Early Discontinuation of Antibiotics in Paediatric High-risk Febrile Neutropenia

Official title

Phase IV, Randomized, Open Label, Parallel Groups Clinical Trial for Evaluating the Early Stop of Antibiotic Treatment in High-risk Febrile Neutropenic Oncohaematological Paediatric Patients (e-STOP 2)

Overview

The goal of this clinical trial is to evaluate whether stopping antibiotic treatment early is safe in paediatric patients with cancer who develop high-risk febrile neutropenia but show good clinical evolution and low biomarker levels 48-72 hours after the episode. The main questions it aims to answer are: Is early discontinuation of antibiotics as safe as the standard strategy in terms of preventing invasive bacterial infections (such as sepsis, microbiologically documented infection, ICU admission, or death)? Does this strategy reduce the number of days on antibiotics without increasing infection-related complications? Researchers will compare early antibiotic discontinuation with the standard care strategy to see whether the early-stop approach provides similar safety while reducing antibiotic exposure. Participants will: Receive standard initial antibiotic therapy for febrile neutropenia. Undergo clinical and biomarker evaluations (including CRP and PCT). Be randomly assigned to: Experimental group: early discontinuation of antibiotics, or Control group: continuation of the standard antibiotic strategy. Be followed for 28 days after randomisation to monitor safety outcomes and treatment effects.

Detailed description

Children with cancer who develop febrile neutropenia (FN) routinely receive broad-spectrum intravenous antibiotics to prevent severe bacterial infections. Although this approach is essential in high-risk cases, prolonged antibiotic exposure increases the risk of adverse effects, antimicrobial resistance, drug toxicity, and longer hospital stays. Advances in risk stratification-particularly through clinical stability assessment and biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT)-now allow earlier identification of patients who may no longer require intensive antibiotic coverage.

This study evaluates whether early discontinuation of antibiotic therapy is safe in paediatric patients with cancer who present high-risk FN but show a favourable clinical course 48-72 hours after onset. Eligible patients must meet predefined criteria indicating low risk of invasive bacterial infection (IBI), including clinical stability, absence of microbiologically documented infection, and decreasing biomarker levels. The trial uses a randomised, controlled, open-label design to compare an early-stop strategy with the current standard management.

The rationale for this approach is to determine whether antibiotic therapy can be safely shortened without compromising infection-related outcomes. Limiting unnecessary antibiotic exposure may reduce adverse drug events, improve patient comfort, minimise disruption of the microbiome, and support antimicrobial stewardship programmes. The study also incorporates biomarker measurements (CRP, PCT, IL-8) to explore their predictive value for IBI and to validate an IBI-risk prediction model for this population.

Participants will be monitored closely for signs of bacterial infection or clinical deterioration throughout the 28-day follow-up period. This design enables robust assessment of safety while reflecting real-world clinical decision-making and the potential benefits of personalised antibiotic duration in paediatric oncology care.

Interventions

• Drug Early Discontinuation of Antibiotics
  Participants assigned to this intervention will stop intravenous antibiotic therapy within 24 hours after randomization, provided they meet all required clinical stability and low-risk criteria at 48-72 hours (or day 5) after the febrile neutropenia episode. Patients may be discharged once clinically appropriate. Antibiotics may be restarted if fever recurs or clinical deterioration suggests infection.
• Drug Standard Antibiotic Continuation Strategy
  Continuation of antibiotic therapy for at least 7 days and/or until marrow recovery (ANC ≥100/mm³) following standard institutional protocols. Therapy may be extended depending on clinical assessment.

Primary outcome measures

• Composite rate of adverse outcomes attributable to invasive or clinically significant bacterial infection [Time frame: Day 0 (randomization) to Day 28]

Secondary outcome measures (6)

• Number of days of antibiotic therapy [Time frame: From Day 0 to Day 28]
• Incidence of antibiotic-related adverse events [Time frame: Up to Day 28]
• Predictive performance of C-reactive protein (CRP) for invasive bacterial infection [Time frame: Measured at episode onset, at 48-72 hours, and optionally on Day 5]
• Predictive performance of procalcitonin (PCT) for invasive bacterial infection [Time frame: Measured at episode onset, at 48-72 hours, and optionally on Day 5]
• Predictive performance of interleukin-8 (IL-8) for invasive bacterial infection [Time frame: Measured at episode onset and at 48-72 hours]
• Validation of an invasive bacterial infection (IBI) prediction model [Time frame: Day 0 to Day 28]

Eligibility criteria

Inclusion criteria

• Male and female patients ≤18 years of age expected to develop prolonged neutropenia (>7 days), with:

• Acute myeloblastic leukaemia at any phase of chemotherapy
• Acute lymphoblastic leukaemia in induction, consolidation, or intensification phases
• Biphenotypic leukaemia at any phase of chemotherapy
• Lymphoblastic lymphoma in induction and consolidation phases
• B-cell and anaplastic lymphoma receiving high-intensity chemotherapy
• Solid tumours receiving high-intensity chemotherapy
• Relapsed leukaemia at any phase of treatment
• Episode of febrile neutropenia (FN), defined as a single axillary temperature ≥38.0°C in a patient with an absolute neutrophil count (ANC) <500 neutrophils/mm³, or expected to fall below this value within the next 48-72 hours.
• Antibiotic treatment initiated for the current FN episode (routine antimicrobial prophylaxis is allowed, as well as teicoplanin 3 days/week for patients with AML included in the CHIP-AML-2022 protocol and therefore in the Pro-teico study).
• Low risk of invasive bacterial infection (IBI) at the start of the FN episode. Patients must meet all of the following:

• CRP <9 mg/dL
• PCT <0.5 ng/mL
• Absence of hypotension
• No microbiologically documented bacterial infection 48-72 hours after the FN episode.
• Good clinical evolution 48-72 hours after the FN episode, defined as:

• Afebrile for >48 hours (axillary temperature <38°C)
• Haemodynamically stable
• Stable paediatric early warning score (PEWS)
• CRP <5 mg/dL, or CRP <9 mg/dL and PCT <0.5 ng/mL, with decreasing trend at the time of randomisation (values will be assessed on day 3 and day 5 after the FN episode).
• ANC <500 neutrophils/mm³ at the time of randomisation.
• Signed informed consent from the patient and/or parent(s)/legal representative(s).
• Patient and/or parent(s)/legal representative(s) must have sufficient reading and writing skills to understand and provide consent to participate in the study.
• Patient and/or parent(s)/legal representative(s) must be considered reliable and capable of adhering to the protocol.

Exclusion criteria

• Antibiotic treatment at the time of the FN episode different from that used prophylactically.
• Empirical antibiotic treatment different from that recommended in international guidelines.
• Patient with poor clinical evolution during the first 12 hours (hemodynamic instability, PICU admission, death).
• Active participation in the same study at the onset of the current FN episode.
• Active participation in another clinical trial that, in the investigators' opinion, may interfere with the assessment of the results.
• Any condition which, in the investigator's opinion, makes study participation unsuitable for the patient or could limit, prevent, or confound the assessments planned in the protocol.
• Female patients who are pregnant or breastfeeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 4 centers

• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Sant Joan de Déu — Esplugues de Llobregat
• Hospital Infantil Universitario Niño Jesús — Madrid
• Hospital Universitario La Paz — Madrid

Publications

• Lucignano B, Cento V, Agosta M, Ambrogi F, Albitar-Nehme S, Mancinelli L, Mattana G, Onori M, Galaverna F, Di Chiara L, Fragasso T, Bianchi R, Tortora F, Auriti C, Dotta A, Cecchetti C, Perdichizzi S, Raponi M, Onetti Muda A, Nerini Molteni S, Villani A, Locatelli F, Perno CF, Bernaschi P. Effective Rapid Diagnosis of Bacterial and Fungal Bloodstream Infections by T2 Magnetic Resonance Technology PMID 36069557
• Clancy CJ, Nguyen MH. T2 magnetic resonance for the diagnosis of bloodstream infections: charting a path forward. J Antimicrob Chemother. 2018 Mar 1;73(suppl_4):iv2-iv5. doi: 10.1093/jac/dky050. PMID 29608754
• Secmeer G, Devrim I, Kara A, Ceyhan M, Cengiz B, Kutluk T, Buyukpamukcu M, Yetgin S, Tuncer M, Uludag AK, Tezer H, Yildirim I. Role of procalcitonin and CRP in differentiating a stable from a deteriorating clinical course in pediatric febrile neutropenia. J Pediatr Hematol Oncol. 2007 Feb;29(2):107-11. doi: 10.1097/MPH.0b013e3180320b5b. PMID 17279007
• Hemming V, Jakes AD, Shenton G, Phillips B. Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia. BMC Pediatr. 2017 Jan 5;17(1):2. doi: 10.1186/s12887-016-0766-8. PMID 28056911
• Santolaya ME, Alvarez AM, Aviles CL, Becker A, King A, Mosso C, O'Ryan M, Paya E, Salgado C, Silva P, Topelberg S, Tordecilla J, Varas M, Villarroel M, Viviani T, Zubieta M. Predictors of severe sepsis not clinically apparent during the first twenty-four hours of hospitalization in children with cancer, neutropenia, and fever: a prospective, multicenter trial. Pediatr Infect Dis J. 2008 Jun;27(6): PMID 18458649
• Cost CR, Stegner MM, Leonard D, Leavey P. IL-8 predicts pediatric oncology patients with febrile neutropenia at low risk for bacteremia. J Pediatr Hematol Oncol. 2013 Apr;35(3):206-11. doi: 10.1097/MPH.0b013e318281e653. PMID 23425997
• Ammann RA, Bodmer N, Hirt A, Niggli FK, Nadal D, Simon A, Ozsahin H, Kontny U, Kuhne T, Popovic MB, Luthy AR, Aebi C. Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin Oncol. 2010 Apr 20;28(12):2008-14. doi: 10.1200/JCO.2009.25.8988. Epub 2010 Mar 15. PMID 20231680
• Ammann RA, Hirt A, Luthy AR, Aebi C. Identification of children presenting with fever in chemotherapy-induced neutropenia at low risk for severe bacterial infection. Med Pediatr Oncol. 2003 Nov;41(5):436-43. doi: 10.1002/mpo.10320. PMID 14515382

Identifiers

NCT: NCT07590648 · EU-CT2025-524264-38-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗