Febrile Neutropenia
Conditions
Keywords
Febrile Neutropenia, Ceftolozane/tazobactam, ESBL, Meropenem
Brief summary
The study proposes a planned, double-blind, non-inferiority clinical trial involving patients with febrile neutropenia and risk of extended-spectrum beta-lactamase (ESBL) infection. The goal is: \- Analyze the efficacy and tolerability of Ceftolozane/tazobactam (CEF/TAZ) compared to the current standard of care (meropenem) in patients with febrile neutropenia and risk of ESBL infection. Patients will be randomly assigned to receive CEF/TAZ or meropenem, with assessment of clinical response, toxicity and microbiological evolution. Stool samples will be collected before, during and after treatment for intestinal microbiota analysis and intestinal microbiome analysis to evaluate possible effects on GVHD. Analysis of the results will include the taxonomic classification of the organisms present. Data will be analyzed to assess non-inferiority in clinical response, incidence of GVHD, antimicrobial resistance and other outcomes.
Interventions
In the intervention arm 3g of ceftolozane-tazobactam are given intravenously every 8 hours. Duration of therapy should follow local guidelines and de-escalation is allowed after identification of causative pathogens.
DRUGMeropenem
The comparator arm consists of 2g of meropenem given intravenously every 8 hours.Duration of therapy should follow local guidelines and de-escalation is allowed after identification of causative pathogens.
Sponsors
Merck Sharp & Dohme LLC
Beneficência Portuguesa de São Paulo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Individuals who present with the onset of febrile neutropenia and at the same time present colonization with an ESBL-producing pathogen (identified through positive routine rectal swabs and/or positive culture of clinical specimen) or risk of infection with an ESBL-producing pathogen (use of 3rd/4th gen cephalosporin or piperacillin/tazobactam for at least 48 hours in the last 30 days).
Exclusion criteria
* Patients known to be colonized with carbapenem-resistant or CEF/TAZ-resistant pathogens * Patients with previous use of carbapenems for at least 48h in the past 30 days are also excluded due to risk of resistance to the study drugs. * Growth of a pathogen resistant to either study drug in a relevant clinical specimen during the intervention phase will be followed by adjustment of therapy according to local protocol, unblinding, and exclusion from the study. * Patients that have received less than 72h of either study drug will also be excluded from the final analyses.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population | Within 24 hours after last dose of study drug (Up to ~Day 15) | To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus meropenem. Clinical response at the EOT visit was defined as cure (complete resolution of fever and symptoms related to Febrile Neutropenia episode), failure (non-resolution, relapse or recurrence of Febrile Neutropenia) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | 7 to 14 days after last dose of study drug (Up to ~Day 30) | To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in participants with Febrile Neutropenia on Patients Colonized With or at Risk for Infection With Extended Spectrum Beta Lactamase - Producing Pathogens at the TOC visit (7 to 14 days after the end-of-therapy \[EOT\] visit) using a non-inferiority margin of 12.5%. Clinical response at the TOC visit was defined as cure (complete resolution of fever and symptoms related to Febrile Neutropenia), failure (non-resolution, relapse or recurrence of Febrile Neutropenia) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate unless the clinical outcome at the EOT visit was failure. |
| Incidence of microbiologically documented infections and identification of causative organisms in culture | Up to 100 days | The incidences of microbiologically documented infections, along with the identification of causative organisms in culture, will be recorded. The measure will be assessed through the counting of cases confirmed by positive cultures. |
| In-hospital mortality | Until100 days after allogenic HSCT | In-hospital mortality in the first 100 days after allogenic hematopoietic stem cell transplant (HSCT) |
| Occurrence of graft versus host disease (GVHD) | Until100 days after allogenic HSCT | Occurrence of GVHD In the first 100 days after allogenic HSCT |
| Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population | 7 to 14 days after last dose of study drug (Up to ~Day 30) | To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus meropenem in the Microbiological Intent-to-Treat (mITT) Population. Clinical response at the EOT visit was defined as cure (complete resolution of fever and symptoms related to Febrile Neutropenia episode), failure (non-resolution, relapse or recurrence of Febrile Neutropenia) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate. |
| Faecal microbiota analysis | Up to 100 days | Patients will also undergo faecal microbiota analysis on baseline and at the end of therapy as a surrogate marker for future GVHD. |
| Percentage of Participants Who Report 1 or More Adverse Event (AE) | Up to 35 days after last dose of study drug | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
| Percentage of Participants With Any Serious Adverse Event (SAE) | Up to 35 days after last dose of study drug (Up to ~Day 50) ] | A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. |
| Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE) | Up to 14 days after the first dose of study drug (Up to ~Day 15) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
| Frequency of multidrug resistant-pathogen infections or colonization | Until100 days after allogenic HSCT | Frequency of multidrug resistant-pathogen infections or colonization by weekly rectal swab screening |
Countries
Brazil
Contacts
Primary ContactResearch Department
Backup ContactBianca Verboski
Outcome results
None listed