Clinical trial NCT05784844: Antimicrobial Revision in Persistent Febrile Neutropenia
Official title: Antimicrobial Revision in Patients With Persistent Febrile Neutropenia: A Prospective, Randomized Trial
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Febrile Neutropenia
Keywords: acute myeloid leukemia
acute lymphocytic leukemia
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2023-03-27
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, open-label, single center trial
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Global Success Rate
timeFrame: Hour 72
Secondary outcomes:
measure: Number of Subjects In-hospital mortality or discharge to hospice
timeFrame: From hospital admission to death/discharge to hospice, up to 4 days
measure: Hospital length of stay (days)
timeFrame: From hospital admission to discharge, up to 4 days
measure: Time to defervescence (hours)
timeFrame: through study completion, an average of 4 days
measure: Days of therapy of meropenem or micafungin
timeFrame: through study completion, an average of 4 days
measure: Rate of Clostridioides difficile infection on meropenem or micafungin
timeFrame: through study completion, an average of 4 days
measure: Collection of Causes of any proven breakthrough infection while on meropenem or micafungin
timeFrame: through study completion, an average of 4 days
Other outcomes:
Locations:
Study officials:
affiliation: Wake Forest University Health Sciences
name: John Williamson, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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