Adjustment of Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Augmented Renal Clearance
NCT ID: NCT06293677
Last Updated: 2024-07-11
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
RECRUITING
PHASE4
30 participants
INTERVENTIONAL
2024-03-01
2026-03-31
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
The main questions this study aims to answer are, in these children:
* Would higher doses of antibiotics result in better blood levels of antibiotics?
* Would they have more sides effects with higher antibiotics dosages?
* Would they recover more quickly with higher antibiotic doses? All patients will undergo a blood test upon hospital arrival, including an assessment of renal function. If renal function is normal or diminished, the patient will receive the standard antibiotic dose. Children with increased renal function will be randomly assigned to two groups during each episode of febrile neutropenia. One group will receive standard antibiotic dosages, while the other will receive higher doses to compensate for renal hyperfiltration. Throughout the study, antibiotic levels in the blood will be monitored for all patients. This monitoring will determine if target concentrations can be achieved more quickly with experimental dosages and will allow doctors to readjust the doses if needed.
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
Short vs Prolonged Antibiotic Treatment for Hospitalized Hemato-oncology Patients With Febrile Neutropenia
NCT02463747
Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Children With Febrile Neutropenia
NCT04000711
Prevention of Infection in Patients With Hematologic Cancer and Persistent Fever Caused by a Low White Blood Cell Count
NCT00003805
Antimicrobial Revision in Persistent Febrile Neutropenia
NCT05784844
Piperacillin/Tazobactam for Empirical Therapy of Febrile Neutropenia
NCT01714570
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
To estimate renal function, molecules such as creatinine or cystatin C are routinely measured in the blood. Clinicians commonly rely on the Schwartz formula for determining the patients glomerular filtration rate (GFR) when adjusting antibiotic treatment. Although other formulas based on creatinine and/or cystatin C have been developed, their effectiveness in oncological patients with ARC remains unexplored. If these alternative formulas prove more effective in ARC situations, it may prompt a reconsideration of how we determine GFR in hyperfiltrating children.
Measurement and procedures Clinicians will decide if prescribe piperacillin-tazobactam or meropenem, according to the clinical situation. The trial will have 3 arms, the two control arms will receive standard dosages of antibiotics (non-hyperfiltrating patients, control group 2, and hyperfiltrating patients randomized to control group 1c). The third group, hyperfiltrating patients randomized to intervention group 1i, will receive experimental doses. The randomization will be made using REDCap®.
A TDM at trough level (Ctrough) of meropenem (MER) or piperacillin-tazobactam (PIP) will be systematically performed just before the fourth dose, and again before the fourth dose after each further dosage adaptation. The dosage will be adjusted if blood levels are outside the target therapeutic ranges. TDM will be monitored at least twice a week and more frequently in case of unfavorable clinical outcome or significant change in serum creatinine.
Objectives
Primary objective:
To compare the proportion of early achievement of antibiotic concentration targets in hyperfiltrating patients, using either standard dosage recommendations (control group, 1C) or a new set of Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) (intervention group, 1i).
Secondary objectives:
1. To compare the proportion of early achievement of antibiotic concentration targets (for MER or PIP) between non hyperfiltrating patients (control group 2) and the intervention group (1i).
2. To compare the mean/median duration of fever episodes between control groups and intervention group (1i)
3. To compare the incidence of intervention-drug adverse effects (CTCAE v5, grade 3 or higher, grade 2 judged to be probably/definitely related to study intervention and SAE) between the control groups (group 1c and 2) and the intervention group (1i)
4. To compare the proportion of patients requiring TDM-based readjustment of antibiotic dosages due to blood level below or above the target ranges between the control group 1c and the intervention group 1i, at any time during the antibiotic treatment.
5. To compare the eGFR estimated by creatinine-based Schwartz formula in comparison to creatinine and cystatin C based Schwartz formula, creatinine-based quadratic formula, combined creatinine and cystatin C Quadratic formulas, Zappitelli formula, and Schwartz-Lyon formula.
Statistical Considerations The proportion of achievement of the target ranges before the fourth antibiotic dose will be compared between the two randomized groups with a mixed effects logistic regression.
Duration of fever will be analyzed by the Kaplan-Meier method. Cox regression analysis will be used to evaluate if the intervention decreases duration of fever.
The occurrence of adverse events and the outcome of the febrile neutropenia episode will be compared between groups using a Chi-square test.
The use of TDM for further adjustment of MER and PIP dosage will be explored with descriptive statistics. A population pharmacokinetic description of MER and PIP concentration will be attempted.
To evaluate different eGFR formulas, we will calculate the mean difference in eGFR estimation for each formula compared to the creatinine-based Schwartz formula and determine a 95% confidence interval for each formula. Comparison between hyperfiltrating non hyperfiltrating will be made using student T-test or Kruskal-Wallis tests.
Unless otherwise stated, the α risk p -values reported will be two-sided and the nominal limit will be set to 0.05.
Risk / Benefit Assessment The risk of this study is over exposure to wide-spectrum antibiotics. This implies drugs dose-dependent adverse events.
High blood trough concentrations (Ctrough) of broad-spectrum antibiotics have been associated with reversible neurological and nephrological side effects in adults. The threshold level chosen in this protocol is well below the values for which there is a risk of a 50% increase in side effects for both antibiotics. Doses of MER and PIP excess of authorized doses, guided by therapeutic drug monitoring, have not been associated with additional toxicities in adults. The evaluation of renal clearance before the choice of dosage, daily clinical and biological monitoring and regular monitoring of Ctrough will limit risks.
The expected benefit will be improved circulating exposure to broad-spectrum antibiotics. This could allow better control of the infection with a more rapid and favorable clinical course.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Control Group 1c
Group 1c includes patients with augmented renal clearance (ARC) who have been randomized to receive a standard dosage of antibiotic (méropenem or piperacilline-tazobactam)
Standard dosages of piperacillin-tazobactam or meropenem
Meropenem dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR\> 50 : 40mg/kg q8h eGFR 25-49 : 40mg/kg q12h eGFR 15-24 : 20mg/kg q12h
Piperacillin-tazobactam :
eGFR \>50 : 100mg/kg q6h eGFR 20-49 : 50mg/kg q6h eGFR 15-29 : 50 mg/kg q8h
Intervention DAR-ARC Group 1i
Group 1i (DAR-ARC) includes patients with ARC who have been randomized to receive an experimental dosage of antibiotic (méropenem or piperacilline-tazobactam)
Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem
Meropenem dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR 120-149 : 40 mg/kg q6 h eGFR 150-199 : 30 mg/kg q4h eGFR 200-299 : 40 mg/kg q4h eGFR \>/= 300 : 40 mg/kg q4h
Piperacillin-tazobatam dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR 120-149 : 150 mg/kg q6 h eGFR 150-199 : 120 mg/kg q4h eGFR 200-299 : 150 mg/kg q4h eGFR \>/= 300 : 180 mg/kg q4h
The maximum doses for the antibiotic prescription before the first drug monitoring will be 2gr of MER every 4 hours and 4gr of PIP every 4 hours.
The duration of infusion will be set to 2 h.
Control Group 2
Control Group 2 includes patients with normal or decreased renal function who will receive standard dosage of antibiotic (méropenem or piperacilline-tazobactam)
Standard dosages of piperacillin-tazobactam or meropenem
Meropenem dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR\> 50 : 40mg/kg q8h eGFR 25-49 : 40mg/kg q12h eGFR 15-24 : 20mg/kg q12h
Piperacillin-tazobactam :
eGFR \>50 : 100mg/kg q6h eGFR 20-49 : 50mg/kg q6h eGFR 15-29 : 50 mg/kg q8h
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem
Meropenem dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR 120-149 : 40 mg/kg q6 h eGFR 150-199 : 30 mg/kg q4h eGFR 200-299 : 40 mg/kg q4h eGFR \>/= 300 : 40 mg/kg q4h
Piperacillin-tazobatam dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR 120-149 : 150 mg/kg q6 h eGFR 150-199 : 120 mg/kg q4h eGFR 200-299 : 150 mg/kg q4h eGFR \>/= 300 : 180 mg/kg q4h
The maximum doses for the antibiotic prescription before the first drug monitoring will be 2gr of MER every 4 hours and 4gr of PIP every 4 hours.
The duration of infusion will be set to 2 h.
Standard dosages of piperacillin-tazobactam or meropenem
Meropenem dosages according to eGFR \[mL/min/1.73 m²\] :
eGFR\> 50 : 40mg/kg q8h eGFR 25-49 : 40mg/kg q12h eGFR 15-24 : 20mg/kg q12h
Piperacillin-tazobactam :
eGFR \>50 : 100mg/kg q6h eGFR 20-49 : 50mg/kg q6h eGFR 15-29 : 50 mg/kg q8h
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* High probability of febrile neutropenia during the study period
* Written informed consent from parents and adolescents older than 14 years
* Febrile neutropenia or agranulocytosis defined as:
* Neutropenia: absolute neutrophils \<500 cells/µL or agranulocytosis: absolute neutrophils \<100 cells/µL or patients expected to be neutropenic in the next 24 hours due to ongoing chemotherapy
* body temperature (tympanic or axillary) ≥38°C during at least one hour or a single T ≥38.5°C
* At least 2 weeks after the end of the previous antibiotic treatment for another included episode of febrile neutropenia.
Exclusion Criteria
* Refusal to participate
* Non-French speaking parents/patients older than 11 years old
* Absence of febrile neutropenia or agranulocytosis during the study period (secondary exclusion)
* Severe renal failure (GFR\<15 mL/min/1.73 m²)
* Pregnancy
* Inability to obtain the first therapeutic drug monitoring (TDM) result within 72 hours of sampling (e.g. admission before or during public holidays laboratory closure)
61 Days
18 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Unisanté Centre universitaire de médecine générale et santé publique
UNKNOWN
FORCE Fondation Recherche sur le Cancer de l'Enfant
UNKNOWN
Centre Hospitalier Universitaire Vaudois
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Pierre Alex Crisinel
Head of the Unit of Pediatric Infectious Diseases and Vaccinology
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Pierre-Alex Crisinel
Role: PRINCIPAL_INVESTIGATOR
Centre Hospitalier Universitaire Vaudois
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Centre Hospitelier Universitaire Vaudois (CHUV)
Lausanne, Canton of Vaud, Switzerland
Countries
Review the countries where the study has at least one active or historical site.
Central Contacts
Reach out to these primary contacts for questions about participation or study logistics.
Facility Contacts
Find local site contact details for specific facilities participating in the trial.
References
Explore related publications, articles, or registry entries linked to this study.
Petersson J, Giske CG, Eliasson E. Standard dosing of piperacillin and meropenem fail to achieve adequate plasma concentrations in ICU patients. Acta Anaesthesiol Scand. 2016 Nov;60(10):1425-1436. doi: 10.1111/aas.12808. Epub 2016 Sep 21.
Scharf C, Paal M, Schroeder I, Vogeser M, Draenert R, Irlbeck M, Zoller M, Liebchen U. Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness-Experience and Recommendations from One Year in Routine Clinical Practice. Antibiotics (Basel). 2020 Mar 21;9(3):131. doi: 10.3390/antibiotics9030131.
Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. 2011 Jul 19;7(9):539-43. doi: 10.1038/nrneph.2011.92.
Hirai K, Ihara S, Kinae A, Ikegaya K, Suzuki M, Hirano K, Itoh K. Augmented Renal Clearance in Pediatric Patients With Febrile Neutropenia Associated With Vancomycin Clearance. Ther Drug Monit. 2016 Jun;38(3):393-7. doi: 10.1097/FTD.0000000000000270.
Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I. Too much of a good thing: a retrospective study of beta-lactam concentration-toxicity relationships. J Antimicrob Chemother. 2017 Oct 1;72(10):2891-2897. doi: 10.1093/jac/dkx209.
McDonald C, Cotta MO, Little PJ, McWhinney B, Ungerer JP, Lipman J, Roberts JA. Is high-dose beta-lactam therapy associated with excessive drug toxicity in critically ill patients? Minerva Anestesiol. 2016 Sep;82(9):957-65. Epub 2016 Apr 7.
de With K, Allerberger F, Amann S, Apfalter P, Brodt HR, Eckmanns T, Fellhauer M, Geiss HK, Janata O, Krause R, Lemmen S, Meyer E, Mittermayer H, Porsche U, Presterl E, Reuter S, Sinha B, Strauss R, Wechsler-Fordos A, Wenisch C, Kern WV. Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases. Infection. 2016 Jun;44(3):395-439. doi: 10.1007/s15010-016-0885-z.
Andre P, Diezi L, Dao K, Crisinel PA, Rothuizen LE, Chtioui H, Decosterd LA, Diezi M, Asner S, Buclin T. Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance! Front Pediatr. 2022 Jan 5;9:768438. doi: 10.3389/fped.2021.768438. eCollection 2021.
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2023-01013
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.