Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With FUO

NCT ID: NCT02149329

Last Updated: 2019-09-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 276 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-31
• Study Completion Date: 2019-08-05

Brief Summary

A multicenter open-label non-inferiority randomized clinical trial comparing the safety (non-inferiority) of short antibiotic treatment (72 hours) with an anti-pseudomonal carbapenem with regard to treatment failure in comparison with extended treatment (at least 9 days) of high-risk febrile neutropenia in hematology patients receiving standard antimicrobial prophylaxis.

Detailed Description

Episodes of fever are very common in patients undergoing intensive chemotherapy treatment for malignant hematological disease. More than 80% of patients experience one or more episodes of fever after their first cycle of chemotherapy. Only 20-30% of these patients have a clinically documented focus and mostly include infections of skin, intestinal tract and lung, while at most 10-25% of these patients have microbiologically proven bacteremia during these episodes. Patients with malignant hematological diseases and intensive chemotherapy induced neutropenia are extremely prone to overwhelming bacterial infections. Therefore, empirical antibiotic treatment is initiated at the first occurrence of fever, even if no apparent cause for the fever is evident. Most protocols advice treatment with very broad-spectrum antibiotics, mostly anti-pseudomonal carbapenems or fourth generation anti-pseudomonal cephalosporins.

Prolonged continuation of treatment may induce bacterial resistance. In view of the possible emergence of bacterial resistance due to prolonged antibiotic administration, continuation until recovery of neutropenia is suboptimal because it is costly because of longer hospital admissions, higher antibiotics costs and more possible adverse reactions.

Recent observational data (Slobbe et al) has showed that in adult hematological patients with febrile neutropenia, discontinuation of empiric antibacterial therapy after three days can be safe if no infectious etiology can be found, even in cases with persistent fever. However no RCT has hitherto been performed to support this observational data.

This study compares the safety (non-inferiority) of short treatment (72 hours) versus extended treatment (at least 9 days) with an anti-pseudomonal carbapenem for hematology patients with unexplained high risk febrile neutropenia. We hypothesize that a more restrictive use of broad-spectrum antibiotic use of three days in unexplained fever in neutropenic hematology patients is non-inferior to the present extended use during at least 9 days which would lead to a more restrictive use of antibiotics and less multiresistant strains of bacteria, costs and hospitalization length in the future.

Conditions

Febrile Neutropenia; Hematological Malignancy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Short treatment

Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.

Group Type: EXPERIMENTAL

Discontinuation of imipenem-cilastatin or meropenem

Intervention Type: DRUG

Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.

Extended treatment

Extended treatment with imipenem-cilastatin or meropenem for at least 6 more days. The treatment with a carbapenem will be continued until patients have been treated for at least 9x24 hours and have been afebrile (tympanic membrane temperature \<38.0°C) for at least five consecutive days or until resolution of neutropenia (ANC \> 0,5 x10\^9/L), whichever comes first.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Discontinuation of imipenem-cilastatin or meropenem

Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.

Intervention Type: DRUG

Other Intervention Names

tienam (imipenem-cilastatin)

Eligibility Criteria

Inclusion Criteria

1. Patients with malignant hematological diseases being treated with cytotoxic chemotherapy or stem cell transplantation;

2. High-risk neutropenia (Absolute neutrophil count (ANC) <0.5x109/L which is expected to last longer than 7 days);

3. Fever (One single measured tympanic membrane temperature of >38.5°C or a temperature of >38.0°C during 2 subsequent measurements separated by at least 2 hours);

4. Age 18 years or older;

5. Written informed consent.

Exclusion Criteria

1. Contraindications to use of imipenem-cilastatin or meropenem such as allergy, previous severe side-effects or previous microbiological cultures with carbapenem-resistant microorganism(s).

2. Corticosteroid use ≥10 mg per day prednisolone or equivalent for more than 3 consecutive day during the previous 7 days.

3. Clinically or microbiologically documented infection.

4. Symptoms of septic shock (systolic blood pressure <90 mm Hg unresponsive to fluid resuscitation and/or oliguria (urine production <500mL/day).

5. Previous enrollment in this study during the same episode of neutropenia.

6. Any critical illness for which Intensive Care Unit treatment is required.

7. Legal incompetency

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

FondsNutsOhra

UNKNOWN

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

Nick de Jonge

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeroen JWM Janssen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Michiel A van Agtmael, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Mark MH Kramer, Prof., MD

Role: STUDY_CHAIR

Amsterdam UMC, location VUmc

Sonja Zweegman, Prof.,MD

Role: STUDY_CHAIR

Amsterdam UMC, location VUmc

Locations

VU university medical center

Amsterdam, , Netherlands

HAGA ziekenhuis

The Hague, , Netherlands

Countries

Netherlands

References

de Jonge NA, Janssen JJWM, Ypma P, Herbers AHE, de Kreuk A, Vasmel W, van den Ouweland JMW, Beeker A, Visser O, Zweegman S, Blijlevens NMA, van Agtmael MA, Sikkens JJ. Mucositis-associated bloodstream infections in adult haematology patients with fever during neutropenia: risk factors and the impact of mucositis severity. Support Care Cancer. 2024 Aug 8;32(9):579. doi: 10.1007/s00520-024-08776-w.

Reference Type: DERIVED

PMID: 39115709 (View on PubMed)

de Jonge NA, Sikkens JJ, Zweegman S, Beeker A, Ypma P, Herbers AH, Vasmel W, de Kreuk A, Coenen JLLM, Lissenberg-Witte B, Kramer MHH, van Agtmael MA, Janssen JJWM. Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial. Lancet Haematol. 2022 Aug;9(8):e563-e572. doi: 10.1016/S2352-3026(22)00145-4. Epub 2022 Jun 9.

Reference Type: DERIVED

PMID: 35691326 (View on PubMed)

Other Identifiers

2014-001546-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL48960.029.14

Identifier Type: REGISTRY

Identifier Source: secondary_id

2000735

Identifier Type: -

Identifier Source: org_study_id