Clinical trial NCT02149329: Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With FUO
Official title: Short Versus Extended Antibiotic Treatment With a Carbapenem for High-risk Febrile Neutropenia in Hematology Patients With Fever of Unknown Origin: a Randomized Multicenter Non-inferiority Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Febrile Neutropenia
Hematological Malignancy
Keywords: fever
neutropenia
febrile neutropenia
carbapenem
imipenem
meropenem
antibiotic stewardship
hematology
oncology
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: FondsNutsOhra
First posted: 2014-05-29
Enrollment: 276
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: The percentage of patients with failed treatment
timeFrame: Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation)
measure: Death/ARDS or Septic shock
timeFrame: From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization.
Secondary outcomes:
measure: All-cause mortality.
timeFrame: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia
measure: Infection-related mortality.
timeFrame: 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia
measure: The length of hospitalization in days.
timeFrame: From admission until discharge, with an estimated average of 4 weeks
measure: Treatment strategy failure
timeFrame: after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode
measure: The total number of febrile episodes during neutropenia.
timeFrame: From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days
measure: Time to defervescence
timeFrame: Onset of fever until defervenscence, an expected average of 5 days.
measure: Incidence and prevalence of Clostridium difficile infection
timeFrame: Onset of fever until 30 days after the end of neutropenia.
measure: Candida spp. colonization in (surveillance) cultures
timeFrame: From onset of fever until 30 days after the end of neutropenia.
measure: Cost of antimicrobial therapy per admission
timeFrame: From admission until discharge, with an estimated average of 4 weeks
measure: The percentage of patients with a MASCC-score≥21 and treatment failure (defined as in primary endpoint)
timeFrame: From the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
measure: The percentage of patients with mucositis and positive blood cultures or short treatment failure.
timeFrame: From onset of fever until 30 days after end of neutropenia.
measure: Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)).
timeFrame: All previous cultures and cultures performed until 30 days after the end of neutropenia.
measure: The incidence and prevalence of fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia
timeFrame: om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
measure: Late treatment failure
timeFrame: Between 9x24hours and 14x24hours after onset of treatment with a carbapemen.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: VU university medical center
city: The Hague
country: Netherlands
facility: HAGA ziekenhuis
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Jeroen JWM Janssen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Michiel A van Agtmael, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Mark MH Kramer, Prof., MD
role: STUDY_CHAIR
affiliation: Amsterdam UMC, location VUmc
name: Sonja Zweegman, Prof.,MD
role: STUDY_CHAIR
References:
citation: 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.