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

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.

Time frame: Day 28

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

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.

Time frame: Up to 14 days after the first dose of study drug (Up to ~Day 15)

Population: All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.

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.

Time frame: Up to 35 days after last dose of study drug (Up to ~Day 50)

Population: All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.

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.

Time frame: Day 14

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

To compare the all cause mortality rates of participants in the ceftolozane/tazobactam versus meropenem arms in microbiological intent-to-treat (mITT) population.

Time frame: Day 28

Population: The mITT population was a subset of the ITT population that included any participant who received any amount of study drug and had at least 1 bacterial respiratory pathogen isolated from the baseline LRT culture that was susceptible to at least 1 of the study drugs.

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.

Time frame: Up to 35 days after last dose of study drug (Up to ~Day 50)

Population: All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety 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 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.

Time frame: Within 24 hours after last dose of study drug (Up to ~Day 15)

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

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.

Time frame: 28 to 35 days after the last dose of study drug (Up to ~Day 50)

Population: The CE population was a subset of the ITT population that included any participant who received study drug, adhered to the study protocol through the TOC visit, and had an evaluable clinical outcome (either Cure or Failure) at the TOC visit (or were classified as a clinical failure prior to the TOC visit).

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.

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

Population: The CE population was a subset of the ITT population that included any participant who received study drug, adhered to the study protocol through the TOC visit, and had an evaluable clinical outcome (either Cure or Failure) at the TOC visit (or were classified as a clinical failure prior to the TOC visit).

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.

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

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

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.

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

Population: The ME population included any participants in the mITT who adhered to the protocol, had an evaluable clinical outcome at TOC and at least 1 pathogen isolated from the baseline LRT culture at the appropriate CFU/mL threshold. The number analyzed per pathogen represents the number of participants in the ME population with that specific pathogen.

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.

Time frame: Within 24 hours after last dose of study drug (Up to ~Day 15)

Population: The ME population was a subset of the mITT population that included any participants who adhered to the study protocol through the TOC visit, had an evaluable clinical outcome (Cure or Failure) at the TOC visit and had at least 1 bacterial respiratory pathogen (at the appropriate CFU/mL threshold) isolated from the baseline LRT culture.

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.

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

Population: The ME population was a subset of the mITT population that included any participants who adhered to the study protocol through the TOC visit, had an evaluable clinical outcome (Cure or Failure) at the TOC visit and had at least 1 bacterial respiratory pathogen (at the appropriate CFU/mL threshold) isolated from the baseline LRT culture.