Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008)

NCT02070757 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 7625A-008CXA-NP-11-04163338MK-7625A-008
• Study Type: interventional
• Target: 726
• Locations: 0 countries
• Sites: N/A

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%.

Conditions

Healthcare-Associated Pneumonia; Ventilator-Associated Pneumonia; Lung Diseases

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28

  To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in stratified adult participants with ventilated nosocomial pneumonia (VNP) (participants with either ventilator-associated bacterial pneumonia \[VABP\] or ventilated hospital-acquired bacterial pneumonia \[HABP\]) based on the difference in all-cause mortality rates in the intent to treat (ITT) population using a non-inferiority margin of 10%. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights.

  Day 28

Secondary Outcomes (12)

• Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population

  7 to 14 days after last dose of study drug (Up to ~Day 30)

• Percentage of Participants With All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28

  Day 28

• Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population

  7 to 14 days after last dose of study drug (Up to ~Day 30)

• 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

  7 to 14 days after last dose of study drug (Up to ~Day 30)

• 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)

  7 to 14 days after last dose of study drug (Up to ~Day 30)

Study Arms (2)

Ceftolozane/tazobactam

EXPERIMENTAL

Participants receive 3000 mg ceftolozane/tazobactam intravenous IV (comprising 2000 mg ceftolozane and 1000 mg tazobactam) every 8 hours for 8-14 days.

Drug: Ceftolozane/tazobactam

Meropenem

ACTIVE COMPARATOR

Participants receive 1000 mg meropenem IV every 8 hours for 8-14 days.

Drug: Meropenem

Interventions

Ceftolozane/tazobactam DRUG

Ceftolozane/tazobactam is an antibacterial consisting of a co-formulation of ceftolozane, a novel antipseudomonal cephalosporin and tazobactam, a well-established beta (β)-lactamase inhibitor (BLI) being developed for the treatment of serious bacterial infections.

Ceftolozane/tazobactam

Meropenem DRUG

Meropenem is a broad spectrum injectable antibiotic widely used to treat serious infections such as ventilator-associated bacterial pneumonia and hospital-acquired bacterial pneumonia.

Also known as: MERREM® IV

Meropenem

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead

Related Publications (10)

• 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.

  PMID: 26096377 RESULT

• Martin-Loeches I, Shorr AF, Wunderink RG, Kollef MH, Timsit JF, Yu B, Huntington JA, Jensen E, Bruno CJ. Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: a subset analysis of the phase 3, randomized, controlled ASPECT-NP trial. Ann Intensive Care. 2023 Feb 11;13(1):8. doi: 10.1186/s13613-022-01084-8.

  PMID: 36773112 DERIVED

• Kollef MH, Timsit JF, Martin-Loeches I, Wunderink RG, Huntington JA, Jensen EH, Yu B, Bruno CJ. Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem. Crit Care. 2022 Dec 1;26(1):373. doi: 10.1186/s13054-022-04192-w.

  PMID: 36457059 DERIVED

• 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.

  PMID: 35781341 DERIVED

• 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.

  PMID: 34600585 DERIVED

• 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.

  PMID: 34380538 DERIVED

• 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.

  PMID: 33318005 DERIVED

• 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.

  PMID: 32996064 DERIVED

• 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.

  PMID: 32988827 DERIVED

• 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.

  PMID: 31563344 DERIVED

MeSH Terms

Conditions

Healthcare-Associated Pneumonia; Pneumonia, Ventilator-Associated; Lung Diseases

Interventions

ceftolozane, tazobactam drug combination; Meropenem

Condition Hierarchy (Ancestors)

Cross Infection; Infections; Pneumonia; Respiratory Tract Infections; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2014
• First Posted: February 25, 2014
• Study Start: September 2, 2014
• Primary Completion: May 15, 2018
• Study Completion: June 6, 2018
• Last Updated: May 5, 2020
• Results First Posted: May 31, 2019

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share