Ceftolozane/Tazobactam Versus Meropenem for Febrile Neutropenia on Patients Colonized With or at Risk for Infection With Extended Spectrum Beta Lactamase - Producing Pathogens

Febrile Neutropenia Clinical Trial

— CLEMENT  

Official title:

Ceftolozane/Tazobactam Versus Meropenem for Febrile Neutropenia on Patients Colonized With or at Risk for Infection With Extended Spectrum Beta Lactamase (ESBL)-Producing Pathogens: a Randomized Double-blind Non-inferiority Trial.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06342115
• Other study ID #: CLEMENT TRIAL
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: June 2024
• Est. completion date: April 2025

Study information

• Verified date: March 2024
• Source: Beneficência Portuguesa de São Paulo
• Contact: Research Department
• Phone: +55 11 3505 5031
• Email: naipe[@]bp.org.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 176
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Febrile Neutropenia
• Fever
• Hyperthermia
• Neutropenia

Intervention

Drug:
• Ceftolozane-Tazobactam
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.
• Meropenem
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.

Locations

Country	Name	City	State
Brazil	A Beneficência Portuguesa de São Paulo	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Beneficência Portuguesa de São Paulo	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

Brazil, 

References & Publications (16)

Bergas A, Albasanz-Puig A, Fernandez-Cruz A, Machado M, Novo A, van Duin D, Garcia-Vidal C, Hakki M, Ruiz-Camps I, Del Pozo JL, Oltolini C, DeVoe C, Drgona L, Gasch O, Mikulska M, Martin-Davila P, Peghin M, Vazquez L, Laporte-Amargos J, Dura-Miralles X, Pallares N, Gonzalez-Barca E, Alvarez-Uria A, Puerta-Alcalde P, Aguilar-Company J, Carmona-Torre F, Clerici TD, Doernberg SB, Petrikova L, Capilla S, Magnasco L, Fortun J, Castaldo N, Carratala J, Gudiol C. Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study). Microbiol Spectr. 2022 Jun 29;10(3):e0229221. doi: 10.1128/spectrum.02292-21. Epub 2022 Apr 27. — View Citation

Bitar I, Salloum T, Merhi G, Hrabak J, Araj GF, Tokajian S. Genomic Characterization of Mutli-Drug Resistant Pseudomonas aeruginosa Clinical Isolates: Evaluation and Determination of Ceftolozane/Tazobactam Activity and Resistance Mechanisms. Front Cell Infect Microbiol. 2022 Jun 15;12:922976. doi: 10.3389/fcimb.2022.922976. eCollection 2022. — View Citation

Camargo JF, Anderson AD, Natori Y, Natori A, Morris MI, Pereira D, Komanduri KV. Early antibiotic use is associated with CMV risk and outcomes following allogeneic hematopoietic cell transplantation. Blood Adv. 2020 Dec 22;4(24):6364-6367. doi: 10.1182/bloodadvances.2020003277. No abstract available. — View Citation

Cattaneo C, Di Blasi R, Skert C, Candoni A, Martino B, Di Renzo N, Delia M, Ballanti S, Marchesi F, Mancini V, Orciuolo E, Cesaro S, Prezioso L, Fanci R, Nadali G, Chierichini A, Facchini L, Picardi M, Malagola M, Orlando V, Trecarichi EM, Tumbarello M, Aversa F, Rossi G, Pagano L; SEIFEM Group. Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria. Ann Hematol. 2018 Sep;97(9):1717-1726. doi: 10.1007/s00277-018-3341-6. Epub 2018 Apr 28. — View Citation

Chaftari AM, Hachem R, Malek AE, Mulanovich VE, Szvalb AD, Jiang Y, Yuan Y, Ali S, Deeba R, Chaftari P, Raad I. A Prospective Randomized Study Comparing Ceftolozane/Tazobactam to Standard of Care in the Management of Neutropenia and Fever in Patients With Hematological Malignancies. Open Forum Infect Dis. 2022 Feb 14;9(6):ofac079. doi: 10.1093/ofid/ofac079. eCollection 2022 Jun. — View Citation

Clerici D, Oltolini C, Greco R, Ripa M, Giglio F, Mastaglio S, Lorentino F, Pavesi F, Farina F, Liberatore C, Castiglion B, Tassan Din C, Bernardi M, Corti C, Peccatori J, Scarpellini P, Ciceri F, Castagna A. The place of ceftazidime/avibactam and ceftolozane/tazobactam for therapy of haematological patients with febrile neutropenia. Int J Antimicrob Agents. 2021 Jun;57(6):106335. doi: 10.1016/j.ijantimicag.2021.106335. Epub 2021 Apr 7. — View Citation

Coates ARM, Hu Y, Holt J, Yeh P. Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction. Expert Rev Anti Infect Ther. 2020 Jan;18(1):5-15. doi: 10.1080/14787210.2020.1705155. — View Citation

Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scime R, Lombardini L, Viscoli C, Rambaldi A; Gruppo Italiano Trapianto Midollo Osseo (GITMO); Gruppo Italiano Trapianto Midollo Osseo GITMO. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant. 2015 Feb;50(2):282-8. doi: 10.1038/bmt.2014.231. Epub 2014 Oct 13. — View Citation

Gomis-Font MA, Cabot G, Lopez-Arguello S, Zamorano L, Juan C, Moya B, Oliver A. Comparative analysis of in vitro dynamics and mechanisms of ceftolozane/tazobactam and imipenem/relebactam resistance development in Pseudomonas aeruginosa XDR high-risk clones. J Antimicrob Chemother. 2022 Mar 31;77(4):957-968. doi: 10.1093/jac/dkab496. — View Citation

Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis. 2016 Feb;3(1):15-21. doi: 10.1177/2049936115621709. — View Citation

Pillinger KE, Bouchard J, Withers ST, Mediwala K, McGee EU, Gibson GM, Bland CM, Bookstaver PB. Inpatient Antibiotic Stewardship Interventions in the Adult Oncology and Hematopoietic Stem Cell Transplant Population: A Review of the Literature. Ann Pharmacother. 2020 Jun;54(6):594-610. doi: 10.1177/1060028019890886. Epub 2019 Nov 26. — View Citation

Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, Yoon M, Collins S, Yuan G, Barie PS, Eckmann C. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis. 2015 May 15;60(10):1462-71. doi: 10.1093/cid/civ097. Epub 2015 Feb 10. — View Citation

Tanaka JS, Young RR, Heston SM, Jenkins K, Spees LP, Sung AD, Corbet K, Thompson JC, Bohannon L, Martin PL, Stokhuyzen A, Vinesett R, Ward DV, Bhattarai SK, Bucci V, Arshad M, Seed PC, Kelly MS. Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 Nov;26(11):2053-2060. doi: 10.1016/j.bbmt.2020.07.011. Epub 2020 Jul 17. — View Citation

Timsit JF, Huntington JA, Wunderink RG, Shime N, Kollef MH, Kivistik U, Novacek M, Rea-Neto A, Martin-Loeches I, Yu B, Jensen EH, Butterton JR, Wolf DJ, Rhee EG, Bruno CJ. Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial. Crit Care. 2021 Aug 11;25(1):290. doi: 10.1186/s13054-021-03694-3. — View Citation

van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation beta-Lactam/beta-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016 Jul 15;63(2):234-41. doi: 10.1093/cid/ciw243. Epub 2016 Apr 20. — View Citation

Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015 May 16;385(9981):1949-56. doi: 10.1016/S0140-6736(14)62220-0. Epub 2015 Apr 27. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population	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.	Within 24 hours after last dose of study drug (Up to ~Day 15)
Secondary	Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population	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.	7 to 14 days after last dose of study drug (Up to ~Day 30)
Secondary	Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population	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.	7 to 14 days after last dose of study drug (Up to ~Day 30)
Secondary	Incidence of microbiologically documented infections and identification of causative organisms in culture	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.	Up to 100 days
Secondary	In-hospital mortality	In-hospital mortality in the first 100 days after allogenic hematopoietic stem cell transplant (HSCT)	Until100 days after allogenic HSCT
Secondary	Occurrence of graft versus host disease (GVHD)	Occurrence of GVHD In the first 100 days after allogenic HSCT	Until100 days after allogenic HSCT
Secondary	Frequency of multidrug resistant-pathogen infections or colonization	Frequency of multidrug resistant-pathogen infections or colonization by weekly rectal swab screening	Until100 days after allogenic HSCT
Secondary	Faecal microbiota analysis	Patients will also undergo faecal microbiota analysis on baseline and at the end of therapy as a surrogate marker for future GVHD.	Up to 100 days
Secondary	Percentage of Participants Who Report 1 or More Adverse Event (AE)	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.	Up to 35 days after last dose of study drug
Secondary	Percentage of Participants With Any Serious Adverse Event (SAE)	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.	Up to 35 days after last dose of study drug (Up to ~Day 50) ]
Secondary	Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE)	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.	Up to 14 days after the first dose of study drug (Up to ~Day 15)