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Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Hematologic Patients (BEATLE)

Primary Purpose

Febrile Neutropenia

Status
Unknown status
Phase
Phase 4
Locations
Spain
Study Type
Interventional
Intervention
Piperacillin-Tazobactam 4 g-0.5 g
Cefepime 2000 mg
Meropenem 1000 mg
Sponsored by
Hospital Universitari de Bellvitge
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Febrile Neutropenia focused on measuring Febrile neutropenia, Beta-lactam antibiotics, Cefepime, Meropenem, Piperacillin-tazobactam, Extended infusion

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Adult patients (age ≥18 years) of both sexes.
  2. Patients admitted in Hematological wards.

  3. With any of the following diagnoses:

    1. Acute leukemia receiving chemotherapy.
    2. Autologous or allogeneic hematopoietic stem cell transplant recipients.
  4. With an episode of febrile neutropenia: ≥ 38.0ºC and <500 neutrophils/mm3 or <1000 with a predicted decrease within 24-48 hours.
  5. Patient requiring treatment with a beta-lactam antibiotic: cefepime, piperacillin /tazobactam or meropenem, in monotherapy or in combination with another antibiotic.
  6. Written informed consent has been obtained from the patient or their legal representative grants.

Exclusion Criteria:

  1. Allergy to study drugs.
  2. Patient receiving systemic antibiotic treatment (except for prophylaxis) at the time of onset of febrile neutropenia.
  3. Absence of fever.
  4. Patients with epilepsy.
  5. Severe renal impairment (defined as creatinine clearance <30 mL / min)
  6. Previously enrolled patients in whom the time between the inclusion and the current episode is less than 5 weeks.
  7. Previously enrolled patients without current resolution of the first episode.

Sites / Locations

  • Hospital Duran i ReynalsRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Extended infusion

Intermittent infusion

Arm Description

Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval

Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes

Outcomes

Primary Outcome Measures

Clinical efficacy of extended infusion: Number of patients with defervescence
Number of patients with defervescence (<37.5 ºC, for 24 hours) without modifying the antibiotic treatment

Secondary Outcome Measures

Pharmacokinetic target
Number of patients in whom the free antibiotic concentration remains above the MIC of the suspected or isolated microorganism, for 50%, 75% and 100% of the dosing interval.
Inflammatory biomarker
Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein.
Overall mortality at 30 days
Number of patients who died for any reason
Bacteraemia clearance
Time in days until bacteraemia clearance.
Adverse events
Incidence of adverse events in both groups
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Volume of distribution
Population mean value of volume of distribution of antibiotics during critical illness. Mean population volume of distribution will be derived from pooled data of antibiotic concentrations. Covariates of influence on volume of distribution will be incorporated within a population pharmacokinetic model.
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Clearance
Population mean value of clearance of antibiotics during critical illness. Mean population clearance will be derived from pooled data of antibiotic concentrations. Covariates of influence on drug clearance will be incorporated within a population pharmacokinetic model
Covariables analysis: biometric values: weight
Assessment of the impact of patient's weight [in kg]
Covariables analysis: biometric values: age
Assessment of the impact of patient's age [in years]
Covariables analysis: biochemical data: serum albumin
Assessment of the impact of total serum albumin [in g/L]
Covariables analysis: biochemical data: blood urea
Assessment of the impact of the urea [in mmol/L]
Covariables analysis: biochemical data: blood creatinine
Assessment of the impact of the creatinine [in umol/L]
Covariables analysis: clinical data: 24h diuresis
Assessment of the impact of 24h diuresis [in mL/day]
Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for plasma concentrations
Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the fraction of the time between two successive drug administrations during which plasma concentrations of meropenem, piperacillin and cefepime remain above a critical value ("S" breakpoint of the corresponding antibiotic [meropenem, piperacillin and cefepime: European Committee for Antimicrobials Susceptibility Testing [EUCAST] value) in the study population, and to determine its value in a simulated population (Monte Carlo simulations; 1000 simulated patients).

Full Information

First Posted
September 4, 2019
Last Updated
February 11, 2021
Sponsor
Hospital Universitari de Bellvitge
Collaborators
Institut d'Investigació Biomèdica de Bellvitge, Instituto de Salud Carlos III
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1. Study Identification

Unique Protocol Identification Number
NCT04233996
Brief Title
Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Hematologic Patients
Acronym
BEATLE
Official Title
Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Haematologic Patients: a Randomised, Multicentre, Open-label, Superiority Clinical Trial (BEATLE)
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Unknown status
Study Start Date
June 5, 2019 (Actual)
Primary Completion Date
December 30, 2021 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Universitari de Bellvitge
Collaborators
Institut d'Investigació Biomèdica de Bellvitge, Instituto de Salud Carlos III

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study evaluates the administration of beta-lactam antibiotics in extended infusion in hematological patients with febrile neutropenia after 5 days of treatment. The beta-lactam antibiotics analyzed are the following: piperacillin-tazobactam, cefepime and meropenem. Half of patients will receive the antibiotic in intermittent infusion, while the other half will receive it in extended infusion.
Detailed Description
Febrile neutropenia (FN) is a very frequent complication in patients with hematological malignancies. It is associated with an important morbidity and mortality. Nowadays the use of betalactam antibiotics (BLA) in extended or continuous infusion (EI, CI) instead of intermittent infusion (II), has demonstrated a therapeutic success and lower mortality rate in critically ill intensive care patients. Neutropenic patients are a particular population since FN is assoicated with pathophysiological variations that compromise pharmacokinetic parameters of BLA, and may therefore, diminish their clinical efficacy. Information regarding the usefulness of BLA in EI in neutropenic hematologic patients is scarce. The objective of this randomized clinical trial is to demonstrate the clinical superiority of the administration of BLA in EI compared to II in patients with FN.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Febrile Neutropenia
Keywords
Febrile neutropenia, Beta-lactam antibiotics, Cefepime, Meropenem, Piperacillin-tazobactam, Extended infusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Extended infusion
Arm Type
Experimental
Arm Description
Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval
Arm Title
Intermittent infusion
Arm Type
Active Comparator
Arm Description
Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes
Intervention Type
Drug
Intervention Name(s)
Piperacillin-Tazobactam 4 g-0.5 g
Intervention Description
Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h
Intervention Type
Drug
Intervention Name(s)
Cefepime 2000 mg
Intervention Description
Patients with FN who required empirical treatment with cefepime 2g/8h
Intervention Type
Drug
Intervention Name(s)
Meropenem 1000 mg
Intervention Description
Patients with FN who required empirical treatment with meropenem 1g/8h
Primary Outcome Measure Information:
Title
Clinical efficacy of extended infusion: Number of patients with defervescence
Description
Number of patients with defervescence (<37.5 ºC, for 24 hours) without modifying the antibiotic treatment
Time Frame
5 days
Secondary Outcome Measure Information:
Title
Pharmacokinetic target
Description
Number of patients in whom the free antibiotic concentration remains above the MIC of the suspected or isolated microorganism, for 50%, 75% and 100% of the dosing interval.
Time Frame
5 days
Title
Inflammatory biomarker
Description
Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein.
Time Frame
5 days
Title
Overall mortality at 30 days
Description
Number of patients who died for any reason
Time Frame
30 days
Title
Bacteraemia clearance
Description
Time in days until bacteraemia clearance.
Time Frame
30 days
Title
Adverse events
Description
Incidence of adverse events in both groups
Time Frame
30 days
Title
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Volume of distribution
Description
Population mean value of volume of distribution of antibiotics during critical illness. Mean population volume of distribution will be derived from pooled data of antibiotic concentrations. Covariates of influence on volume of distribution will be incorporated within a population pharmacokinetic model.
Time Frame
5 days
Title
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Clearance
Description
Population mean value of clearance of antibiotics during critical illness. Mean population clearance will be derived from pooled data of antibiotic concentrations. Covariates of influence on drug clearance will be incorporated within a population pharmacokinetic model
Time Frame
5 days
Title
Covariables analysis: biometric values: weight
Description
Assessment of the impact of patient's weight [in kg]
Time Frame
5 days
Title
Covariables analysis: biometric values: age
Description
Assessment of the impact of patient's age [in years]
Time Frame
5 days
Title
Covariables analysis: biochemical data: serum albumin
Description
Assessment of the impact of total serum albumin [in g/L]
Time Frame
5 days
Title
Covariables analysis: biochemical data: blood urea
Description
Assessment of the impact of the urea [in mmol/L]
Time Frame
5 days
Title
Covariables analysis: biochemical data: blood creatinine
Description
Assessment of the impact of the creatinine [in umol/L]
Time Frame
5 days
Title
Covariables analysis: clinical data: 24h diuresis
Description
Assessment of the impact of 24h diuresis [in mL/day]
Time Frame
5 days
Title
Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for plasma concentrations
Description
Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the fraction of the time between two successive drug administrations during which plasma concentrations of meropenem, piperacillin and cefepime remain above a critical value ("S" breakpoint of the corresponding antibiotic [meropenem, piperacillin and cefepime: European Committee for Antimicrobials Susceptibility Testing [EUCAST] value) in the study population, and to determine its value in a simulated population (Monte Carlo simulations; 1000 simulated patients).
Time Frame
5 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients (age ≥18 years) of both sexes. Patients admitted in Hematological wards. With any of the following diagnoses: Acute leukemia receiving chemotherapy. Autologous or allogeneic hematopoietic stem cell transplant recipients. With an episode of febrile neutropenia: ≥ 38.0ºC and <500 neutrophils/mm3 or <1000 with a predicted decrease within 24-48 hours. Patient requiring treatment with a beta-lactam antibiotic: cefepime, piperacillin /tazobactam or meropenem, in monotherapy or in combination with another antibiotic. Written informed consent has been obtained from the patient or their legal representative grants. Exclusion Criteria: Allergy to study drugs. Patient receiving systemic antibiotic treatment (except for prophylaxis) at the time of onset of febrile neutropenia. Absence of fever. Patients with epilepsy. Severe renal impairment (defined as creatinine clearance <30 mL / min) Previously enrolled patients in whom the time between the inclusion and the current episode is less than 5 weeks. Previously enrolled patients without current resolution of the first episode.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Carlota Gudiol, PhD
Phone
0034675786820
Email
carlotagudiol@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Julia Laporte-Amargos, MD
Email
j.laporte@bellvitgehospital.cat
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlota Gudiol, PhD
Organizational Affiliation
Hospital Universitari de Bellvitge
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Duran i Reynals
City
Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08908
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carlota Gudiol, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32423462
Citation
Laporte-Amargos J, Gudiol C, Arnan M, Puerta-Alcalde P, Carmona-Torre F, Huguet M, Albasanz-Puig A, Parody R, Garcia-Vidal C, Del Pozo JL, Batlle M, Tebe C, Rigo-Bonnin R, Munoz C, Padulles A, Tubau F, Videla S, Sureda A, Carratala J. Efficacy of extended infusion of beta-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE). Trials. 2020 May 18;21(1):412. doi: 10.1186/s13063-020-04323-0.
Results Reference
derived
Links:
URL
https://reec.aemps.es/reec/public/detail.html
Description
Spanish clinical trial registration (REEC, registro español de estudios clínicos)

Learn more about this trial

Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Hematologic Patients

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