Imipenem/Cilastatin-XNW4107 Versus Imipenem/Cilastatin/Relebactam for Treatment of Participants With Bacterial Pneumonia (XNW4107-302, REITAB-2)

The all-cause mortality rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14.

Time frame: Day 14

Population: Measured in the Modified Intent-To-Treat (MITT) population, which included all participants from the Intent-to-Treat (ITT) who received at least 1 dose of study drug.

Blood samples were taken for analysis of XNW4107, imipenem, and cilastatin concentrations. The data at each time point was calculated as an average across Days 4, 5 and 6.

Time frame: Predose, 5-25 minutes post-dose, and 2-3 hours post-dose on Day 4, 5, or 6

Population: Measured in the pharmacokinetic (PK) population, which included all participants from the safety population during the study with at least 1 reportable concentration of XNW4107, imipenem, or cilastatin. As pre-specified, data for PK was collected and reported only for the study drug treatment group (Imipenem/Cilastatin and XNW4107).

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Population: Measured in the CR-MITT Population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which is resistant to any carbapenem.

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Population: Measured in the CE population, which included all participants from the MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP), had no important protocol deviations that affected the assessment of clinical outcome, and had no missing nor indeterminate assessment of clinical outcome.

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Population: Measured in the Extended micro-MITT population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which was susceptible to either the investigational medicinal product or comparator.

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Population: Measured in the ME population, which included all participants from the micro-MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of HABP/VABP, had no important protocol deviations that affected the assessment of microbiological outcome, and had no missing nor indeterminate assessment of microbiological outcome. 'n' = participants evaluable at specified timepoint.

The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 14 and Day 28.

Time frame: Day 14, Day 28

Population: Measured in the microbiologic (micro)-MITT population, which included all participants from the MITT who had a Gram-negative pathogen identified at baseline and the pathogen was susceptible to the investigational medicinal product and comparator.

The all-cause mortality rate at Day 28 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from randomization up to Day 28.

Time frame: Day 28

Population: Measured in the MITT, which included all participants from the ITT who received at least 1 dose of study drug.

A TEAE was defined as any untoward medical occurrence after first dose associated with the use of a drug in humans, whether or not considered drug-related. An SAE was defined as any adverse event (AE) occurring at any dose that met one or more of the following criteria: resulted in death, was life-threatening, required participant hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, a congenital anomaly or birth defect or an important medical event.

Time frame: Day 1 to Day 28

Population: Measured in the safety population, which included all participants who received at least 1 dose of study drug during the study. Participants were analyzed according to the treatment received during the study.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

Population: Measured in the CE population, which included all participants from the MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP), had no important protocol deviations that affected the assessment of clinical outcome, and had no missing nor indeterminate assessment of clinical outcome.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

Population: Measured in the CR-MITT Population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which is resistant to any carbapenem.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the Extended micro-MITT, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which was susceptible to either the investigational medicinal product or comparator.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

Population: Measured in the ME population, which included all participants from the micro-MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of HABP/VABP, had no important protocol deviations that affected the assessment of microbiological outcome, and had no missing nor indeterminate assessment of microbiological outcome.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For EOT or TOC visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the micro-MITT, which included all participants from the MITT who had a Gram-negative pathogen identified at baseline and the pathogen was susceptible to the investigational medicinal product and comparator.

Clinical success was defined as: For Day 4 visit: a participant was alive with resolution or improvement in at least 1 baseline sign/symptom AND no worsening of any baseline signs/symptoms AND no development of new signs/symptoms of pneumonia requiring the initiation of a non-study antibacterial therapy for the index infection. For end of treatment (EOT) or test-of-cure (TOC) visits: a participant was alive with complete resolution or significant improvement of signs and symptoms that were present at baseline and no new signs/symptoms of pneumonia, such that no further antibacterial therapy is necessary. For LFU, Clinical success at TOC with sustained resolution or marked improvement of baseline signs and symptoms of pneumonia during TOC and LFU without antimicrobial therapy (pneumonia).

Time frame: Day 4, end of treatment (EOT) (up to Day 14), Test-of-Cure (TOC) (Day 21), and Late Follow-up (LFU) (Day 28)

Population: Measured in the MITT, which included all participants from the ITT who received at least 1 dose of study drug.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the CR-MITT Population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which is resistant to any carbapenem. Overall number of participants analysed=participants evaluable for the endpoint, n=number evaluable at the specified timepoint.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the Extended micro-MITT, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which was susceptible to either the investigational medicinal product or comparator. Overall number of participants analysed=participants evaluable for the endpoint, n=number evaluable at the specified timepoint.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the ME population, which included all participants from the micro-MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of HABP/VABP, had no important protocol deviations that affected the assessment of microbiological outcome, and had no missing nor indeterminate assessment of microbiological outcome. Overall number of participants analysed=participants evaluable for the endpoint, n=number evaluable at the specified timepoint.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the micro-MITT, which included all participants from the MITT who had a Gram-negative pathogen identified at baseline and the pathogen was susceptible to the investigational medicinal product and comparator. Overall number of participants analysed=participants evaluable for the endpoint, n=number evaluable at the specified timepoint.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the CR-MITT Population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which is resistant to any carbapenem.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the Extended micro-MITT, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which was susceptible to either the investigational medicinal product or comparator.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the ME population, which included all participants from the micro-MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of HABP/VABP, had no important protocol deviations that affected the assessment of microbiological outcome, and had no missing nor indeterminate assessment of microbiological outcome.

Microbiological success was defined as: • Eradication: Absence of the baseline Gram-negative pathogen from an appropriate clinical specimen • Presumed eradication: Absence of appropriate post-baseline culture material in a participant, but judged to be a clinical success.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the micro-MITT, which included all participants from the MITT who had a Gram-negative pathogen identified at baseline and the pathogen was susceptible to the investigational medicinal product and comparator.

Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the CR-MITT Population, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which is resistant to any carbapenem.

Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the Extended micro-MITT, which included all participants from the MITT who had a baseline Gram-negative pathogen identified which was susceptible to either the investigational medicinal product or comparator.

Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the ME population, which included all participants from the micro-MITT who received at least 72 hours of IV study treatment, had an appropriate diagnosis of HABP/VABP, had no important protocol deviations that affected the assessment of microbiological outcome, and had no missing nor indeterminate assessment of microbiological outcome.

Overall success was defined as clinical success and microbiological success at the visits of EOT or TOC, or sustained success for clinical outcome and microbiological success at the visit of LFU. Microbiological success included eradication or presumed eradication.

Time frame: EOT (up to Day 14), TOC (Day 21), and LFU (Day 28)

Population: Measured in the micro-MITT, which included all participants from the MITT who had a Gram-negative pathogen identified at baseline and the pathogen was susceptible to the investigational medicinal product and comparator.