A Phase 4 interventional study of Discontinuation of imipenem-cilastatin or meropenem in Febrile Neutropenia and Hematological Malignancy, sponsored by Amsterdam UMC, location VUmc. Completed at 2 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-09-25.
Sponsored by Amsterdam UMC, location VUmc · Phase 4, Interventional, and Treatment
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.
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.
1,464 studies on the registry are indexed under Hematologic Neoplasms; 433 are open to participants now.
This study's enrollment of 276 is above the median of 45 across 1,068 interventional studies indexed under Hematologic Neoplasms.
Browse Hematologic Neoplasms studies →Amsterdam UMC, location VUmc is the lead sponsor of 302 studies on the registry; 84 are open to participants now.
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Exclusion Criteria:
Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.
Drug: Discontinuation of imipenem-cilastatin or meropenem
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.
Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.
Also known as: tienam (imipenem-cilastatin)
The percentage of patients with failed treatment
Treatment failure is defined as the occurrence of one of the following events after 3x24 hours and before 9x24hours after treatment initiation with a carbapenem: -A clinically or microbiologically documented carbapenem-sensitive infection; treatment. Recurrence of fever after previous defervescence (tympanic temperature \<38.0 °C during 24 hours) which is not attributable to administration of a blood product or to a drug reaction. o In case of clinical doubt whether the fever is of infectious etiology, the recurrence of fever will be considered as failure.
Time frame: Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation)
Death/ARDS or Septic shock
The occurrence of death, ARDS/respiratory insufficiency, septic shock (systolic blood pressure \<90 mmHg and oliguria \<500 mL/day) due to any cause.
Time frame: From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization.
All-cause mortality.
Time frame: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia
Infection-related mortality.
Time frame: 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia
The length of hospitalization in days.
Time frame: From admission until discharge, with an estimated average of 4 weeks
Treatment strategy failure
Treatment strategy failure is defined as occurrence of any of the following events after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode: 1. Any clinically or microbiologically documented infection. 2. The recurrence of fever after previous defervescence during neutropenia. 3. Death, septic shock or ARDS/respiratory failure due to any cause 4. Adverse drug-related events due to a carbapenem requiring (temporary) interruption of treatment, including but not exclusively: liver and kidney dysfunction, convulsion and allergic reactions. 5. Unexpected re-admission within 30 days after discharge other than for planned chemotherapy or other elective treatment. 6. Antibiotic or antifungal treatment within 30days after discharge other than standard antibiotic prophylaxis.
Time frame: after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode
The total number of febrile episodes during neutropenia.
Time frame: From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days
Time to defervescence
Fever is defined as 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. Defervescence is defined as three times a tympanic membrane temperature \<37.5 °C with a minimal measurement interval of at least 8 hours
Time frame: Onset of fever until defervenscence, an expected average of 5 days.
Incidence and prevalence of Clostridium difficile infection
Time frame: Onset of fever until 30 days after the end of neutropenia.
Candida spp. colonization in (surveillance) cultures
Time frame: From onset of fever until 30 days after the end of neutropenia.
Cost of antimicrobial therapy per admission
Time frame: From admission until discharge, with an estimated average of 4 weeks
The percentage of patients with a MASCC-score≥21 and treatment failure (defined as in primary endpoint)
Time frame: From the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
The percentage of patients with mucositis and positive blood cultures or short treatment failure.
Time frame: From onset of fever until 30 days after end of neutropenia.
Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)).
Time frame: All previous cultures and cultures performed until 30 days after the end of neutropenia.
The incidence and prevalence of fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia
Time frame: om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
Late treatment failure
Defined as primary endpoint.
Time frame: Between 9x24hours and 14x24hours after onset of treatment with a carbapemen.
This study is completed, as verified in Sep 2019. You cannot join it, but the record below documents what was studied.
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Amsterdam UMC, location VUmc