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-…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the percentage of patients with failed treatment.
Treatment failure is defined as
1. The occurrence of any of the following events after randomization at
3x24hours and before 9x24hours after treatment with a carbapenem:
* A clinically or microbiologically documented carbapenem-sensitive infection;
* 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 if the fever is of infectious etiology, the
recurrence of fever will be considered as failure.
2. 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.
Secondary outcome
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.
Background summary
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. Most protocols advice treatment with very broad-spectrum antibiotics.
These antibiotics are administered for variable durations, often at least 9
days or until fever or neutropenia have resolved. In 56% of cases no infectious
agent can be cultured and the fever remains of unknown origin. Current clinical
guidelines bring about the use of large amounts of antimicrobials, while
clinical evidence regarding optimal length of antibacterial therapy is
lacking. 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. Moreover, it is costly because of longer hospital admissions,
higher antibiotics costs and more possible adverse reactions. Recent,
observational studies have shown that discontinuation of broad-spectrum
antibiotics is safe if no clinical or microbiological infection has been found
after 3 days. However, no randomized clinical trial has yet been performed to
support this data.
We therefore propose a randomized clinical trial investigating whether the
duration of empiric antibacterial therapy in these patients can be safely
reduced to 3x24 hours if no bacterial explanation has been found by that time.
This study compares the safety (non-inferiority) of short treatment (3x24hours)
versus extended treatment (at least 9x24 hours) 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
multiresistent strains of bacteria, costs and hospitalization length in the
future.
Study 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.
Study design
Multicenter open-label randomized non-inferiority clinical trial
Intervention
In patients in the short treatment arm (intervention) the intravenous empirical
antibiotics will be discontinued if no clinical, radiological or
microbiological documented infection has been found that could explain the
fever after 3 days of treatment. After this, the patients will resume their
standard oral antibiotic prophylaxis. In the extended treatment arm (control),
the empirical antibiotics will be continued at least 9 days until fever
resolved at least consecutive 5 days. The treatment in this arm will be up to
14 days, in case of unexplained fever.
Study burden and risks
In patients in the short treatment arm the intravenous empirical antibiotics
will be discontinued if no clinical, radiological or microbiological documented
infection has been found that could explain the fever after 3 days of
treatment. After this, the patients will resume their standard oral antibiotic
prophylaxis. There is a small chance a bacterial infection appears after
discontinuation of intravenous antibiotics. Because neutropenic patients are
more vulnerable to infectious disease there is a bigger chance of complications
of bacteremia and/or sepsis than in immunocompetent patients.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
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.
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001546-25-NL |
| ClinicalTrials.gov | NCT02149329 |
| CCMO | NL48960.029.14 |