Antimicrobial Revision in Persistent Febrile Neutropenia

Study Overview
=================
Brief Summary
-----------------
Febrile neutropenia is often seen in patients with hematologic malignancies who receive cytotoxic chemotherapy. These patients are usually placed on posaconazole prophylaxis upon starting chemotherapy. If an episode of febrile neutropenia occurs, generally an anti-pseudomonal beta lactam, like cefepime or piperacillin-tazobactam, is initiated. In patients who continue to fever on these agents, the optimal method of antimicrobial revision has yet to be determined.

Detailed Description
-----------------
In this prospective, randomized, open-label, single-center trial, the primary objective is to compare the clinical efficacy of two approaches to antimicrobial revision among patients with persistent febrile neutropenia. Neutropenic patients on cefepime or piperacillin-tazobactam who continue to fever for greater than 96 hours will be randomized to receive either meropenem or micafungin dosed according to local guidelines. The primary outcome is a global success rate including a composite of defervescence within 72 hours of meropenem or micafungin initiation, absence of signs or symptoms of infection, and no modification to antimicrobial regimen after initiation of meropenem or micafungin. The secondary outcomes to be collected include in-hospital mortality or discharge to hospice, hospital length of stay, time to defervescence, days of therapy of meropenem or micafungin, rate of Clostridioides difficile infection on meropenem or micafungin, and cause of any proven breakthrough infection while on meropenem or micafungin.

Official Title
-----------------
Antimicrobial Revision in Patients With Persistent Febrile Neutropenia: A Prospective, Randomized Trial

Conditions
-----------------
Febrile Neutropenia

Intervention / Treatment
-----------------
* Drug: Meropenem
* Drug: Micafungin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥ 18 years of age Diagnosis of hematologic malignancy Receiving chemotherapy as treatment of hematologic malignancy Neutropenia defined as an absolute neutrophil count (ANC) ≤ 500 cells/mm3 or an ANC ≤ 1000 cells/mm3 with a predicted decline to < 500 cells/mm3 within 48 hours Prescribed cefepime or piperacillin-tazobactam as initial treatment for febrile neutropenia Persistent fever for ≥ 96 hours since initiation of cefepime or piperacillin-tazobactam OR recurrent fever that occurs ≥ 96 hours since initiation of cefepime or piperacillin-tazobactam (fever defined as single temperature of ≥ 38.3°C (101°F) or a temperature of ≥ 38°C (100.4°F) on two consecutive measures separated by at least one hour) Receipt of posaconazole as neutropenia prophylaxis for at least 3 calendar days Exclusion Criteria: Clinically or microbiologically confirmed infection at time of enrollment, For example, a positive culture or rapid diagnostic test, positive imaging (X-ray, CT, MRI) or biomarker, such as galactomannan, that is consistent with infection History of infection with organism known to be resistant to meropenem or micafungin Documented allergy to carbapenems or echinocandins Concomitant use of valproic acid Uncontrolled seizure disorder Pregnancy Previous enrollment in this study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, open-label, single center trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Meropenem Arm<br>Patients who meet inclusion criteria may be randomized to meropenem (routine standard of care) dose according to local dosing guidelines to include the use of extended-infusions and adjustments to account for renal function. Duration will be managed by the primary team. | Drug: Meropenem<br>* Carbapenem antibiotic<br>* Other names: Merrem;|
| Active Comparator: Micafungin Arm<br>Patients who meet inclusion criteria may be randomized to micafungin dosed as 150mg intravenously every 24 hours according to local dosing guidelines. Duration will be managed by the primary team. | Drug: Micafungin<br>* Echinocandin antifungal<br>* Other names: Mycamine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Success Rate | Percentage of study candidates who meet all of the following criteria: Defervescence, as defined by a temperature < 38°C (100.4°F) sustained for at least 24 consecutive hours, within 72 hours of meropenem or micafungin initiation Absence of signs or symptoms of infection within 72 hours of meropenem or micafungin initiation including but not limited to hypotension, erythema at catheter sites or cellulitis, positive imaging concerning for infection (e.g., pneumonia, osteomyelitis, abscesses etc.), positive cultures or rapid diagnostic tests, positive biomarkers (e.g. galactomannan), dysuria, hypothermia (≤ 35°C or ≤ 95°F) etc. No modification to antimicrobial regimen after initiation of meropenem or micafungin unless the antibiotic modification is considered de-escalation (e.g. discontinuation of vancomycin) | Hour 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects In-hospital mortality or discharge to hospice | Death during in-hospital admission or discharge from in-hospital admission to hospice care | From hospital admission to death/discharge to hospice, up to 4 days | 
| Hospital length of stay (days) | Number of days admitted to hospital | From hospital admission to discharge, up to 4 days | 
| Time to defervescence (hours) | Time of defervescence defined as the beginning of the 24 consecutive hour afebrile period Time to defervescence defined as the time in hours from the initial documented fever to the beginning of the 24 consecutive hour afebrile period | through study completion, an average of 4 days | 
| Days of therapy of meropenem or micafungin | 1 antibiotic x the number of days administered, any calendar day in which at least one dose is given counts as a full day of therapy - Time in days from initiation to discontinuation of meropenem or micafungin | through study completion, an average of 4 days | 
| Rate of Clostridioides difficile infection on meropenem or micafungin | Percentage of patients who develop Clostridioides difficile infection while on meropenem or micafungin | through study completion, an average of 4 days | 
| Collection of Causes of any proven breakthrough infection while on meropenem or micafungin | Collection of origin of proven breakthrough infection | through study completion, an average of 4 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acute myeloid leukemia, acute lymphocytic leukemia