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%.
Brief Title
Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008)
Categories
Completion Date
Completion Date Type
Actual
Conditions
Healthcare-Associated Pneumonia
Ventilator-Associated Pneumonia
Lung Diseases
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.
* 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.
Inclusion Criteria
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.
* 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.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02070757
Org Class
Industry
Org Full Name
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Org Study Id
7625A-008
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
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.
Outcome Measure
Percentage of Participants With All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28
Outcome Time Frame
Day 28
Secondary Ids
Secondary Id
CXA-NP-11-04
Secondary Id
163338
Secondary Id
MK-7625A-008
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
7 to 14 days after last dose of study drug (Up to ~Day 30)
Outcome Measure
Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population
Outcome Description
To compare the all cause mortality rates of participants in the ceftolozane/tazobactam versus meropenem arms in microbiological intent-to-treat (mITT) population.
Outcome Time Frame
Day 28
Outcome Measure
Percentage of Participants With All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28
Outcome Description
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.
Outcome Time Frame
7 to 14 days after last dose of study drug (Up to ~Day 30)
Outcome Measure
Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population
Outcome Description
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.
Outcome Time Frame
7 to 14 days after last dose of study drug (Up to ~Day 30)
Outcome 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
Outcome Description
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.
Outcome Time Frame
7 to 14 days after last dose of study drug (Up to ~Day 30)
Outcome 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)
Outcome Description
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.
Outcome Time Frame
Day 14
Outcome Measure
Percentage of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14
Outcome Description
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.
Outcome Time Frame
Within 24 hours after last dose of study drug (Up to ~Day 15)
Outcome Measure
Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population
Outcome Description
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.
Outcome Time Frame
Within 24 hours after last dose of study drug (Up to ~Day 15)
Outcome 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
Outcome Description
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."
Outcome Time Frame
28 to 35 days after the last dose of study drug (Up to ~Day 50)
Outcome Measure
Percentage of Participants With Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population
Outcome Description
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.
Outcome Time Frame
Up to 35 days after last dose of study drug (Up to ~Day 50)
Outcome Measure
Percentage of Participants Who Report 1 or More Adverse Event (AE)
Outcome Description
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.
Outcome Time Frame
Up to 35 days after last dose of study drug (Up to ~Day 50)
Outcome Measure
Percentage of Participants With Any Serious Adverse Event (SAE)
Outcome Description
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.
Outcome Time Frame
Up to 14 days after the first dose of study drug (Up to ~Day 15)
Outcome Measure
Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Paul Riska
Investigator Email
priska@montefiore.org
Investigator Phone
718-020-6494