Short versus extended antibiotic treatment for fever during low white blood cell counts in hematology patients with fever of unknown origin.

• Register: EUCTR
• Last refreshed on: 7 September 2020
• Main ID: EUCTR2014-001546-25-NL
• Date of registration: 19/11/2014
• Prospective Registration: Yes
• Primary sponsor: VU University Medical Center
• Public title: Short versus extended antibiotic treatment for fever during low white blood cell counts in hematology patients with fever of unknown origin.
• Scientific 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 open-label non-inferiority trial. - SHORT-trial
• Date of first enrolment: 06/01/2015
• Target sample size: 240
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001546-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Extended antibiotic treatment with the same IMP Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Netherlands

Contacts

• Name: Clinical Trials Information
• Affiliation: VU University Medical Center

• Name: Clinical Trials Information
• Affiliation: VU University Medical Center

Key inclusion & exclusion criteria

Inclusion criteria:
1.Patients with malignant hematological diseases being treated with cytotoxic chemotherapy or stem cell transplantation;
2.High-risk neutropenia;
3.Fever;
4.Age 18 years or older;
5.Written informed consent.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 220
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

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 days 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



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Febrile neutropenia
MedDRA version: 19.1 Level: PT Classification code 10063581 Term: Stem cell transplant System Organ Class: 10042613 - Surgical and medical procedures
MedDRA version: 19.1 Level: LLT Classification code 10002969 Term: Aplastic anemia System Organ Class: 10005329 - Blood and lymphatic system disorders
MedDRA version: 19.1 Level: LLT Classification code 10003999 Term: Bacteremia System Organ Class: 10021881 - Infections and infestations
MedDRA version: 19.1 Level: LLT Classification code 10007810 Term: Catheter related infection System Organ Class: 10021881 - Infections and infestations
MedDRA version: 19.1 Level: LLT Classification code 10028566 Term: Myeloma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 19.1 Level: LLT Classification code 10062957 Term: Catheter bacteraemia System Organ Class: 10021881 - Infections and infestations
MedDRA version: 19.1 Level: PT Classification code 10025310 Term: Lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 19.1 Level: LLT Classification code 10024329 Term: Leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 19.1 Level: PT Classification code 10056520 Term: Catheter site infection System Organ Class: 10021881 - Infections and infestations
MedDRA version: 19.1 Level: PT Classification code 10016288 Term: Febrile neutropenia System Organ Class: 10005329 - Blood and lymphatic system disorders

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Trade Name: imipenem-cilastatine
Product Name: imipenem / cilastatine
Product Code: RVG 101614
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: IMIPENEM
CAS Number: 64221-86-9
Concentration unit: g gram(s)
Concentration type: up to
Concentration number: 1-
INN or Proposed INN: Cilastatin
CAS Number: 82009-34-5
Other descriptive name: CILASTATIN
Concentration unit: g gram(s)
Concentration type: up to
Concentration number: 1-

Trade Name: Meropenem
Product Name: meropenem
Product Code: RVG 105155
Pharmaceutical Form: Infusion
INN or Proposed INN: Meropenem
CAS Number: 96036-03-2
Other descriptive name: MEROPENEM
Concentration unit: g gram(s)
Concentration type: up to
Concentration number: 3-

Primary Outcome(s)

Primary end point(s): The primary endpoint is the percentage of patients with failed treatment. Treatment failure is defined as the occurrence of any of the following events after 3x24hours of treatment with a carbapenem: -A clinically or microbiologically documented carbapenem-sensitive infection during treatment or within 7 days after discontinuation of carbapenem treatment. -Recurrence of fever after previous defervescence (tympanic temperature <38.0 °C during 24 hours) during treatment or within 7 days after discontinuation of carbapenem which is not attributable to administration of a blood product or to a drug reaction. o In case of clinical doubt if the fever is of infectious etiology, the recurrence of fever will be considered as failure. -The occurrence of death, ARDS/respiratory insufficiency, septic shock (systolic blood pressure <90mmHg and oliguria <500mL/day) due to any cause until the end of neutropenia. NOTE: The occurrence of fungal, viral or carbapenem-resistant (inherent or acquired) bacterial infections will not be considered as treatment failure. Examples of inherent carbapenem resistant bacteria include: E. faecium, commensal skin flora (ie. CNS), MRSA, Legionella spp., S. maltophilia, Bulkholderia cepacia, Chlamydia spp, Chlamydophilia spp., Mycoplasma spp., Ureoplasma urealyticum.

Main Objective: To assess if short antibiotic treatment (3x24 hours) with an anti-pseudomonal carbapenem (imipenem-cilastatin or meropenem) is safe (NON-INFERIOR) with regard to treatment failure in comparison with extended treatment (at least 9x24hours) of high-risk febrile neutropenia in hematology patients receiving standard antimicrobial prophylaxis.

Secondary Objective: To assess if short antibiotic treatment (3x24 hours) with an anti-pseudomonal carbapenem (imipenem-cilastatin or meropenem) is NON-INFERIOR in comparison with extended treatment (at least 9x24hours) of high-risk febrile neutropenia in hematology patients receiving standard antimicrobial prophylaxis with regard to:
-Patient survival
-Fever characteristics
-Economic aspects
-Antimicrobial use and its complications.
-MASCC-score in relation to treatment failure
-Mucositis as a risk factor for bacteremia (positive blood cultures) and treatment failure.

Timepoint(s) of evaluation of this end point: At day 9 after onset of treatment with a carbapenem

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1-4,7-14: 30 days after the end of the neutropenic episode
5,6: End of the neutropenic episode
15: After the final patient has conpleted the end of the study (expected January 2017)

Secondary end point(s): 1) Treatment failure (as defined by primary endpoint) from 9x24hours until 14x24 hours after onset of fever. 2) All-cause mortality from 3x24hours of treatment until the end of neutropenia. 3) Infection related mortality from 3x24hours of treatment until the end of neutropenia. 4) All-cause mortality within 30 days after recovery of neutropenia. 5) Infection related mortality within 30 days after recovery of neutropenia. 6) Treatment strategy failure, defined as the necessity to modify the antibacterial regimen after randomization other than for antibacterial prophylaxis. 7) The incidence and prevalence of all clinical or microbiological documented infections. fungal, viral, or carbapenem-resistant (inherent/acquired) infections until the end of neutropenia. 8) The incidence and prevalence of Clostridium difficile infections until 30 days after the end of neutropenia. 9) The length of hospitalization in days. 10) Time to defervescence. 11) The total number of febrile episodes during neutropenia. 12) Bacterial resistance in blood cultures and surveillance cultures (including minimal inhibitory concentrations (MIC)). 13) Candida spp. colonization in (surveillance) cultures; 14) Cost of antimicrobial therapy per admission 15) The percentage of patients with a MASCC-score =21 and treatment failure (defined as in primary endpoint) 16) The percentage of patients with mucositis and positive blood cultures or antibiotic treatment failure.

Secondary ID(s)

NL48960.029.14

NTR3675

NCT02149329

Source(s) of Monetary Support

Fonds Nuts Ohra

ZonMW

Ethics review

Status: Approved
Approval date: 29/10/2014
Contact: