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Febrile NeutropeniaPhase 4SHORTNCT02149329

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

A Phase 4 study testing Discontinuation of imipenem-cilastatin or meropenem in people with Febrile Neutropenia and Hematological Malignancy, run by Amsterdam UMC, location VUmc at 2 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Febrile Neutropenia, Hematological Malignancy
What is being tested?
Discontinuation of imipenem-cilastatin or meropenem
Could I receive a placebo?
No, everyone receives an active treatment
How many people
276 participants
Where
2 sitesNetherlands
Study dates
Dec 2014to 5 Aug 2019
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with malignant hematological diseases being treated with cytotoxic chemotherapy or stem cell transplantation;
  • High-risk neutropenia (Absolute neutrophil count (ANC) <0.5x109/L which is expected to last longer than 7 days);
  • 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);
  • Age 18 years or older;
  • Written informed consent.

Who cannot join

  • Contraindications to use of imipenem-cilastatin or meropenem such as allergy, previous severe side-effects or previous microbiological cultures with carbapenem-resistant microorganism(s).
  • Corticosteroid use ≥10 mg per day prednisolone or equivalent for more than 3 consecutive day during the previous 7 days.
  • Clinically or microbiologically documented infection.
  • Symptoms of septic shock (systolic blood pressure <90 mm Hg unresponsive to fluid resuscitation and/or oliguria (urine production <500mL/day).
  • Previous enrollment in this study during the same episode of neutropenia.
  • Any critical illness for which Intensive Care Unit treatment is required.
  • Legal incompetency

Trial locations and contacts

2 sites in 1 country.

Netherlands2 sites
  • VU university medical center

    Amsterdam, 1081 HV

  • HAGA ziekenhuis

    The Hague

Other trials in Netherlands

About this study

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.

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.

Read the 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.

Being tested
Discontinuation of imipenem-cilastatin or meropenem
Keywords
fever, neutropenia, febrile neutropenia, carbapenem, imipenem, meropenem, antibiotic stewardship, hematology, oncology
Medical subject headings
Febrile Neutropenia, Hematologic Neoplasms, Fever, Neutropenia, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Discontinuation of imipenem-cilastatin or meropenemDrug

    Also called tienam (imipenem-cilastatin)

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

Study groups in NCT02149329
Study groupRoleWhat they receive
Short treatmentExperimentalDiscontinuation of imipenem-cilastatin or meropenem after 3x24 hours irrespective of presence of fever.
Receives: Drug: Discontinuation of imipenem-cilastatin or meropenem
Extended treatmentNo interventionExtended 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 being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    • In case of clinical doubt whether the fever is of infectious etiology, the recurrence of fever will be considered as failure.

    Measured: Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation)

  2. 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.

    Measured: From randomization until the end of neutropenia (neutrophil count >=0.5x10e9/L) up to 6 months after randomization.

Secondary outcomes (14)
  1. All-cause mortality.

    Measured: 1. From 3x24hours of treatment until the end of neutropenia. 2. Within 30 days after the end of neutropenia

  2. Infection-related mortality.

    Measured: 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.

    Measured: From admission until discharge, with an estimated average of 4 weeks

  4. 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.

    Measured: after 3x24hours of treatment with a carbapenem and until the end of the neutropenic episode

  5. The total number of febrile episodes during neutropenia.

    Measured: From the start of neutropenia (ANC<0.5x10^9) until the end of neutropenia, an expected average of 21 days

  6. 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

    Measured: Onset of fever until defervenscence, an expected average of 5 days.

  7. Incidence and prevalence of Clostridium difficile infection

    Measured: Onset of fever until 30 days after the end of neutropenia.

  8. Candida spp. colonization in (surveillance) cultures

    Measured: From onset of fever until 30 days after the end of neutropenia.

  9. Cost of antimicrobial therapy per admission

    Measured: 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)

    Measured: 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.

    Measured: 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)).

    Measured: 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

    Measured: om the onset of fever until the end of the neutropenic episode, with an estimated average of 21 days.

  14. Late treatment failure

    Defined as primary endpoint.

    Measured: Between 9x24hours and 14x24hours after onset of treatment with a carbapemen.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 May 2014 (estimated)
  2. Study startDec 2014
  3. Primary completion5 Aug 2019
  4. Study completion5 Aug 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
276 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02149329
Sponsor's protocol ID
2000735
Other IDs
2014-001546-25, NL48960.029.14, 2014
Acronym
SHORT
Status last verified
Sep 2019
First submitted
19 May 2014
Last updated
25 Sep 2019
Results posted
No
Data monitoring committee
Yes

Publications

  • de Jonge NA, Janssen JJWM, Ypma P, Herbers AHE, de Kreuk A, Vasmel W, van den Ouweland JMW, Beeker A, Visser O, Zweegman S, Blijlevens NMA, van Agtmael MA, Sikkens JJ. Mucositis-associated bloodstream infections in adult haematology patients with fever during neutropenia: risk factors and the impact of mucositis severity. Support Care Cancer. 2024 Aug 8;32(9):579. doi: 10.1007/s00520-024-08776-w.

    PubMed 39115709
  • 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.

    PubMed 35691326

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Discontinuation of imipenem-cilastatin or meropenem in people with Febrile Neutropenia and Hematological Malignancy, run by Amsterdam UMC, location VUmc at 2 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The percentage of patients with failed treatment (time frame: Between randomization (at 3x24 hours) and before 9x24hours after treatment initiation)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02149329, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2019.

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