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

• ClinicalTrials.gov Identifier: NCT02070757
• Recruitment Status: Completed
• First Posted: February 25, 2014
• Results First Posted: May 31, 2019
• Last Update Posted: May 5, 2020
• Sponsor: Cubist Pharmaceuticals LLC
• Information provided by (Responsible Party): Cubist Pharmaceuticals LLC

Study Description

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%.

Condition or disease	Intervention/treatment	Phase
Healthcare-Associated Pneumonia; Ventilator-Associated Pneumonia; Lung Diseases	Drug: Ceftolozane/tazobactam; Drug: Meropenem	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 726 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 2, 2014
• Actual Primary Completion Date: May 15, 2018
• Actual Study Completion Date: June 6, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ceftolozane/tazobactam; 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; 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.
Active Comparator: Meropenem; Participants receive 1000 mg meropenem IV every 8 hours for 8-14 days.	Drug: Meropenem; Meropenem is a broad spectrum injectable antibiotic widely used to treat serious infections such as ventilator-associated bacterial pneumonia and hospital-acquired bacterial pneumonia.; Other Name: MERREM® IV

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28 [ Time Frame: 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.

Secondary Outcome Measures :

1. Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population [ Time Frame: 7 to 14 days after last dose of study drug (Up to ~Day 30) ]
   To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) 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 with no new signs of VNP), failure (progression, relapse or recurrence of VNP) 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. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights.
2. Percentage of Participants With All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28 [ Time Frame: Day 28 ]
   To compare the all cause mortality rates of participants in the ceftolozane/tazobactam versus meropenem arms in microbiological intent-to-treat (mITT) population.
3. Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population [ Time Frame: 7 to 14 days after last dose of study drug (Up to ~Day 30) ]
   To compare the clinical response rates of ceftolozane/tazobactam versus meropenem in adult participants with VNP (participants with either ventilator-associated bacterial pneumonia [VABP] or ventilated hospital-acquired bacterial pneumonia [HABP]) at the TOC visit in the CE population. Clinical response at the TOC visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) 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. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.
4. 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 [ Time Frame: 7 to 14 days after last dose of study drug (Up to ~Day 30) ]
   To compare the per-participant microbiological response rates of ceftolozane/tazobactam versus meropenem at the TOC visit in the microbiologically evaluable (ME) population. The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the TOC visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.
5. 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) [ Time Frame: 7 to 14 days after last dose of study drug (Up to ~Day 30) ]
   To compare the percentage of participants with a microbiological outcome of eradication or presumed eradication, by pathogen. The microbiological outcome was classified as "eradication", "presumed eradication", "persistence", 'presumed persistence", "indeterminate" or "recurrence." "Eradication" was defined as a ≥1- log reduction in bacterial burden of the original baseline LRT pathogen AND a per pathogen count of ≤10^4 colony-forming unit (CFU)/mL for endotracheal aspirate (ETA) or sputum specimens, ≤10^3 CFU/mL for a bronchoalveolar lavage (BAL) specimen, or ≤10^2 CFU/mL for a protected brush specimen (PBS) from a follow-up LRT culture. Presumed eradication was defined as an absence of material to culture (e.g. inability to obtain a culture in an extubated patient) in a patient deemed a clinical cure.
6. Percentage of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14 [ Time Frame: Day 14 ]
   To compare the all cause mortality rates of participants (ceftolozane/tazobactam versus meropenem arms). Participants whose Day 14 mortality outcomes are missing or unknown are analysed as deceased.
7. Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population [ Time Frame: Within 24 hours after last dose of study drug (Up to ~Day 15) ]
   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 with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate.
8. 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 [ Time Frame: Within 24 hours after last dose of study drug (Up to ~Day 15) ]
   To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the EOT visit. The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the EOT visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.
9. Percentage of Participants With Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population [ Time Frame: 28 to 35 days after the last dose of study drug (Up to ~Day 50) ]
   To compare the clinical response rates at the Late Follow-up (LFU) visit for ceftolozane/tazobactam versus meropenem in the CE population. Clinical response at the LFU visit will be classified as sustained cure, relapse, or indeterminate only in participants deemed a clinical cure at the TOC visit. A favorable clinical response is "sustained clinical cure."
10. Percentage of Participants Who Report 1 or More Adverse Event (AE) [ Time Frame: Up to 35 days after last dose of study drug (Up to ~Day 50) ]
    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.
11. Percentage of Participants With Any Serious Adverse Event (SAE) [ Time Frame: Up to 35 days after last dose of study drug (Up to ~Day 50) ]
    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.
12. Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE) [ Time Frame: Up to 14 days after the first dose of study drug (Up to ~Day 15) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Sponsors and Collaborators

Cubist Pharmaceuticals LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Cubist Pharmaceuticals LLC:

Study Protocol and Statistical Analysis Plan  [PDF] June 28, 2018

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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.

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.

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.

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.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT02070757
• Other Study ID Numbers: 7625A-008; CXA-NP-11-04 ( Other Identifier: Cubist Protocol Number ); 163338 ( Registry Identifier: JAPIC-CTI ); MK-7625A-008 ( Other Identifier: Merck Protocol Number )
• First Posted: February 25, 2014
• Results First Posted: May 31, 2019
• Last Update Posted: May 5, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pneumonia; Pneumonia, Ventilator-Associated; Healthcare-Associated Pneumonia; Lung Diseases; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Cross Infection; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Meropenem; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination; Anti-Bacterial Agents; Anti-Infective Agents; beta-Lactamase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Urinary; Renal Agents