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

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ClinicalTrials.gov Identifier: NCT02149329
Recruitment Status : Recruiting
First Posted : May 29, 2014
Last Update Posted : March 13, 2019
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
FondsNutsOhra
Information provided by (Responsible Party):
Nick de Jonge, VU University Medical Center

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.

Condition or disease Intervention/treatment Phase
Febrile Neutropenia Hematological Malignancy Drug: Discontinuation of imipenem-cilastatin or meropenem Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 276 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : December 2014
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2019


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 Name: 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.



Primary Outcome Measures :
  1. The percentage of patients with failed treatment [ Time Frame: Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation) ]

    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.


  2. Death/ARDS or Septic shock [ Time Frame: From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization. ]
    The occurrence of death, ARDS/respiratory insufficiency, septic shock (systolic blood pressure <90 mmHg and oliguria <500 mL/day) due to any cause.


Secondary Outcome Measures :
  1. All-cause mortality. [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia ]
  2. Infection-related mortality. [ Time Frame: 1. From 3x24hours of treatment until the end of neutropenia. 2.Within 30 days after recovery of neutropenia ]
  3. The length of hospitalization in days. [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  4. Treatment strategy failure [ Time Frame: after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode ]

    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.

  5. 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 ]
  6. Time to defervescence [ Time Frame: Onset of fever until defervenscence, an expected average of 5 days. ]

    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


  7. Incidence and prevalence of Clostridium difficile infection [ Time Frame: Onset of fever until 30 days after the end of neutropenia. ]
  8. Candida spp. colonization in (surveillance) cultures [ Time Frame: From onset of fever until 30 days after the end of neutropenia. ]
  9. Cost of antimicrobial therapy per admission [ Time Frame: From admission until discharge, with an estimated average of 4 weeks ]
  10. 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. ]
  11. 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. ]
  12. 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. ]
  13. 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. ]
  14. Late treatment failure [ Time Frame: Between 9x24hours and 14x24hours after onset of treatment with a carbapemen. ]
    Defined as primary endpoint.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02149329


Contacts
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Contact: Nick A de Jonge, MD +31(0)204444334 short@vumc.nl
Contact: Jonne J Sikkens, MD +31(0)204442799 j.sikkens@vumc.nl

Locations
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Netherlands
VU university medical center Recruiting
Amsterdam, Netherlands, 1081 HV
Contact: Nick A de Jonge, MD    +31(0)20-444334    short@vumc.nl   
Principal Investigator: Jeroen JWM Janssen, MD, PhD         
Principal Investigator: Michiel A van Agtmael, MD, PhD         
Sub-Investigator: Nick A de Jonge, MD         
Sub-Investigator: Jonne J Sikkens, MD         
HAGA ziekenhuis Not yet recruiting
The Hague, Netherlands
Sponsors and Collaborators
VU University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
FondsNutsOhra
Investigators
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Principal Investigator: Jeroen JWM Janssen, MD, PhD VU University Medical Center
Principal Investigator: Michiel A van Agtmael, MD, PhD VU University Medical Center
Study Chair: Mark MH Kramer, Prof., MD VU University Medical Center
Study Chair: Sonja Zweegman, Prof.,MD VU University Medical Center

Additional Information:
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Responsible Party: Nick de Jonge, MD, VU University Medical Center
ClinicalTrials.gov Identifier: NCT02149329     History of Changes
Other Study ID Numbers: 2000735
2014-001546-25 ( EudraCT Number )
NL48960.029.14 ( Registry Identifier: CCMO (Nationale research committee) file number )
First Posted: May 29, 2014    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019

Keywords provided by Nick de Jonge, VU University Medical Center:
fever
neutropenia
febrile neutropenia
carbapenem
imipenem
meropenem
antibiotic stewardship
hematology
oncology

Additional relevant MeSH terms:
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Neutropenia
Fever
Febrile Neutropenia
Agranulocytosis
Leukopenia
Leukocyte Disorders
Hematologic Diseases
Body Temperature Changes
Signs and Symptoms
Anti-Bacterial Agents
Meropenem
Imipenem
Cilastatin, Imipenem Drug Combination
Antibiotics, Antitubercular
Cilastatin
Anti-Infective Agents
Antitubercular Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action