Clinical trial NCT02070757: Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008)
Official title: A Prospective, Randomized, Double-Blind, Multicenter, Phase 3 Study to Assess the Safety and Efficacy of Intravenous Ceftolozane/Tazobactam Compared With Meropenem in Adult Patients With Ventilated Nosocomial Pneumonia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Healthcare-Associated Pneumonia
Ventilator-Associated Pneumonia
Lung Diseases
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2014-02-25
Enrollment: 726
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase 3, multicenter, prospective, randomized study of intravenous (IV) ceftolozane/tazobactam versus IV meropenem in the treatment of adult participants with either ventilator-associated bacterial pneumonia (VABP) or ventilated hospital-acquired bacterial pneumonia (HABP). The primary objective is to demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) based on the difference in Day 28 all-cause mortality rates in the Intent-to-treat (ITT) population using a non-inferiority margin of 10%.


Eligibility criteria: Key Inclusion Criteria:

* Adult participants diagnosed with either VABP or ventilated HABP requiring IV antibiotic therapy;
* Intubated and on mechanical ventilation at the time of randomization;
* New or progressive infiltrate on chest radiography consistent with pneumonia;
* Presence of clinical criteria consistent with a diagnosis of ventilated nosocomial pneumonia.

Key Exclusion Criteria:

* History of moderate or severe hypersensitivity reactions to beta-lactam antibiotics;
* Prior non-study antibiotics for \> 24 hours;
* Gram stain of lower respiratory tract specimen showing only gram positive bacteria;
* Active immunosuppression;
* End-stage renal disease or requirement for dialysis;
* Expected survival \< 72 hours;
* Severe confounding respiratory condition (i.e., chest trauma with paradoxical respiration);
* Known or suspected community-acquired bacterial pneumonia.
* Anticipated concomitant use of any of the following medications during the course of study therapy: valproic acid or divalproex sodium. Anticipated concomitant use of serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin 5-HT1 receptor agonists (triptans), meperidine, or buspirone during the course of linezolid treatment.
* Receipt of a monoamine oxidase inhibitor within 14 days prior to the first dose of study drug or anticipated concomitant use during the course of linezolid therapy.

Primary outcomes:
measure: Percentage of Participants With All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28
timeFrame: Day 28
Secondary outcomes:
measure: Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population
timeFrame: 7 to 14 days after last dose of study drug (Up to ~Day 30)
measure: Percentage of Participants With All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28
timeFrame: Day 28
measure: Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population
timeFrame: 7 to 14 days after last dose of study drug (Up to ~Day 30)
measure: Percentage of Participants With Per-Participant Microbiological Response of Cure or Presumed Cure at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population
timeFrame: 7 to 14 days after last dose of study drug (Up to ~Day 30)
measure: Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline)
timeFrame: 7 to 14 days after last dose of study drug (Up to ~Day 30)
measure: Percentage of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14
timeFrame: Day 14
measure: Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population
timeFrame: Within 24 hours after last dose of study drug (Up to ~Day 15)
measure: Percentage of Participants With Per-Participant Microbiological Response of Cure or Presumed Cure at the End-of-Therapy (EOT) Visit in the Microbiologically Evaluable (ME) Population
timeFrame: Within 24 hours after last dose of study drug (Up to ~Day 15)
measure: Percentage of Participants With Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population
timeFrame: 28 to 35 days after the last dose of study drug (Up to ~Day 50)
measure: Percentage of Participants Who Report 1 or More Adverse Event (AE)
timeFrame: Up to 35 days after last dose of study drug (Up to ~Day 50)
measure: Percentage of Participants With Any Serious Adverse Event (SAE)
timeFrame: Up to 35 days after last dose of study drug (Up to ~Day 50)
measure: Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE)
timeFrame: Up to 14 days after the first dose of study drug (Up to ~Day 15)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016 Jan;56(1):56-66. doi: 10.1002/jcph.566. Epub 2015 Aug 25.
citation: Paterson DL, Bassetti M, Motyl M, Johnson MG, Castanheira M, Jensen EH, Huntington JA, Yu B, Wolf DJ, Bruno CJ. Ceftolozane/tazobactam for hospital-acquired/ventilator-associated bacterial pneumonia due to ESBL-producing Enterobacterales: a subgroup analysis of the ASPECT-NP clinical trial. J Antimicrob Chemother. 2022 Aug 25;77(9):2522-2531. doi: 10.1093/jac/dkac184.
citation: Shorr AF, Bruno CJ, Zhang Z, Jensen E, Gao W, Feng HP, Huntington JA, Yu B, Rhee EG, De Anda C, Basu S, Kollef MH. Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial. Crit Care. 2021 Oct 2;25(1):354. doi: 10.1186/s13054-021-03773-5.
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.
citation: Castanheira M, Johnson MG, Yu B, Huntington JA, Carmelitano P, Bruno C, Rhee EG, Motyl M. Molecular Characterization of Baseline Enterobacterales and Pseudomonas aeruginosa Isolates from a Phase 3 Nosocomial Pneumonia (ASPECT-NP) Clinical Trial. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02461-20. doi: 10.1128/AAC.02461-20. Print 2021 Feb 17.
citation: Lodise T, Yang J, Puzniak LA, Dillon R, Kollef M. Healthcare Resource Utilization of Ceftolozane/Tazobactam Versus Meropenem for Ventilated Nosocomial Pneumonia from the Randomized, Controlled, Double-Blind ASPECT-NP Trial. Infect Dis Ther. 2020 Dec;9(4):953-966. doi: 10.1007/s40121-020-00343-0. Epub 2020 Sep 30.
citation: Huntington JA, Yu B, Li L, Jensen E, Bruno C, Boakye M, Zhang Z, Gao W, Feng HP, Rhee E. Outcomes in Participants with Renal Impairment from a Phase 3 Clinical Trial for Ceftolozane/Tazobactam Treatment of Nosocomial Pneumonia (ASPECT-NP). Antimicrob Agents Chemother. 2020 Nov 17;64(12):e00731-20. doi: 10.1128/AAC.00731-20. Print 2020 Nov 17.
citation: Kollef MH, Novacek M, Kivistik U, Rea-Neto A, Shime N, Martin-Loeches I, Timsit JF, Wunderink RG, Bruno CJ, Huntington JA, Lin G, Yu B, Butterton JR, Rhee EG. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2019 Dec;19(12):1299-1311. doi: 10.1016/S1473-3099(19)30403-7. Epub 2019 Sep 25.