatment
Hospital clinicians are responsible for administration of the allocated treatment. They are free to modify or stop study treatment if they feel that it is in the best interests of the patients without the need for the patient to withdraw from the study. The clinicians will decide on any further treatment. The use of medication will be subject to standard pharmacy reviews, which will guide modifications to both the study treatment and the use of concomitant medications (eg, in the case of potential drug interactions). Results of investigations may also guide modifications of treatment.
Baseline data
We will collect baseline and follow-up data using the REDCap (Research Electronic Data Capture) system, which is freely available through The University of Hong Kong (HKU) Clinical Trials Centre and IISupreme to collect data. Investigations will be requested in the local hospitals according to normal clinical practice. Platforms of commonly available point-of-care and early diagnostic tests should be used according to normal practice. SoC typically includes blood samples sent for complete blood count, urea and electrolytes, liver function tests, C-reactive protein, procalcitonin, bacterial culture and sensitivity; sputum and/or saliva sent for microbiology and virology; and radiology (chest radiographs and/or CT scan).
Follow-up
All patients will receive a diary to record protocol adherence, symptoms and adverse events (AEs). Information will be collected up to 30 days after enrolment by telephone call, clinical attendance, data retrieval from electronic medical records in the Hospital Authority Clinical Management System (CMS) or Clinical Data Analysis and Reporting System (CDARS), registries and medical staff. Compliance with medication will also be checked. All trial participants will be followed-up until death or discharge or at 30 days, whichever is sooner.
Implementation evaluation
The implementation evaluation will be guided by the 17 elements of the Proctor framework to evaluate the implementation of the ASTERIC protocol ( online supplemental table 1 ). 22 We will use a mixed methods design to collect qualitative and quantitative data concurrently at multiple levels and analyse them separately to assess different elements of implementation. No interim analysis is planned, but we do propose constant review and feedback to each department with monthly reports on protocol adherence. We will (1) prospectively monitor fidelity (eg, fast-track ANC uptake, initial UBSA prescribing, time to de-escalation), (2) provide remedial education if drift is detected and (3) report adherence metrics alongside outcomes. While no formal efficacy interim analysis is planned, the Trial Steering Committee’s oversight and regular fidelity audits will guide supportive actions without compromising the stepped-wedge structure. Three rounds of focus group interviews will be conducted: the first before the commencement of the effectiveness trial (T1), the second before phase 2 (T2) and at or after the end of phase 2 (T3). In each study site, a minimum initial stratified sample of six participants (one consultant/associate consultant, two junior doctors, one senior nurse of the rank advanced practice nurse or above and two junior nurses) will be invited. For the inclusion criteria of staff recruitment, three ED doctors and three nurses will be invited with no exclusion criteria for staff recruitment.
Outcomes and definitions
Co-primary outcome 1: 7-day mean UBSA dose
The mean antibiotic dose is defined as the average dose in milligrams of UBSA per patient from ED registration over 7 days. Examples of UBSAs include meropenem and piperacillin/tazobactam. Data on antibiotic, dose and duration of medication dispensing records will be collected from the CMS or CDARS. These data are centrally processed by the trial data management team. In Proctor’s Conceptual Framework and Taxonomy, this effectiveness criterion is a service outcome.
Antibiotic stewardship is not an all-or-nothing process. It requires clinical experience, available information and professional judgement on personalised escalation/de-escalation resources. Capturing all these aspects into a single outcome—a meaningful reduction of UBSA use—is a worthwhile measure of success.
Co-primary outcome 2: 30-day severe adverse events
The proportion of patients with an SAE (Binary Y/N) (Time Frame: up to 30 days). See online supplemental appendix 2 for the definition of an SAE. SAEs are recorded each day. This refers specifically to SAEs (not to AEs, suspected unexpected SAEs or suspected SAEs). In Proctor’s Conceptual Framework and Taxonomy, this safety criterion is a service outcome.
Our prior data showed that SAEs in patients with sNF varied from 11% to 21%. Although no SAEs were deemed to be due to current pathways or antibiotic treatment, we identified fewer SAEs in patients in whom UBSAs were quickly de-escalated when not needed. With such information, we will report on SAEs as a co-primary outcome.
Secondary outcomes
Mortality
The proportion of patients with mortality (Binary Y/N) (Time Frame: up to 30 days). Mortality data will be collected from the daily diary, medical notes either from the CMS or CDARS. These data were centrally processed by the trial data management team.
Length of hospital stay
Difference in the median LOS (length of stay) between the SoC and implementation periods (Numerical) (Time Frame: up to 30 days) will be collected from the daily diary, patient hospital admission time records in the CMS or CDARS.
Efficiency
The proportion of eligible patients who receive SoC and ASTERIC protocol in the respective periods will be measured (Binary Y/N) (Time Frame: 30 days), which indicates the extent of adoption of the ASTERIC protocol.
Safety
The mean of the total number of SAEs per patient who receive SoC and ASTERIC protocol (Numerical) (Time Frame: 30 days).
Effectiveness in avoiding UBSA use
The proportion of patients in each group who do not receive any UBSAs (Binary Y/N) (Time Frame: 7 days) will be measured to assess the effectiveness of the ASTERIC protocol in preventing unnecessary UBSA use in patients with non-NF.
Equity
Extent to which the ASTERIC protocol has achieved its goals, reached beneficiaries and addressed specific health needs (Qualitative) (Time Frame: 7 days). Measure of staff attitude and behaviour to adopt and implement the ASTERIC protocol.
Staff satisfaction regarding patient centredness
Differentiation of median staff satisfaction score regarding putting the patient first (Score: 0–10) (Time Frame: up to 7 days). Staff satisfaction score is a 10-point score where 0 is total dissatisfaction and 10 is maximal satisfaction. The score relates to satisfaction with trial treatment rather than overall hospital care.
Staff satisfaction regarding timeliness
Differentiation of median staff satisfaction score regarding the speed that steps were enacted (Score: 0–10) (Time Frame: up to 7 days). Staff satisfaction score is a 10-point score where 0 is total dissatisfaction and 10 is maximal satisfaction. The score relates to satisfaction with trial treatment rather than overall hospital care.
Acceptability
The perception that the ASTERIC protocol is agreeable (Numerical Score 0–10) (Time Frame: 7 days). Acceptability is the perception among implementation stakeholders that a given treatment, service, practice or innovation is agreeable, palatable or satisfactory. In each hospital, it is assessed at three points—prior to period 1 commencement, prior to period 2 commencement and after period 2 completion. Patient participants are asked to evaluate the first 7 days of care.
Adoption
The perception that the ASTERIC protocol employs evidence-based practice (Numerical Score: 0–10) (Time Frame: 7 days). Adoption is the intention, initial decision or action to try or employ an innovation or evidence-based practice. It is assessed at two points—prior to period 1 commencement and prior to period 2 commencement.
Appropriateness
The perception that the ASTERIC protocol is a good fit for emergency medicine and ward settings (Numerical Score: 0–10) (Time Frame: 7 days). Appropriateness is the perceived fit, relevance or compatibility of the innovation or evidence-based practice for a given practice setting, provider or consumer; and/or perceived fit of the innovation to address a particular issue or problem. It is assessed at two points—prior to period 1 commencement and prior to period 2 commencement.
Cost-effectiveness analysis
Cost-effectiveness comparison between SoC and ASTERIC protocol (Numerical) (Time Frame: 7 days). Cost-effectiveness analysis measure is the total cost difference between treatment group and placebo group divided by total quality-adjusted life years (QALY) difference between treatment group and placebo group; total cost difference between treatment group and placebo group divided by difference in primary and secondary outcomes between treatment group and placebo group.
Feasibility
Perception of the extent to which the ASTERIC protocol can be carried out in EDs and hospital wards (Numerical Score: 0–10) (Time Frame: 7 days). Measure of the extent to which a new treatment, or an innovation, can be successfully used or carried out within a given agency or setting.
Fidelity
The extent to which the ASTERIC protocol is carried out in the study EDs and hospital wards (Numerical Score: 0–10) (Time Frame: 7 days). Measure of the extent to which a new treatment, or an innovation, can be successfully used or carried out within a given agency or setting. It is assessed at the end of period 2.
Penetration
The extent to which the ASTERIC protocol was integrated into the study EDs and hospital ward (Numerical Score: 0–10) (Time Frame: 7 days). Measure of the extent to which a new treatment, or an innovation, integrated within a given agency or setting. It is assessed at the end of period 2.
Sustainability
The extent to which the ASTERIC protocol was maintained in the EDs and hospital wards (Numerical Score: 0–10) (Time Frame: 30 days). Measure of the extent to which a new treatment, or an innovation, was maintained within a given agency or setting. It is assessed at the end of period 2.
Patient satisfaction
Differentiation of median patient satisfaction score (Score: 0–10) (Time Frame: up to 7 days). Patient satisfaction score is a 10-point score where 0 is total dissatisfaction and 10 is maximal satisfaction. The score relates to satisfaction with the overall hospital experience.
Functional Assessment of Cancer Therapy – General
Functional Assessment of Cancer Therapy – General (FACT-G) score comparison between the period 1 care and period 2 care (Numerical) (Time Frame: 30 days). FACT-G is a quality-of-life assessment score. 26
Functional Assessment of Chronic Illness Therapy – Neutropenia
Functional Assessment of Chronic Illness Therapy – Neutropenia (FACT-N) score comparison between the period 1 care and period 2 care (Numerical) (Time Frame: 30 days). FACT-N is a quality-of-life assessment score. 27
Functional Assessment of Chronic Illness Therapy – COST
Functional Assessment of Chronic Illness Therapy – COST (FACIT-COST) score comparison between the period 1 care and period 2 care (Numerical) (Time Frame: 30 days). FACT-COST is a quality-of-life assessment score. 28
Hospital admission
Proportion of patients admitted to hospital (Binary Y/N) (Time Frame: 30 days).
Other prespecified subsidiary outcomes (if resources permit)
Quality of life FACT-G (endpoints 30 days); quality of life FACT-N (endpoints 30 days); quality of life FACIT-COST (30 days); antibiotic stewardship: the proportion of patients in each group receiving meropenem in 7 days (endpoints 7 and 15 days); hospital antibiotics use (as total days of therapy) (endpoints 7 and 15 days); hospital antibiotics use (as defined daily dose per admission) (endpoints 7 and 15 days); cost-effectiveness including health resources use, antimicrobial expenditure (30 days); ED staff time cost (30 days); hospital stay cost (hospital authority standard rates) (30 days); emergence of antimicrobial resistant bacteria including Clostridioides (Clostridium) difficile infection (endpoints 30).
Sample size calculation
For co-primary efficacy outcome I
For antibiotic stewardship
Our pilot feasibility study of 70 patients showed that the adoption of an antibiotic stewardship protocol reduced the mean UBSA (eg, meropenem or piperacillin/tazobactam) use in the first 7 days of hospitalisation from 21 (SD 25) to 12 (SD 18) g. There were 8 SAEs out of 35 (23%) cases in the control arm and 3 SAEs out of 35 (9%) cases in the intervention group.
Aiming for superiority in the primary outcome, with a stepped-wedge design, a total sample size of 360 patients (180 in each group) is required to have a 90% chance of detecting, as significant at the 5% level, a decrease in the mean dose of UBSAs (primary outcome measure) from 21 (SD 22) in the control group to 12 in the experimental group. 29
For co-primary safety outcome II
Aiming for superiority in the co-primary outcome (proportion of patients without an SAE), with a stepped-wedge design, 648 patients (324 in each group) are required to have an 80% chance of detecting, as significant at the 5% level, an increase in the co-primary safety outcome measure from 77% in the control group to 91% in the experimental group. 28 As there may be variation between hospitals, we will adopt a conservative sample requirement of 648 patients (324 patients in each group, or 81 patients per hospital in a 1-year period).
Data analysis
5% of all data will be checked for accuracy. All prevailing regulations by HKU and Hospital Authroity (HA) will be followed. An audit trail will be made to include the number of patients screened, approached, recruited and excluded (with reasons). Patient and clinical staff responses, and data completeness will be evaluated.
Primary analysis
The baseline characteristics of the two groups will be assessed for potential imbalances, which will be adjusted for when comparing outcomes. Intention-to-treat, per-protocol and as treated analyses will be performed by imputing all non-responses at follow-ups with baseline values, which yields more conservative estimates of effect sizes. The missing data for the primary outcome is expected to be <1% because most data is retrievable from electronic patient records with electronic time stamps. Missing values will not be imputed. We will report continuous variables as means and SDs, or medians and IQRs and categorical variables as proportions, as appropriate. Preliminary clinical impacts will be reported with estimates of the 95% CIs. In addition, we will describe the distribution of demographic characteristics, comorbidities and clinical severity of the patients recruited before and after the crossover date to identify factors that might require adjustment in the full-scale trial. We will use the Statistical Package for the Social Sciences for Windows V.27.0 (IBM, Armonk, New York, USA) or R V.4.2.2 for statistical analysis with biostatistician support.
The first main effect is intervention versus control on mean dose of UBSA in 7 days. The second main effect is intervention versus control on SAE in 30 days. All secondary outcomes at different time points will be analysed using generalised mixed effect model for multiple intrasubject and intersubject observations. The main and interaction effects will be assessed. For the cost analysis, we will evaluate healthcare resource use, including length of hospital stay, clinical and ED visits, drug and time costs.
Qualitative analysis
Qualitative data related to the barriers to and facilitators of the implementation of the ASTERIC protocol in routine care services will be analysed using grounded theory methodology with thematic analysis of responses to open-ended questions. Responses across individuals will be sorted, coded and compared by a trained research nurse and research assistant to determine the core categories. Categories will be clustered to form a broader scope of categories. After systematic comparisons of the categories are made, properties and dimensions for the studied concepts will be developed from the interview data. 30 31 We will maintain accountability and auditability (capacity to cross-check interpretation against data). 30 31 Disputes will be resolved by repeated discussion and re-coding. Outstanding coding disputes will be examined by an expert in qualitative research.
Health economics
Costs will be calculated according to activities, which include the intervention, preparation and administration of all drugs, investigations, procedures and admission to hospital. We will obtain estimates for the time required to use each resource in each activity and the unit costs for each of these resources. Drugs will be costed separately according to dose, and cost estimates will be made for the actual treatment time for AEs. Care will be taken to avoid double counting. QALY will be quantified by the baseline and 30-day EuroQual-5D-L (EQ-5D-5L) Health Questionnaire utility scores based on the Hong Kong value set 32 using the standard area under the curve approach. Incremental cost-effectiveness ratio will be measured in terms of cost per QALY gained, Δcost ASTERIC+SoC/ΔQALY NF+SoC, where incremental cost-effectiveness ratio below the willingness-to-pay threshold will be interpreted by the Phase 2 study group as cost-effective.
Ethics and dissemination
We have obtained research ethical approval from the institutional review boards of all study sites (HKU/HA HKW IRB Reference Number: UW 24–146; HA Central IRB Reference Number: CIRB-2024-540-4; HKU-GHK IRB Reference Number: GHK-2024–07). The study will be conducted in full compliance with the Declaration of Helsinki. All items from the WHO Trial Registration Data set have been included ( online supplemental file 2 ). 33
The data are centrally processed by the trial data management team. 5% of all data will be checked for accuracy. All prevailing regulations by HKU and HA will be followed. An audit trail will be made to include the number of patients screened, approached, recruited and excluded (with reasons).
We will disseminate the findings through peer-reviewed publications, conference presentations and educational activities.
Discussion
The ASTERIC trial will provide real-world data from multiple sources to improve antibiotic stewardship and management in patients with sNF presenting in ED and ward settings. Information gathered from the implementation evaluation will help us improve and tailor implementation strategies based on the barriers and facilitators identified across different study sites.
There are several inherent limitations of the stepped wedge study design. We attempt to avoid selection bias of the cluster by performing randomisation at a single time point after all study sites have consented to participate. However, we cannot conceal the allocation of the crossover date because of the need for implementation. The recruitment bias caused by recruiting staff foreknowledge of treatment assignment would be minimal because of the well-defined patient participant recruitment criteria. Blinding is also not possible because of the differences in clinical intervention in the standard care and ASTERIC periods. Our study findings can be generalised to EDs where ASTERICS is not routinely used.
Reporting and dissemination
We will report our findings according to the Consolidated Standards of Reporting Trials extension for the stepped wedge cluster randomised trial and Standard Protocol Items: Recommendations for Interventional Trials statements 24 34 ; Reporting Implementation Studies Standards for Reporting Implementation Studies Statement 35 ; Consolidated Criteria for Reporting Qualitative Research 36 ; and Consolidated Health Economic Evaluation Reporting Standards 2022 statement. 37 We will disseminate the results through peer-reviewed publications, conference presentations and educational activities with the public and professional bodies.
Supplementary material
Footnotes
Funding: This study is supported by the Heath and Medical Research Fund of the Health Bureau of the Government of the Hong Kong Special Administrative Region (Project No. HMRF 21222361). The funder has no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online ( https://doi.org/10.1136/bmjopen-2025-108010 ).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
References
1. Weycker D, Li X, Edelsberg J, et al. Risk and Consequences of Chemotherapy-Induced Febrile Neutropenia in Patients With Metastatic Solid Tumors. J Oncol Pract. 2015;11:47–54. doi: 10.1200/JOP.2014.001492.
2. Culakova E, Thota R, Poniewierski MS, et al. Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study. Cancer Med. 2014;3:434–44. doi: 10.1002/cam4.200.
3. Klastersky J, Ameye L, Maertens J, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007;30 Suppl 1:S51–9. doi: 10.1016/j.ijantimicag.2007.06.012.
4. Caggiano V, Weiss RV, Rickert TS, et al. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005;103:1916–24. doi: 10.1002/cncr.20983.
5. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258–66. doi: 10.1002/cncr.21847.
6. Ihbe-Heffinger A, Paessens BJ, von Schilling C, et al. Management of febrile neutropenia--a German prospective hospital cost analysis in lymphoproliferative disorders, non-small cell lung cancer, and primary breast cancer. Onkologie. 2011;34:241–6. doi: 10.1159/000327711.
7. Pasikhova Y, Ludlow S, Baluch A. Fever in Patients With Cancer. Cancer Control. 2017;24:193–7. doi: 10.1177/107327481702400212.
8. Pizzo PA, Robichaud KJ, Wesley R, et al. Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes. Medicine (Baltimore) 1982;61:153–65. doi: 10.1097/00005792-198205000-00003.
9. Boxer L, Dale DC. Neutropenia: causes and consequences. Semin Hematol. 2002;39:75–81. doi: 10.1053/shem.2002.31911.
10. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1443–53. doi: 10.1200/JCO.2017.77.6211.
11. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;44:925–8. doi: 10.1007/s00134-018-5085-0.
12. Ko HF, Tsui SS, Tse JWK, et al. Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients. Hong Kong Med J. 2015;21:10–5. doi: 10.12809/hkmj144280.
13. Rainer TH, Lee SY, Yu YY, et al. Epidemiology and outcome of suspected neutropenic fever in emergency department patients: a retrospective study. Acad Emerg Med. 2024;31:145. doi: 10.1016/j.annemergmed.2025.06.043.
14. Rainer TH, Lee SY, Leung SC, et al. Fast-track absolute neutrophil count in suspected neutropenic fever – The FRANCIS-NF trial: a feasibility study. Acad Emerg Med. 2024;31:145.
15. Zhu J, Zhou K, Jiang Y, et al. Bacterial Pathogens Differed Between Neutropenic and Non-neutropenic Patients in the Same Hematological Ward: An 8-Year Survey. Clin Infect Dis. 2018;67:S174–8. doi: 10.1093/cid/ciy643.
16. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:427–31. doi: 10.1093/cid/ciq147.
17. Peyrony O, Gerlier C, Barla I, et al. Antibiotic prescribing and outcomes in cancer patients with febrile neutropenia in the emergency department. PLoS One. 2020;15:e0229828. doi: 10.1371/journal.pone.0229828.
18. Mohindra R, Mathew R, Yadav S, et al. CISNE versus MASCC: Identifying low risk febrile neutropenic patients. Am J Emerg Med. 2020;38:2259–63. doi: 10.1016/j.ajem.2019.09.016.
19. Carnine D. Bridging the Research-to-Practice Gap. Except Child. 1997;63:513–21. doi: 10.1177/001440299706300406.
20. Mettert K, Lewis C, Dorsey C, et al. Measuring implementation outcomes: An updated systematic review of measures’ psychometric properties. Implement Res Pract . 2020;1:2633489520936644. doi: 10.1177/2633489520936644.
21. Curran GM, Bauer M, Mittman B, et al. Effectiveness-implementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact. Med Care. 2012;50:217–26. doi: 10.1097/MLR.0b013e3182408812.
22. Proctor E, Silmere H, Raghavan R, et al. Outcomes for implementation research: conceptual distinctions, measurement challenges, and research agenda. Adm Policy Ment Health. 2011;38:65–76. doi: 10.1007/s10488-010-0319-7.
23. Glasgow RE, Vogt TM, Boles SM. Evaluating the public health impact of health promotion interventions: the RE-AIM framework. Am J Public Health. 1999;89:1322–7. doi: 10.2105/ajph.89.9.1322.
24. Eldridge SM, Chan CL, Campbell MJ, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355:i5239. doi: 10.1136/bmj.i5239.
25. Ho PL, Wu TC, Chao DVK, et al. Reducing Bacterial Resistance with IMPACT. 5th. Hong Kong; 2017. edn.
26. Functional Assessment of Cancer Therapy-General (FACT-G) Elmhurst (IL): FACIT.org; [6-May-2025]. https://www.facit.org/measures/fact-g Available. Accessed.
27. Functional Assessment of Chronic Illness Therapy-Neutropenia (FACIT-N) Elmhurst (IL): FACIT.org; [6-May-2025]. https://www.facit.org/measures/fact-n Available. Accessed.
28. Functional Assessment of Chronic Illness Therapy-COST (FACIT-COST) Elmhurst (IL): FACIT.org; [6-May-2025]. https://www.facit.org/measures/facit-cost Available. Accessed.
29. Baio G, Copas A, Ambler G, et al. Sample size calculation for a stepped wedge trial. Trials. 2015;16:354. doi: 10.1186/s13063-015-0840-9.
30. Glaser BG, Strauss AL. The Discovery of Grounded Theory: Strategies for Qualitative Research. New York: Aldine de Gruyter; 1967.
31. Strauss A, Corbin J. Basics of Qualitative Research: Techniques and Procedures for Developing Grounded Theory. Thousand Oaks (CA): Sage; 1998.
32. Wong ELY, Ramos-Goñi JM, Cheung AWL, et al. Assessing the Use of a Feedback Module to Model EQ-5D-5L Health States Values in Hong Kong. Patient. 2018;11:235–47. doi: 10.1007/s40271-017-0278-0.
33. World Health Organization . WHO Trial Registration Data Set (Version 1.3.1) Geneva, WHO; [28-Sep-2025]. https://www.who.int/tools/clinical-trials-registry-platform/network/who-data-set Available. Accessed.
34. Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158:200–7. doi: 10.7326/0003-4819-158-3-201302050-00583.
35. Pinnock H, Barwick M, Carpenter CR, et al. Standards for Reporting Implementation Studies (StaRI) Statement. BMJ. 2017;356:i6795. doi: 10.1136/bmj.i6795.
36. Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int J Qual Health Care. 2007;19:349–57. doi: 10.1093/intqhc/mzm042.
37. Husereau D, Drummond M, Augustovski F, et al. Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations. BMJ. 2022;376:e067975. doi: 10.1136/bmj-2021-067975.