Febrile NeutropeniaPhase 4DAR-ARCNCT06293677
Adjustment of Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Augmented Renal Clearance
A Phase 4 study testing Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem and Standard dosages of piperacillin-tazobactam or meropenem in people with Febrile Neutropenia, run by Centre Hospitalier Universitaire Vaudois at 1 site in Switzerland.
Trial summary
This clinical trial focuses on children with cancer who face infections after receiving chemotherapy. Chemotherapy affects the bone marrow, leading to a decrease in the production of certain white blood cells, particularly those that defend against bacterial infections (neutrophils). Read more about this study
- Who is it for?
- Ages 61 days to 18 years
- Conditions the study is for
- Febrile Neutropenia
- What is being tested?
- Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem and Standard dosages of piperacillin-tazobactam or meropenem
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteSwitzerland
- Study dates
- 1 Mar 2024to Mar 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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 61 days to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Patients' inclusion criteria
- Oncologic patients aged 2 months to 17 years (older than 60 days and younger than 18 years),
- High probability of febrile neutropenia during the study period
- Written informed consent from parents and adolescents older than 14 years
Patients' exclusion criteria
- Neutropenia not related to cancer and/or chemotherapy
- 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)
Febrile neutropenia episodes inclusion criteria
- 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.
Febrile neutropenia episodes exclusion criteria:
- 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)
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Switzerland1 site, 1 recruiting
- Recruiting
Centre Hospitelier Universitaire Vaudois (CHUV)
Lausanne, Canton of Vaud, 1011
Margherita Plebani, +41795563598, Margherita.Plebani@chuv.ch
Pierre-Alex Crisinel
About this study
Official title: Upwards Initial Adjustment of Wide-Spectrum Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Suspected Augmented Renal Clearance: A Randomized Controlled Trial With Therapeutic Drug Monitoring
This clinical trial focuses on children with cancer who face infections after receiving chemotherapy. Chemotherapy affects the bone marrow, leading to a decrease in the production of certain white blood cells, particularly those that defend against bacterial infections (neutrophils). One significant concern is febrile neutropenia, where children experience a fever during a period of low white blood cell count. This condition often results from bacterial infections, necessitating prompt wide-spectrum antibiotic treatment. However, some children eliminate antibiotics in the urine too quickly during febrile neutropenia. Their kidneys function more than they normally do (renal hyperfiltration). This can lead to insufficient exposure to antibiotics to control the infection. The current standard antibiotic regimens do not account for this variable elimination rate. In this study we focus on two antibiotics used in this context: piperacillin-tazobactam and meropenem.
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.
Read the detailed description
Background and Rationale In pediatric cancer patients, Augmented Renal Clearance (ARC) is a common factor that affects outcomes. Febrile neutropenia, a frequent occurrence during cancer treatment, requires anti-infective drugs for treatment. However, ARC increases the elimination of these drugs through glomerular filtration, posing a risk of antibiotics insufficient blood levels. This may lead to difficulties in managing infections and the risk of antibiotic-resistant bacterial strains emerging. Febrile neutropenia is often associated with ARC, and in these patients standard antibiotic dosages frequently miss target concentrations. We propose defining categories of renal hyperfiltration to adjust antibiotic dosages upward in pediatric patients with ARC.
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:
- 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).
- To compare the mean/median duration of fever episodes between control groups and intervention group (1i)
- 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)
- 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.
- 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
- Febrile Neutropenia
- Being tested
- Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem, Standard dosages of piperacillin-tazobactam or meropenem
- Keywords
- Febrile neutropenia, Augmented Renal Clearance, Pediatric cancer, Therapeutic Drug monitoring TDM, Children, Wilde-spectrum antibiotic dosage, Glomerular filtration rate GFR
- 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.
Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenemDrug
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 \&gt;/= 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 \&gt;/= 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 meropenemDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Control Group 1c | Active comparator | Group 1c includes patients with augmented renal clearance (ARC) who have been randomized to receive a standard dosage of antibiotic (méropenem or piperacilline-tazobactam) Receives: Drug: Standard dosages of piperacillin-tazobactam or meropenem |
| Intervention DAR-ARC Group 1i | Experimental | Group 1i (DAR-ARC) includes patients with ARC who have been randomized to receive an experimental dosage of antibiotic (méropenem or piperacilline-tazobactam) Receives: Drug: Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem |
| Control Group 2 | Active comparator | Control Group 2 includes patients with normal or decreased renal function who will receive standard dosage of antibiotic (méropenem or piperacilline-tazobactam) Receives: Drug: Standard dosages of piperacillin-tazobactam or meropenem |
What is being measured
The primary outcome is the main question the study is designed to answer.
Achievement of antibiotic concentration targets in the intervention group (1i) vs control groupe (1c)
Intervention-drug blood concentration both above the lower limit and below the upper limit of the therapeutic target ranges on the first trough dosage before the fourth dose after treatment initiation.
Measured: During the first 24 hours of the intervention, before the fourth dose of antibiotic
Secondary outcomes (5)
Achievement of antibiotic concentration targets in control group 2
Intervention-drug blood concentration both above the lower limit and below the upper limit of the therapeutic target ranges on the first trough dosage before the fourth dose after treatment initiation in group 2
Measured: During the first 24 hours of the intervention, before the fourth dose of antibiotic
Fever duration
Duration of fever (T ≥38°C) after initiation of antibiotherapy (time between first dose of antibiotic and last measurement of T ≥38°C followed by at least 24 hours of T <38°C)
Measured: During the intervention
Side effects of antibiotic therapy
Any relevant adverse event judged to be probably/definitely related to study intervention and all serious adverse events (SAEs)
Measured: During the intervention and up to 2 weeks after
Number of dosage adjustments required to achieve the target concentration
Readjustment of the intervention drug dosage because of blood concentration either below the lower limit or above the upper limit of the therapeutic target ranges (at any time)
Measured: During the intervention
Difference between eGFR measured by creatinine-based Schwartz formula and other eGFR calculation formulas
Measured: Baseline, pre-intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2024
- Study start1 Mar 2024
- Primary completionMar 2028 (estimated)
- Study completionMar 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Febrile NeutropeniaStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire VaudoisThe sponsor's other registered studies.
- 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
- Model description
- Our study is an open-label, re-randomized controlled trial in multi-episodes settings. So the care team, researchers and patients will be informed of the allocation group. Patients will be able to participate in each episode of febrile neutropenia. At each inclusion the patient may be in a different group.
- Masking
- None (open label)
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Universitaire Vaudois
- Sponsor type
- University, hospital or other
- Collaborators
- Unisanté Centre universitaire de médecine générale et santé publique, FORCE Fondation Recherche sur le Cancer de l'Enfant
- Responsible party
- Principal investigator, Pierre Alex Crisinel, Centre Hospitalier Universitaire Vaudois
- Investigators
- Pierre-Alex Crisinel, Principal investigator, Centre Hospitalier Universitaire Vaudois
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06293677
- Sponsor's protocol ID
- 2023-01013
- Other IDs
- 2023
- Acronym
- DAR-ARC
- Status last verified
- Oct 2026
- First submitted
- 20 Feb 2024
- Last updated
- 3 Nov 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 27655029Scharf 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.
PubMed 32245195Udy 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.
PubMed 21769107Hirai 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.
PubMed 27172381Imani 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.
PubMed 29091190McDonald 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.
PubMed 27054905de 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.
PubMed 27066980Andre 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.
PubMed 35083184
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Upwards Initial Adjustment of Wide-Spectrum Antibiotic Dosage in Pediatric Oncology Patients With Febrile Neutropenia and Suspected Augmented Renal Clearance: A Randomized Controlled Trial With Therapeutic Drug Monitoring
- ClinicalTrials.gov ID
- NCT06293677
- Acronym / sponsor ID
- DAR-ARC / 2023-01013
- Conditions
- Febrile Neutropenia
- Keywords
- Febrile neutropenia, Augmented Renal Clearance, Pediatric cancer, Therapeutic Drug monitoring TDM, Children, Wilde-spectrum antibiotic dosage, Glomerular filtration rate GFR
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Centre Hospitalier Universitaire VaudoisUniversity, hospital or other
- Collaborators
- Unisanté Centre universitaire de médecine générale et santé publique, FORCE Fondation Recherche sur le Cancer de l'Enfant
- Study start
- 1 Mar 2024 (actual)
- Primary completion
- Mar 2028 (estimated)
- Study completion
- Mar 2028 (estimated)
- First posted
- 5 Mar 2024 (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.
This clinical trial focuses on children with cancer who face infections after receiving chemotherapy. Chemotherapy affects the bone marrow, leading to a decrease in the production of certain white blood cells, particularly those that defend against bacterial infections (neutrophils). One significant concern is febrile neutropenia, where children experience a fever during a period of low white blood cell count. This condition often results from bacterial infections, necessitating prompt wide-spectrum antibiotic treatment. However, some children eliminate antibiotics in the urine too quickly during febrile neutropenia. Their kidneys function more than they normally do (renal hyperfiltration). This can lead to insufficient exposure to antibiotics to control the infection. The current standard antibiotic regimens do not account for this variable elimination rate. In this study we focus on two antibiotics used in this context: piperacillin-tazobactam and meropenem.
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.
Detailed description
Background and Rationale In pediatric cancer patients, Augmented Renal Clearance (ARC) is a common factor that affects outcomes. Febrile neutropenia, a frequent occurrence during cancer treatment, requires anti-infective drugs for treatment. However, ARC increases the elimination of these drugs through glomerular filtration, posing a risk of antibiotics insufficient blood levels. This may lead to difficulties in managing infections and the risk of antibiotic-resistant bacterial strains emerging. Febrile neutropenia is often associated with ARC, and in these patients standard antibiotic dosages frequently miss target concentrations. We propose defining categories of renal hyperfiltration to adjust antibiotic dosages upward in pediatric patients with ARC.
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:
- 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).
- To compare the mean/median duration of fever episodes between control groups and intervention group (1i)
- 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)
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Our study is an open-label, re-randomized controlled trial in multi-episodes settings. So the care team, researchers and patients will be informed of the allocation group. Patients will be able to participate in each episode of febrile neutropenia. At each inclusion the patient may be in a different group.
| Arm | Type | Receives |
|---|---|---|
| Control Group 1c | Active comparator | Drug: Standard dosages of piperacillin-tazobactam or meropenemGroup 1c includes patients with augmented renal clearance (ARC) who have been randomized to receive a standard dosage of antibiotic (méropenem or piperacilline-tazobactam) |
| Intervention DAR-ARC Group 1i | Experimental | Drug: Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenemGroup 1i (DAR-ARC) includes patients with ARC who have been randomized to receive an experimental dosage of antibiotic (méropenem or piperacilline-tazobactam) |
| Control Group 2 | Active comparator | Drug: Standard dosages of piperacillin-tazobactam or meropenemControl Group 2 includes patients with normal or decreased renal function who will receive standard dosage of antibiotic (méropenem or piperacilline-tazobactam) |
Who may qualify
- Ages
- 61 days to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
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 |
|---|---|---|
| Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenemMeropenem 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 \&gt;/= 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 \&gt;/= 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. | Drug | Intervention DAR-ARC Group 1i |
| Standard dosages of piperacillin-tazobactam or meropenemMeropenem 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 | Drug | Control Group 1c, Control Group 2 |
Primary outcome
Achievement of antibiotic concentration targets in the intervention group (1i) vs control groupe (1c)
Time frame: During the first 24 hours of the intervention, before the fourth dose of antibiotic
Intervention-drug blood concentration both above the lower limit and below the upper limit of the therapeutic target ranges on the first trough dosage before the fourth dose after treatment initiation.
5 secondary outcomes
Achievement of antibiotic concentration targets in control group 2
Time frame: During the first 24 hours of the intervention, before the fourth dose of antibiotic
Fever duration
Time frame: During the intervention
Side effects of antibiotic therapy
Time frame: During the intervention and up to 2 weeks after
Number of dosage adjustments required to achieve the target concentration
Time frame: During the intervention
Difference between eGFR measured by creatinine-based Schwartz formula and other eGFR calculation formulas
Time frame: Baseline, pre-intervention
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2026.
- Background: PubMed 27655029Petersson 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.
- Background: PubMed 32245195Scharf 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.
- Background: PubMed 21769107Udy 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.
- Background: PubMed 27172381Hirai 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.
- Background: PubMed 29091190Imani 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.
- Background: PubMed 27054905McDonald 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.
- Background: PubMed 27066980de 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.
- Background: PubMed 35083184Andre 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.
- Individual participant dataSharing planned: No
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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.
Pierre-Alex Crisinel principal investigator
Centre Hospitalier Universitaire Vaudois
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dosage Adjustment Rules for Augmented Renal Clearance (DAR-ARC) for piperacillin-tazobactam and meropenem and Standard dosages of piperacillin-tazobactam or meropenem in people with Febrile Neutropenia, run by Centre Hospitalier Universitaire Vaudois at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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: looking for participants now, as of the sponsor's last update on 3 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. 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.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Margherita Plebani (+41(0)795563598, Margherita.Plebani@chuv.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Achievement of antibiotic concentration targets in the intervention group (1i) vs control groupe (1c) (time frame: During the first 24 hours of the intervention, before the fourth dose of antibiotic). 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 NCT06293677, which also lists 8 linked publications.
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 3 Nov 2026.