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

Febrile Neutropenia Clinical Trial

— SHORT  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02149329
• Other study ID #: 2000735
• Secondary ID: 2014-001546-25NL
• Status: Completed
• Phase: Phase 4
• Start date: December 2014
• Est. completion date: August 5, 2019

Study information

• Verified date: September 2019
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 276
• Est. completion date: August 5, 2019
• Est. primary completion date: August 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Febrile Neutropenia
• Fever
• Hematological Malignancy
• Neutropenia

Intervention

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

Locations

Country	Name	City	State
Netherlands	VU university medical center	Amsterdam
Netherlands	HAGA ziekenhuis	The Hague

Sponsors (3)

Lead Sponsor	Collaborator
VU University Medical Center	FondsNutsOhra, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation)
Primary	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.	From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization.
Secondary	All-cause mortality.		1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia
Secondary	Infection-related mortality.		1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia
Secondary	The length of hospitalization in days.		From admission until discharge, with an estimated average of 4 weeks
Secondary	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: Any clinically or microbiologically documented infection.; The recurrence of fever after previous defervescence during neutropenia.; Death, septic shock or ARDS/respiratory failure due to any cause; 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.; Unexpected re-admission within 30 days after discharge other than for planned chemotherapy or other elective treatment.; Antibiotic or antifungal treatment within 30days after discharge other than standard antibiotic prophylaxis.	after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode
Secondary	The total number of febrile episodes during neutropenia.		From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days
Secondary	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	Onset of fever until defervenscence, an expected average of 5 days.
Secondary	Incidence and prevalence of Clostridium difficile infection		Onset of fever until 30 days after the end of neutropenia.
Secondary	Candida spp. colonization in (surveillance) cultures		From onset of fever until 30 days after the end of neutropenia.
Secondary	Cost of antimicrobial therapy per admission		From admission until discharge, with an estimated average of 4 weeks
Secondary	The percentage of patients with a MASCC-score=21 and treatment failure (defined as in primary endpoint)		From the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
Secondary	The percentage of patients with mucositis and positive blood cultures or short treatment failure.		From onset of fever until 30 days after end of neutropenia.
Secondary	Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)).		All previous cultures and cultures performed until 30 days after the end of neutropenia.
Secondary	The incidence and prevalence of fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia		om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.
Secondary	Late treatment failure	Defined as primary endpoint.	Between 9x24hours and 14x24hours after onset of treatment with a carbapemen.

External Links

•   Trial website