Antimicrobial Revision in Persistent Febrile Neutropenia

Sponsor

Wake Forest University Health Sciences (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05784844

Collaborator

(none)

120

Enrollment

Location

Arms

19.1

Anticipated Duration (Months)

6.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Febrile Neutropenia	Drug: Meropenem Drug: Micafungin	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, randomized, open-label, single center trialProspective, randomized, open-label, single center trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Meropenem Arm 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 Carbapenem antibiotic Other Names: Merrem
Active Comparator: Micafungin Arm 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 Echinocandin antifungal Other Names: Mycamine

Arm

Intervention/Treatment

Active Comparator: Meropenem Arm

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

Carbapenem antibiotic

Other Names:

Merrem

Active Comparator: Micafungin Arm

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

Echinocandin antifungal

Other Names:

Mycamine

Outcome Measures

Primary Outcome Measures

Global Success Rate [Hour 72]
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)

Secondary Outcome Measures

Number of Subjects In-hospital mortality or discharge to hospice [From hospital admission to death/discharge to hospice, up to 4 days]
Death during in-hospital admission or discharge from in-hospital admission to hospice care
Hospital length of stay (days) [From hospital admission to discharge, up to 4 days]
Number of days admitted to hospital
Time to defervescence (hours) [through study completion, an average of 4 days]
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
Days of therapy of meropenem or micafungin [through study completion, an average of 4 days]
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
Rate of Clostridioides difficile infection on meropenem or micafungin [through study completion, an average of 4 days]
Percentage of patients who develop Clostridioides difficile infection while on meropenem or micafungin
Collection of Causes of any proven breakthrough infection while on meropenem or micafungin [through study completion, an average of 4 days]
Collection of origin of proven breakthrough infection

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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