Febrile Neutropenia (FN)Phase 4E-STOP2NCT07590648
Early Discontinuation of Antibiotics in Paediatric High-risk Febrile Neutropenia
A Phase 4 study testing Early Discontinuation of Antibiotics and Standard Antibiotic Continuation Strategy in people with Febrile Neutropenia (FN) and Pediatric Cancer, run by Hospital Universitari Vall d'Hebron Research Institute at 4 sites in Spain.
Trial summary
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. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Febrile Neutropenia (FN), Pediatric Cancer, Hematologic Malignancies
- What is being tested?
- Early Discontinuation of Antibiotics and Standard Antibiotic Continuation Strategy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 136 participants
- Where
- 4 sitesSpain
- Study dates
- 1 Jun 2026to 1 Jul 2028
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Spain4 sites
Hospital Universitari Vall d'Hebron
Barcelona, Barcelona, 08035
Natalia A Mendoza Palomar, MD, +34 934893000 ext. 3077, nataliaana.mendoza@vallhebron.cat
Natalia A Mendoza Palomar, MD
Hospital Sant Joan de Déu
Esplugues de Llobregat, Barcelona, 08950
Silvia Simó Nebot, MD, PhD, +34 932532100, silvia.simo@sjd.es
Silvia Simó Nebot, MD, PhD
Hospital Infantil Universitario Niño Jesús
Madrid, Madrid, 28009
Blanca Herrero Velasco, MD, +34 915035900, blanca.herrero@salud.madrid.org
Blanca Herrero Velsaco, MD
Hospital Universitario La Paz
Madrid, Madrid, 28046
Pilar Guerra García, MD, +34 917277000, pilar.guerra@salud.madrid.org
Pilar Guerra García, MD
About this study
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)
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:
Read more
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.
Read the 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.
- Conditions
- Febrile Neutropenia (FN), Pediatric Cancer, Hematologic Malignancies, Solid Tumors, Invasive Bacterial Infection
- Being tested
- Early Discontinuation of Antibiotics, Standard Antibiotic Continuation Strategy
- Keywords
- Febrile Neutropenia, Pediatric Oncology, Hematologic Malignancies, Solid Tumors, Invasive Bacterial Infection, Antibiotic Discontinuation, Antibiotic Stewardship, Biomarkers (CRP, PCT, IL-8), Early Stop Strategy, Randomized Clinical Trial, Non-Inferiority Trial, Neutropenia
- Medical subject headings
- Febrile Neutropenia, Neoplasms, Hematologic Neoplasms, Neutropenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Early Discontinuation of AntibioticsDrug
Also called Drug stop within 24 hours after randomization:Piperacillin-tazobactam, amikacin, meropenem, cefepime, ceftazidime, vancomycin, teicoplanin, ciprofloxacin, levofloxacine and metronidazole
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.
Standard Antibiotic Continuation StrategyDrug
Also called Drug continuation for at least 7d and/or until marrow recovery:Piperacillin-tazobactam,amikacin,meropenem,cefepime, ceftazidime, vancomycin, teicoplanin, ciprofloxacin, levofloxacine and metronidazole
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.
| Study group | Role | What they receive |
|---|---|---|
| Early Discontinuation of Antibiotics | Experimental | Participants assigned to this arm will have intravenous antibiotic therapy discontinued within 24 hours after randomization, provided they meet all clinical stability and low-risk criteria. Patients may be discharged if no other clinical reasons require hospitalization. Antibiotics may be reintroduced if fever recurs or if clinical deterioration suggests infection. Receives: Drug: Early Discontinuation of Antibiotics |
| Standard Antibiotic Strategy | Active comparator | Participants assigned to this arm will continue antibiotic therapy for at least 7 days and/or until signs of marrow recovery are present (ANC ≥100/mm³), according to each center's standard protocol. Hospital discharge will occur once clinical criteria permit. Receives: Drug: Standard Antibiotic Continuation Strategy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite rate of adverse outcomes attributable to invasive or clinically significant bacterial infection
Composite endpoint including any of the following events: death, pediatric intensive care unit admission, sepsis or septic shock, microbiologically documented bacterial infection, or radiologically confirmed pneumonia. The proportion of participants experiencing at least one component of the composite endpoint will be compared between the early discontinuation arm and the standard continuation arm to assess non-inferiority in safety.
Measured: Day 0 (randomization) to Day 28
Secondary outcomes (6)
Number of days of antibiotic therapy
Total duration of systemic antimicrobial therapy will be compared between the early-stop arm and the standard-therapy arm to evaluate reduction in antibiotic exposure.
Measured: From Day 0 to Day 28
Incidence of antibiotic-related adverse events
Number of participants experiencing adverse effects attributable to antimicrobial therapy, including drug toxicity or complications associated with prolonged antibiotic use.
Measured: Up to Day 28
Predictive performance of C-reactive protein (CRP) for invasive bacterial infection
Retrospective evaluation of CRP levels as a predictor of invasive bacterial infection in pediatric high-risk febrile neutropenia episodes.
Measured: Measured at episode onset, at 48-72 hours, and optionally on Day 5
Predictive performance of procalcitonin (PCT) for invasive bacterial infection
Retrospective evaluation of procalcitonin levels as a predictor of invasive bacterial infection in pediatric high-risk febrile neutropenia episodes.
Measured: Measured at episode onset, at 48-72 hours, and optionally on Day 5
Predictive performance of interleukin-8 (IL-8) for invasive bacterial infection
Retrospective evaluation of IL-8 levels as a predictor of invasive bacterial infection in pediatric high-risk febrile neutropenia episodes.
Measured: Measured at episode onset and at 48-72 hours
Validation of an invasive bacterial infection (IBI) prediction model
Evaluation of a predictive model combining clinical variables, biomarker measurements, and risk scores to classify pediatric high-risk febrile neutropenia episodes according to risk of invasive bacterial infection.
Measured: Day 0 to Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2026
- Study start1 Jun 2026 (estimated)
- Primary completion1 Jul 2028 (estimated)
- Study completion1 Jul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Febrile Neutropenia (FN)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 136 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Universitari Vall d'Hebron Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07590648
- Sponsor's protocol ID
- EU-CT2025-524264-38-00
- Acronym
- E-STOP2
- Status last verified
- May 2026
- First submitted
- 16 Feb 2026
- Last updated
- 15 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
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 in the Pediatric Population. J Clin Microbiol. 2022 Oct 19;60(10):e0029222. doi: 10.1128/jcm.00292-22. Epub 2022 Sep 7.
PubMed 36069557Clancy 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.
PubMed 29608754Secmeer 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.
PubMed 17279007Hemming 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.
PubMed 28056911Santolaya 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):538-43. doi: 10.1097/INF.0b013e3181673c3c.
PubMed 18458649Cost 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.
PubMed 23425997Ammann 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.
PubMed 20231680Ammann 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.
PubMed 14515382Santolaya ME, Alvarez AM, Becker A, Cofre J, Enriquez N, O'Ryan M, Paya E, Pilorget J, Salgado C, Tordecilla J, Varas M, Villarroel M, Viviani T, Zubieta M. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 2001 Jul 15;19(14):3415-21. doi: 10.1200/JCO.2001.19.14.3415.
PubMed 11454890Rondinelli PI, Ribeiro Kde C, de Camargo B. A proposed score for predicting severe infection complications in children with chemotherapy-induced febrile neutropenia. J Pediatr Hematol Oncol. 2006 Oct;28(10):665-70. doi: 10.1097/01.mph.0000212996.94929.0b.
PubMed 17023827Alexander SW, Wade KC, Hibberd PL, Parsons SK. Evaluation of risk prediction criteria for episodes of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol. 2002 Jan;24(1):38-42. doi: 10.1097/00043426-200201000-00011.
PubMed 11902738Rackoff WR, Gonin R, Robinson C, Kreissman SG, Breitfeld PB. Predicting the risk of bacteremia in childen with fever and neutropenia. J Clin Oncol. 1996 Mar;14(3):919-24. doi: 10.1200/JCO.1996.14.3.919.
PubMed 8622040Santolaya ME, Alvarez AM, Acuna M, Aviles CL, Salgado C, Tordecilla J, Varas M, Venegas M, Villarroel M, Zubieta M, Toso A, Bataszew A, Farfan MJ, de la Maza V, Vergara A, Valenzuela R, Torres JP. Efficacy and safety of withholding antimicrobial treatment in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial. Clin Microbiol Infect. 2017 Mar;23(3):173-178. doi: 10.1016/j.cmi.2016.11.001. Epub 2016 Nov 14.
PubMed 27856269Aguilar-Guisado M, Espigado I, Martin-Pena A, Gudiol C, Royo-Cebrecos C, Falantes J, Vazquez-Lopez L, Montero MI, Rosso-Fernandez C, de la Luz Martino M, Parody R, Gonzalez-Campos J, Garzon-Lopez S, Calderon-Cabrera C, Barba P, Rodriguez N, Rovira M, Montero-Mateos E, Carratala J, Perez-Simon JA, Cisneros JM. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017 Dec;4(12):e573-e583. doi: 10.1016/S2352-3026(17)30211-9. Epub 2017 Nov 15.
PubMed 29153975Martinez Campos L, Perez-Albert P, Ferres Ramis L, Rincon-Lopez EM, Mendoza-Palomar N, Soler-Palacin P, Aguilera-Alonso D; en representacion del Grupo de trabajo de Infecciones Bacterianas de la Sociedad Espanola de Infectologia Pediatrica (SEIP); Grupo de Soporte de la Sociedad Espanola de Hematologia y Oncologia Pediatrica (SEHOP); Grupo de trabajo de Infeccion Fungica Invasiva de la Sociedad Espanola de Infectologia Pediatrica (SEIP). Consensus document on the management of febrile neutropenia in paediatric haematology and oncology patients of the Spanish Society of Pediatric Infectious Diseases (SEIP) and the Spanish Society of Pediatric Hematology and Oncology (SEHOP). An Pediatr (Engl Ed). 2023 Jun;98(6):446-459. doi: 10.1016/j.anpede.2023.03.010. Epub 2023 May 31.
PubMed 37268527