Antimicrobial Revision in Persistent Febrile Neutropenia

NCT05784844 | Withdrawn Phase 4 FDA Drug

• 1 other identifier: IRB00088805
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Febrile Neutropenia

Keywords

acute myeloid leukemia; acute lymphocytic leukemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Number of Subjects In-hospital mortality or discharge to hospice

  From hospital admission to death/discharge to hospice, up to 4 days

• Hospital length of stay (days)

  From hospital admission to discharge, up to 4 days

• Time to defervescence (hours)

  through study completion, an average of 4 days

• Days of therapy of meropenem or micafungin

  through study completion, an average of 4 days

• Rate of Clostridioides difficile infection on meropenem or micafungin

  through study completion, an average of 4 days

Study Arms (2)

Meropenem Arm

ACTIVE COMPARATOR

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

Micafungin Arm

ACTIVE COMPARATOR

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

Interventions

Meropenem DRUG

Carbapenem antibiotic

Also known as: Merrem

Meropenem Arm

Micafungin DRUG

Echinocandin antifungal

Also known as: Mycamine

Micafungin Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead

Related Publications (11)

• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prevention and Treatment of Cancer-Related Infections Version 1.2022. Accessed July 12, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1457

  BACKGROUND

• Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073.

  PMID: 21258094 BACKGROUND

• Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013 Dec;98(12):1826-35. doi: 10.3324/haematol.2013.091025.

  PMID: 24323983 BACKGROUND

• Zimmer AJ, Freifeld AG. Optimal Management of Neutropenic Fever in Patients With Cancer. J Oncol Pract. 2019 Jan;15(1):19-24. doi: 10.1200/JOP.18.00269.

  PMID: 30629902 BACKGROUND

• Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004 Sep 30;351(14):1391-402. doi: 10.1056/NEJMoa040446.

  PMID: 15459300 BACKGROUND

• Oyake T, Kowata S, Murai K, Ito S, Akagi T, Kubo K, Sawada K, Ishida Y. Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial. Eur J Haematol. 2016 Jun;96(6):602-9. doi: 10.1111/ejh.12641. Epub 2015 Aug 26.

  PMID: 26216048 BACKGROUND

• Oztoprak N, Piskin N, Aydemir H, Celebi G, Akduman D, Keskin AS, Gokmen A, Engin H, Ankarali H. Piperacillin-tazobactam versus carbapenem therapy with and without amikacin as empirical treatment of febrile neutropenia in cancer patients: results of an open randomized trial at a university hospital. Jpn J Clin Oncol. 2010 Aug;40(8):761-7. doi: 10.1093/jjco/hyq046. Epub 2010 Apr 28.

  PMID: 20427546 BACKGROUND

• Wang Y, Du Z, Chen Y, Liu Y, Yang Z. Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia. Medicine (Baltimore). 2021 Feb 26;100(8):e24883. doi: 10.1097/MD.0000000000024883.

  PMID: 33663117 BACKGROUND

• Nakane T, Tamura K, Hino M, Tamaki T, Yoshida I, Fukushima T, Tatsumi Y, Nakagawa Y, Hatanaka K, Takahashi T, Akiyama N, Tanimoto M, Ohyashiki K, Urabe A, Masaoka T, Kanamaru A; Japan Febrile Neutropenia Study Group. Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial. J Infect Chemother. 2015 Jan;21(1):16-22. doi: 10.1016/j.jiac.2014.08.026. Epub 2014 Sep 17.

  PMID: 25239059 BACKGROUND

• Nakagawa Y, Suzuki K, Ohta K, Hino M, Ohyashiki K, Kanamaru A, Tamura K, Urabe A, Masaoka T; Japan Febrile Neutropenia Study Group. Prospective randomized study of cefepime, panipenem, or meropenem monotherapy for patients with hematological disorders and febrile neutropenia. J Infect Chemother. 2013 Feb;19(1):103-11. doi: 10.1007/s10156-012-0466-8. Epub 2012 Sep 5.

  PMID: 22948387 BACKGROUND

• Ratliff CM, Beardsley JR, Kennedy L, Ohl C, Johnson JW, Luther VP, William JC. Efficacy of doripenem compared with meropenem for treatment of febrile neutropenia among patients who became febrile while on cefepime or piperacillin-tazobactam. Poster Presented at: Infectious Diseases Society of America Annual Meeting; October 21, 2011; Boston, MA. https://idsa.confex.com/idsa/2011/webprogram/Paper30902.html

  BACKGROUND

Related Links

• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

MeSH Terms

Conditions

Febrile Neutropenia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Meropenem; Micafungin

Condition Hierarchy (Ancestors)

Neutropenia; Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lipopeptides; Lipids; Peptides; Amino Acids, Peptides, and Proteins; Echinocandins; Peptides, Cyclic

Study Officials

• John Williamson, PharmD

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, randomized, open-label, single center trial

Study Record Dates

• First Submitted: March 2, 2023
• First Posted: March 27, 2023
• Study Start: August 1, 2024
• Primary Completion: April 1, 2025
• Study Completion: April 1, 2025
• Last Updated: September 19, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share