Neutropenia, FebrileNCT04637464
Early Termination of Empirical Antibiotics in Febrile Neutropenia in Children With Cancer
A study testing Early termination of empirical antibiotics in people with Neutropenia, Febrile and Pediatric Cancer, run by Kjeld Schmiegelow at 3 sites in Denmark.
Trial summary
The study is a nationwide, multicenter, open label, randomized controlled trial. A target population of 220 children in treatment for cancer with neutropenic fever and a neutrophil count below 0.5 × 10⁹ cells/L with expected duration for more than 7 days will be recruited during the first 48 hours of antibiotic… Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Neutropenia, Febrile, Pediatric Cancer
- What is being tested?
- Early termination of empirical antibiotics
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 93 participants
- Where
- 3 sitesDenmark
- Study dates
- 20 Nov 2020to 11 Mar 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
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
- patient with cancer aged 18 years or below,
- absolute neutrophil count below 0.5x10⁹/L with expected duration of neutropenia for more than 7 days, and
- a single temperature of at least 38.5°C, or a temperature above 38.0°C sustained over a 1-hour period (auricular, oral or rectal).
Who cannot join
- known etiology of fever, defined by a clinically significant positive culture (blood, urine, tracheal) collected during the feverish episode or a clinically documented focal infection despite negative cultures (e.g. pneumonia and cellulitis),
- obvious non-infectious causes of fever (e.g. drug and transfusion related),
- children requiring prophylactic antibacterial antibiotics according to protocol besides co-trimoxazole for Pneumocystis jirovecii after the febrile episode.
Trial locations and contacts
3 sites in 1 country.
Denmark3 sites
Aarhus University Hospital Skejby
Aarhus, 8200
Rigshospitalet
Copenhagen, 2100
Odense Univesity Hospital
Odense, 5000
About this study
Official title: Early Termination of Empirical Antibiotics in High-risk Febrile Neutropenia in Children With Cancer: an Open-label, Randomised, Controlled Trial
The study is a nationwide, multicenter, open label, randomized controlled trial.
A target population of 220 children in treatment for cancer with neutropenic fever and a neutrophil count below 0.5 × 10⁹ cells/L with expected duration for more than 7 days will be recruited during the first 48 hours of antibiotic treatment (24 months inclusion period). They will be randomized 1:1 as follows:
Read more
- Experimental group: Discontinuation of antibiotics, despite neutrophil count below 0.5 × 10⁹ cells/L, after 48 hours of apyrexia and clinical stability
- Control group: Discontinuation of antibiotics when neutrophil count is equal to or above 0.5 × 10⁹ cells/L and the child is afebrile and clinically stable (up to maximum of 14 days after apyrexia and clinical stability).
Primary endpoint is the number of days without antibiotic treatment in 28 days after treatment initiation. Secondary endpoints are crude mortality, severe adverse events, days with relapsing fever, and alterations of the microbiome.
Read the detailed description
BACKGROUND: In children with cancer, infections are a major cause of morbidity and mortality due to chemotherapy-related immunosuppression, comprising up to 70% of all treatment-related deaths. The relationship between neutropenia and life-threatening infection has been well established, and any signs of infection including fever has to be treated promptly with broad spectrum antibiotics. However, the duration of antibiotic therapy in pediatric cancer patients with febrile neutropenia without a known source is unknown. Traditionally, antibiotic therapy is continued until neutrophil recovery, due to fear of relapse of infection potentially as life-threatening sepsis, but scientific evidence supporting this strategy is limited. It has been debated that the strategy may be over-cautious, leading to unnecessarily prolonged antibiotic treatments with important side effects, including extended hospital admissions, adverse drug events, super-infection with fungi and multi-resistant bacteria, and thus affecting the children on both short and long term.
Studies in adults have shown that withdrawal of empirical antimicrobial therapy based on clinical assessment, despite severe neutropenia, can reduce antibiotic treatment significantly without compromising patient safety. This approach is warranted in children with cancer, but no randomized studies have been conducted in high risk children with prolonged neutropenia. A few studies have documented that early discontinuation of empirical antibiotics in low-risk children with short-lasting neutropenia is safe, but as stressed by recent international guidelines, the question of optimal duration of empirical antibiotics for high-risk children with prolonged bone marrow suppression continues to be a major research gap.
HYPOTHESIS: Empirical antibiotic therapy of febrile neutropenia can safely be discontinued after 48 hours of apyrexia and clinical stability, despite severe neutropenia, in high-risk children with expected prolonged neutropenia.
AIM: To establish evidence-based treatment strategies for children with febrile neutropenia by performing a randomized controlled trial investigating the efficacy and safety of early termination of empirical antibiotic therapy.
METHODS: Children treated at one of the 4 pediatric oncology departments in Denmark who are admitted with neutropenic fever will be evaluated according to current routines, including complete physical examination, assessment of severity signs and source, blood samples (biochemistry and hematology), blood cultures (collected from the central venous catheter), and additional samples from infected sites as clinically indicated. After obtaining cultures, empiric antibiotic therapy for neutropenic fever is started. The type of antibiotics will depend on current local guideline. Children who remain febrile despite empirical antibiotic therapy will be treated and investigated according to local and international guidelines.
Eligible subjects will be screened and included as described.
Included subjects will be followed for 28 days after initiation of empirical antibiotic treatment or until neutrophile recovery, whichever is longest.
They will be assessed at the following protocolled time points:
- At 48 hours of apyrexia
- At recovery of neutropenia
- At 28 (±2) days (final assessment)
- In the event of relapsing fever after the initial 48 hours of apyrexia during the follow-up period.
Each assessment will include a clinical interview, targeted physical examination and review of patient chart including biochemistry and hematology. A fecal and a pharyngeal swap will be collected and stored at the final assessment.
Children receiving antibiotics with no additional need for in-hospital treatment can receive their antibiotic treatment by continuous infusion on a portable pump and discharged to outpatient therapy, according to local department guidelines.
STATISTICS: The number of days free of antibiotics will be compared between the groups by linear regression analysis. A multivariate linear regression analysis will be carried out adjusting for age, gender, neutropenia duration, and underlying malignant disease and other significant risk factors.
Secondary outcomes will be compared by a non-inferiority assumption with an inferiority margin of 10%. All tests will be two-sided, with p values of 0.05 considered significant. An interim analysis will be conducted when 50% of the patients have been recruited to assess the safety of the study. A worst-case imputation method will be used for missing data in an exploratory sensitivity analysis.
- Conditions
- Neutropenia, Febrile, Pediatric Cancer
- Being tested
- Early termination of empirical antibiotics
- Medical subject headings
- Febrile Neutropenia, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Early termination of empirical antibioticsOther
Termination of empirical antibiotics for febrile neutropenia based on clinical parameters, regardless of neutrophile count.
| Study group | Role | What they receive |
|---|---|---|
| Experimental group | Experimental | Discontinuation of empirical antibiotics, despite neutrophil count below 0.5x10⁹ cells/L, after 48 hours of apyrexia and clinical stability.
A child is considered clinically stable when there is resolution of all symptoms and signs of infection, and normalization of vital signs including heart rate, respiratory rate, oxygen saturation, blood pressure, and daily diuresis. Receives: Other: Early termination of empirical antibiotics |
| Control group | No intervention | Discontinuation of antibiotics when neutrophil count is equal to or above 0.5x10⁹ cells/L, and the child is afebrile and clinical stable OR the child has received 10 days of antibiotics and have been afebrile and clinically stable for 7 days |
What is being measured
The primary outcome is the main question the study is designed to answer.
Days without antibiotics
Number of days without antibiotic treatment
Measured: 28 days from randomization
Secondary outcomes (7)
Mortality
Crude mortality
Measured: 28 days from randomization
Severe adverse events
Severe adverse events
Measured: 28 days from randomization
New episode of neutropenic fever
New episode of neutropenic fever
Measured: 28 days from randomization
Days with fever
Days with fever
Measured: 28 days from randomization
Time to bone marrow recovery
Time to bone marrow recovery
Measured: Patients are monitored for when this has happened up to three months after randomisation
Time to next chemotherapy
Time to next chemotherapy
Measured: Patients are monitored for when this has happened up to three months after randomisation
Alterations in gut microbiome
Alterations in gut microbiome composition measured by bacterial whole genome sequencing on fecal samples collected at 28 days after randomisation.
Measured: At day 28 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Nov 2020
- Study start20 Nov 2020
- Primary completion31 Jan 2025
- Study completion11 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neutropenia, FebrileStudies 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Model description
- Patients receiving empirical antibiotic treatment due to high risk neutropenic fever will be randomly assigned 1:1 to one of two groups regimens. Randomization can occur from 36 hours after initiation of antibiotics until 48 hours of apyrexia and clinical stability. The allocated treatment regimen is followed from randomization until neutrophil recovery, also in case of relapsing fever after termination of antibiotic treatment. A participant can be randomized more than once, but only one time during each episode of neutropenia, i.e. bone marrow recovery and subsequent chemotherapy treatment must have taken place before a new randomization can occur.
- Masking
- None (open label)
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kjeld Schmiegelow
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Kjeld Schmiegelow, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Nadja Vissing, MD, PhD, Principal investigator, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04637464
- Sponsor's protocol ID
- EarlyTerm
- Status last verified
- Apr 2025
- First submitted
- 6 Nov 2020
- Last updated
- 9 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Vissing NH, Skajaa T, Grosen D, Albertsen BK, Als-Nielsen B, Hasle H, Koch MM, Rasmussen AH, Brok JS, Hjalgrim L, Blanche P, Schmiegelow K, Nygaard U. Early discontinuation of empirical antibiotics versus extended treatment in children with cancer and high-risk febrile neutropenia in Denmark: an open-label, randomised controlled trial. Lancet Child Adolesc Health. 2026 Jun;10(6):418-428. doi: 10.1016/S2352-4642(26)00039-8. Epub 2026 Apr 13.
PubMed 41990768
Study at a glance
From the registry record, last updated by the sponsor on 9 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Early Termination of Empirical Antibiotics in High-risk Febrile Neutropenia in Children With Cancer: an Open-label, Randomised, Controlled Trial
- ClinicalTrials.gov ID
- NCT04637464
- Acronym / sponsor ID
- EarlyTerm
- Conditions
- Neutropenia, Febrile, Pediatric Cancer
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 93 participants (actual)
- Lead sponsor
- Kjeld SchmiegelowUniversity, hospital or other
- Study start
- 20 Nov 2020 (actual)
- Primary completion
- 31 Jan 2025 (actual)
- Study completion
- 11 Mar 2025 (actual)
- First posted
- 19 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study is a nationwide, multicenter, open label, randomized controlled trial.
A target population of 220 children in treatment for cancer with neutropenic fever and a neutrophil count below 0.5 × 10⁹ cells/L with expected duration for more than 7 days will be recruited during the first 48 hours of antibiotic treatment (24 months inclusion period). They will be randomized 1:1 as follows:
- Experimental group: Discontinuation of antibiotics, despite neutrophil count below 0.5 × 10⁹ cells/L, after 48 hours of apyrexia and clinical stability
- Control group: Discontinuation of antibiotics when neutrophil count is equal to or above 0.5 × 10⁹ cells/L and the child is afebrile and clinically stable (up to maximum of 14 days after apyrexia and clinical stability).
Primary endpoint is the number of days without antibiotic treatment in 28 days after treatment initiation. Secondary endpoints are crude mortality, severe adverse events, days with relapsing fever, and alterations of the microbiome.
Detailed description
BACKGROUND: In children with cancer, infections are a major cause of morbidity and mortality due to chemotherapy-related immunosuppression, comprising up to 70% of all treatment-related deaths. The relationship between neutropenia and life-threatening infection has been well established, and any signs of infection including fever has to be treated promptly with broad spectrum antibiotics. However, the duration of antibiotic therapy in pediatric cancer patients with febrile neutropenia without a known source is unknown. Traditionally, antibiotic therapy is continued until neutrophil recovery, due to fear of relapse of infection potentially as life-threatening sepsis, but scientific evidence supporting this strategy is limited. It has been debated that the strategy may be over-cautious, leading to unnecessarily prolonged antibiotic treatments with important side effects, including extended hospital admissions, adverse drug events, super-infection with fungi and multi-resistant bacteria, and thus affecting the children on both short and long term.
Studies in adults have shown that withdrawal of empirical antimicrobial therapy based on clinical assessment, despite severe neutropenia, can reduce antibiotic treatment significantly without compromising patient safety. This approach is warranted in children with cancer, but no randomized studies have been conducted in high risk children with prolonged neutropenia. A few studies have documented that early discontinuation of empirical antibiotics in low-risk children with short-lasting neutropenia is safe, but as stressed by recent international guidelines, the question of optimal duration of empirical antibiotics for high-risk children with prolonged bone marrow suppression continues to be a major research gap.
HYPOTHESIS: Empirical antibiotic therapy of febrile neutropenia can safely be discontinued after 48 hours of apyrexia and clinical stability, despite severe neutropenia, in high-risk children with expected prolonged neutropenia.
AIM: To establish evidence-based treatment strategies for children with febrile neutropenia by performing a randomized controlled trial investigating the efficacy and safety of early termination of empirical antibiotic therapy.
METHODS: Children treated at one of the 4 pediatric oncology departments in Denmark who are admitted with neutropenic fever will be evaluated according to current routines, including complete physical examination, assessment of severity signs and source, blood samples (biochemistry and hematology), blood cultures (collected from the central venous catheter), and additional samples from infected sites as clinically indicated. After obtaining cultures, empiric antibiotic therapy for neutropenic fever is started. The type of antibiotics will depend on current local guideline. Children who remain febrile despite empirical antibiotic therapy will be treated and investigated according to local and international guidelines.
Eligible subjects will be screened and included as described.
Included subjects will be followed for 28 days after initiation of empirical antibiotic treatment or until neutrophile recovery, whichever is longest.
They will be assessed at the following protocolled time points:
- At 48 hours of apyrexia
- At recovery of neutropenia
- At 28 (±2) days (final assessment)
- In the event of relapsing fever after the initial 48 hours of apyrexia during the follow-up period.
Each assessment will include a clinical interview, targeted physical examination and review of patient chart including biochemistry and hematology. A fecal and a pharyngeal swap will be collected and stored at the final assessment.
Children receiving antibiotics with no additional need for in-hospital treatment can receive their antibiotic treatment by continuous infusion on a portable pump and discharged to outpatient therapy, according to local department guidelines.
STATISTICS: The number of days free of antibiotics will be compared between the groups by linear regression analysis. A multivariate linear regression analysis will be carried out adjusting for age, gender, neutropenia duration, and underlying malignant disease and other significant risk factors.
Secondary outcomes will be compared by a non-inferiority assumption with an inferiority margin of 10%. All tests will be two-sided, with p values of 0.05 considered significant. An interim analysis will be conducted when 50% of the patients have been recruited to assess the safety of the study. A worst-case imputation method will be used for missing data in an exploratory sensitivity analysis.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Patients receiving empirical antibiotic treatment due to high risk neutropenic fever will be randomly assigned 1:1 to one of two groups regimens. Randomization can occur from 36 hours after initiation of antibiotics until 48 hours of apyrexia and clinical stability. The allocated treatment regimen is followed from randomization until neutrophil recovery, also in case of relapsing fever after termination of antibiotic treatment. A participant can be randomized more than once, but only one time during each episode of neutropenia, i.e. bone marrow recovery and subsequent chemotherapy treatment must have taken place before a new randomization can occur.
| Arm | Type | Receives |
|---|---|---|
| Experimental group | Experimental | Other: Early termination of empirical antibioticsDiscontinuation of empirical antibiotics, despite neutrophil count below 0.5x10⁹ cells/L, after 48 hours of apyrexia and clinical stability. A child is considered clinically stable when there is resolution of all symptoms and signs of infection, and normalization of vital signs including heart rate, respiratory rate, oxygen saturation, blood pressure, and daily diuresis. |
| Control group | No intervention | –Discontinuation of antibiotics when neutrophil count is equal to or above 0.5x10⁹ cells/L, and the child is afebrile and clinical stable OR the child has received 10 days of antibiotics and have been afebrile and clinically stable for 7 days |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- patient with cancer aged 18 years or below,
- absolute neutrophil count below 0.5x10⁹/L with expected duration of neutropenia for more than 7 days, and
- a single temperature of at least 38.5°C, or a temperature above 38.0°C sustained over a 1-hour period (auricular, oral or rectal).
Key exclusion criteria (3 listed)
- known etiology of fever, defined by a clinically significant positive culture (blood, urine, tracheal) collected during the feverish episode or a clinically documented focal infection despite negative cultures (e.g. pneumonia and cellulitis),
- obvious non-infectious causes of fever (e.g. drug and transfusion related),
- children requiring prophylactic antibacterial antibiotics according to protocol besides co-trimoxazole for Pneumocystis jirovecii after the febrile episode.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Early termination of empirical antibioticsTermination of empirical antibiotics for febrile neutropenia based on clinical parameters, regardless of neutrophile count. | Other | Experimental group |
Primary outcome
Days without antibiotics
Time frame: 28 days from randomization
Number of days without antibiotic treatment
7 secondary outcomes
Mortality
Time frame: 28 days from randomization
Severe adverse events
Time frame: 28 days from randomization
New episode of neutropenic fever
Time frame: 28 days from randomization
Days with fever
Time frame: 28 days from randomization
Time to bone marrow recovery
Time frame: Patients are monitored for when this has happened up to three months after randomisation
Time to next chemotherapy
Time frame: Patients are monitored for when this has happened up to three months after randomisation
Alterations in gut microbiome
Time frame: At day 28 days after randomization
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Apr 2025.
- Derived from this study: PubMed 41990768Vissing NH, Skajaa T, Grosen D, Albertsen BK, Als-Nielsen B, Hasle H, Koch MM, Rasmussen AH, Brok JS, Hjalgrim L, Blanche P, Schmiegelow K, Nygaard U. Early discontinuation of empirical antibiotics versus extended treatment in children with cancer and high-risk febrile neutropenia in Denmark: an open-label, randomised controlled trial. Lancet Child Adolesc Health. 2026 Jun;10(6):418-428. doi: 10.1016/S2352-4642(26)00039-8. Epub 2026 Apr 13.
- Individual participant dataSharing planned: No
Related trials for Neutropenia, Febrile
RecruitingPhase 4
Adjustment of Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Augmented Renal Clearance
Febrile Neutropenia
Not yet recruiting
Diagnostic Accuracy, Clinical Utility and Implementation of Point-of-Care Absolute Neutrophil Count in Suspected Neutropenic Fever (DUCATIS) - Diagnostic Accuracy (S1)
Suspected Neutropenic Fever, Confirmed Neutropenic Fever
RecruitingObservational study
Mecapegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Advanced Breast Cancer
Breast Cancer, Chemotherapy-induced Neutropenia
Not yet recruiting
Impact of a Telemonitoring Device on the Occurever at Home in Children at Risk of Chemotherapy-Induced Neutropenia
Oncopediatrics, Febrile Neutropenia
Recruiting
Swiss 2024 Continous Fever Monitoring in Pediatric Oncology Patients
Pediatric Oncology Patients With Risk for Infections
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nadja Vissing, MD, PhD principal investigator
Copenhagen University Hospital, Rigshospitalet
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Early termination of empirical antibiotics in people with Neutropenia, Febrile and Pediatric Cancer, run by Kjeld Schmiegelow at 3 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Days without antibiotics (time frame: 28 days from randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04637464, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Apr 2025.