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

NCT02149329 | Completed Phase 4 DMC

• 3 other identifiers: 20007352014-001546-25NL48960.029.14
• Study Type: interventional
• Target: 276
• Locations: 1 country
• Sites: 2

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.

Conditions

Febrile Neutropenia; Hematological Malignancy

Keywords

fever; neutropenia; febrile neutropenia; carbapenem; imipenem; meropenem; antibiotic stewardship; hematology; oncology

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• 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

  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

Study Arms (2)

Short treatment

EXPERIMENTAL

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

Drug: Discontinuation of imipenem-cilastatin or meropenem

Extended treatment

NO INTERVENTION

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.

Interventions

Discontinuation of imipenem-cilastatin or meropenem DRUG

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

Also known as: tienam (imipenem-cilastatin)

Short treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• FondsNutsOhra: collaborator

Study Sites (2)

VU university medical center

Amsterdam, 1081 HV, Netherlands

Location

HAGA ziekenhuis

The Hague, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 39115709 DERIVED

• 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.

  PMID: 35691326 DERIVED

MeSH Terms

Conditions

Febrile Neutropenia; Hematologic Neoplasms; Fever; Neutropenia; Neoplasms

Interventions

Meropenem; Cilastatin, Imipenem Drug Combination

Condition Hierarchy (Ancestors)

Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Neoplasms by Site; Body Temperature Changes; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Imipenem; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Jeroen JWM Janssen, MD, PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

• Michiel A van Agtmael, MD, PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

• Mark MH Kramer, Prof., MD

  Amsterdam UMC, location VUmc

  STUDY CHAIR

• Sonja Zweegman, Prof.,MD

  Amsterdam UMC, location VUmc

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: May 19, 2014
• First Posted: May 29, 2014
• Study Start: December 1, 2014
• Primary Completion: August 5, 2019
• Study Completion: August 5, 2019
• Last Updated: September 25, 2019

Record last verified: 2019-09

Locations

NL (2)