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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Febrile Neutropenia
• Intervention / Treatment: Drug: Piperacillin-Tazobactam 4 g-0.5 g; Drug: Cefepime 2000 mg; Drug: Meropenem 1000 mg

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.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Carlota Gudiol, PhD; Phone Number: 0034675786820; Email: carlotagudiol@gmail.com
• Study Contact Backup: Name: Julia Laporte-Amargos, MD; Email: j.laporte@bellvitgehospital.cat

Study Locations

• Spain
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Recruiting
      • Hospital Duran I Reynals
      • Contact: Carlota Gudiol, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Extended infusion; Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval	Drug: Piperacillin-Tazobactam 4 g-0.5 g; Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h; Drug: Cefepime 2000 mg; Patients with FN who required empirical treatment with cefepime 2g/8h; Drug: Meropenem 1000 mg; Patients with FN who required empirical treatment with meropenem 1g/8h
Active Comparator: Intermittent infusion; Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes	Drug: Piperacillin-Tazobactam 4 g-0.5 g; Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h; Drug: Cefepime 2000 mg; Patients with FN who required empirical treatment with cefepime 2g/8h; Drug: Meropenem 1000 mg; Patients with FN who required empirical treatment with meropenem 1g/8h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 days
Inflammatory biomarker	Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein.	5 days
Overall mortality at 30 days	Number of patients who died for any reason	30 days
Bacteraemia clearance	Time in days until bacteraemia clearance.	30 days
Adverse events	Incidence of adverse events in both groups	30 days
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.	5 days
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	5 days
Covariables analysis: biometric values: weight	Assessment of the impact of patient's weight [in kg]	5 days
Covariables analysis: biometric values: age	Assessment of the impact of patient's age [in years]	5 days
Covariables analysis: biochemical data: serum albumin	Assessment of the impact of total serum albumin [in g/L]	5 days
Covariables analysis: biochemical data: blood urea	Assessment of the impact of the urea [in mmol/L]	5 days
Covariables analysis: biochemical data: blood creatinine	Assessment of the impact of the creatinine [in umol/L]	5 days
Covariables analysis: clinical data: 24h diuresis	Assessment of the impact of 24h diuresis [in mL/day]	5 days
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).	5 days

Collaborators and Investigators

• Sponsor: Hospital Universitari de Bellvitge
• Collaborators: Institut d'Investigació Biomèdica de Bellvitge; Instituto de Salud Carlos III
• Investigators: Principal Investigator: Carlota Gudiol, PhD, Hospital Universitari de Bellvitge

Publications and helpful links

General Publications

• 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.

Helpful Links

• Spanish clinical trial registration (REEC, registro español de estudios clínicos)

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2019
• Primary Completion (Anticipated): December 30, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: September 4, 2019
• First Submitted That Met QC Criteria: January 16, 2020
• First Posted (Actual): January 21, 2020

Study Record Updates

• Last Update Posted (Actual): February 12, 2021
• Last Update Submitted That Met QC Criteria: February 11, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Beta-lactam antibiotics; Febrile neutropenia; Cefepime; Meropenem; Piperacillin-tazobactam; Extended infusion
• Additional Relevant MeSH Terms: Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Neutropenia; Hyperthermia; Fever; Febrile Neutropenia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Meropenem; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefepime
• Other Study ID Numbers: 2018-001476-37

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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