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

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.

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.

Study Overview

• Status: Completed
• Conditions: Febrile Neutropenia; Hematological Malignancy
• Intervention / Treatment: Drug: Discontinuation of imipenem-cilastatin or meropenem

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.

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • The Hague, Netherlands
    • Haga ziekenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Short treatment; Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.	Drug: Discontinuation of imipenem-cilastatin or meropenem; Discontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.; Other Names: tienam (imipenem-cilastatin)
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality.		1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia
Infection-related mortality.		1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia
The length of hospitalization in days.		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: 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
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
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.
Incidence and prevalence of Clostridium difficile infection		Onset of fever until 30 days after the end of neutropenia.
Candida spp. colonization in (surveillance) cultures		From onset of fever until 30 days after the end of neutropenia.
Cost of antimicrobial therapy per admission		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)		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.		From onset of fever until 30 days after end of neutropenia.
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.
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.
Late treatment failure	Defined as primary endpoint.	Between 9x24hours and 14x24hours after onset of treatment with a carbapemen.

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; FondsNutsOhra
• Investigators: Principal Investigator: Jeroen JWM Janssen, MD, PhD, Amsterdam UMC, location VUmc; Principal Investigator: Michiel A van Agtmael, MD, PhD, Amsterdam UMC, location VUmc; Study Chair: Mark MH Kramer, Prof., MD, Amsterdam UMC, location VUmc; Study Chair: Sonja Zweegman, Prof.,MD, Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• 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. Erratum In: Lancet Haematol. 2022 Sep;9(9):e641.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): August 5, 2019
• Study Completion (Actual): August 5, 2019

Study Registration Dates

• First Submitted: May 19, 2014
• First Submitted That Met QC Criteria: May 23, 2014
• First Posted (Estimate): May 29, 2014

Study Record Updates

• Last Update Posted (Actual): September 25, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: oncology; fever; neutropenia; meropenem; antibiotic stewardship; febrile neutropenia; hematology; imipenem; carbapenem
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Hematologic Neoplasms; Neutropenia; Hyperthermia; Fever; Febrile Neutropenia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Imipenem; Cilastatin; Meropenem; Cilastatin, Imipenem Drug Combination
• Other Study ID Numbers: 2000735; 2014-001546-25 (EudraCT Number); NL48960.029.14 (Registry Identifier: CCMO (Nationale research committee) file number)