Bacterial Pneumonia
Conditions
Brief summary
This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the incidence rate of all-cause mortality.
Interventions
DRUGImipenem
Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
DRUGRelebactam
Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
DRUGCilastatin
Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
DRUGPiperacillin
Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
DRUGTazobactam
Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
DRUGLinezolid
Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Requires treatment with IV antibiotic therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) * Fulfills clinical and radiographic criteria, with onset of criteria occurring after more than 48 hours of hospitalization or within 7 days after discharge from a hospital (for HABP); or at least 48 hours after mechanical ventilation (for VABP) * Has an adequate baseline lower respiratory tract specimen obtained for Gram stain and culture * Has an infection known or thought to be caused by microorganisms susceptible to the IV study therapy * Agrees to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided to the Central Microbiology Reference Laboratory for study-related microbiological testing, long term storage, and other future testing * Is not of reproductive potential; or if of reproductive potential agrees to avoid impregnating a partner or avoid becoming pregnant, by practicing abstinence or using acceptable contraception
Exclusion criteria
* Has a baseline lower respiratory tract specimen Gram stain that shows the presence of Gram-positive cocci only * Has confirmed or suspected community-acquired bacterial pneumonia (CABP) * Has confirmed or suspected pneumonia of viral, fungal or parasitic origin * Has HABP/VABP caused by an obstructive process, including lung cancer or other known obstruction * Has a carcinoid tumor or carcinoid syndrome * Has active immunosuppression defined as either receiving immunosuppressive medications or having a medical condition associated with immunodeficiency * Is expected to survive for less than 72 hours * Has a concurrent condition or infection that would preclude evaluation of therapeutic response * Has received effective antibacterial drug therapy for the index infection of HABP/VABP for more than 24 hours continuously, during the previous 72 hours * Has a history of serious allergy, hypersensitivity or a serious reaction to any penicillin or beta-lactamase inhibitors * Female is pregnant, expecting to conceive, is breastfeeding or plans to breastfeed * Has a history of seizure disorder requiring ongoing prior treatment with anti-convulsive therapy within the last 3 years * Anticipates treatment with the following: valproic acid or divalproex sodium, serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin receptor antagonists, meperidine, buspirone, concomitant systemic antibacterial agents, antifungal or antiviral therapy for the index infection of HABP/VABP * Is currently undergoing hemodialysis or peritoneal dialysis * Is currently participating in, has participated in during the previous 30 days, or anticipates to participate in any other clinical study involving the administration of experimental medication * Has previously participated in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population | Up to 28 days | The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥1 Adverse Event (AE) | Up to 30 days | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Percentage of Participants Discontinuing Study Therapy Due to an AE | Up to 14 days | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population | Up to 28 days | The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. |
| Percentage of Participants With ACM at EFU in the MITT Population | Up to 16 days after end of therapy (up to 30 days) | The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm. |
| Percentage of Participants With ACM at EFU in the mMITT Population | Up to 16 days after end of therapy (up to 30 days) | The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm. |
| Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] | Day 3 (OTX1) | The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) | Day 6 (OTX2) | The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) | Day 10 (OTX3) | The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the CE Population With a FCR at EOT Visit | From Day 7 to Day 14 | The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required) or improved (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
| Percentage of Participants in the CE Population With a FCR at Day 28 | Day 28 | The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
| Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit | Up to 16 days after end of therapy (up to 30 days) | The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
| Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) | Day 3 (OTX1) | The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) | Day 6 (OTX2) | The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) | Day 10 (OTX3) | The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]). |
| Percentage of Participants in the MITT Population With a FCR at EOT | From Day 7 to Day 14 | The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required) or improved (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
| Percentage of Participants in the MITT Population With a FCR at Day 28 | Day 28 | The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
| Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit | From Day 7 to Day 14 | The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved). |
| Percentage of Participants in the mMITT Population With a FMR at EFU Visit | Up to 16 days after end of therapy (up to Day 30) | The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved). |
| Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit | From Day 7 to Day 14 | The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved). |
| Percentage of Participants in the ME Population With a FMR at EFU Visit | Up to 16 days after end of therapy (up to Day 30) | The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved). |
| Percentage of Participants in the CE Population With a FCR at EFU Visit | Up to 16 days after end of therapy (up to Day 30) | The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required). |
Participant flow
Recruitment details
Adult male and female participants requiring intravenous (IV) therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-assisted bacterial pneumonia (VABP) were recruited at 120 study centers in 28 countries.
Participants by arm
| Arm | Count |
|---|---|
| IMI/REL Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. | 268 |
| PIP/TAZ Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. | 269 |
| Total | 537 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 44 | 58 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Participant moved | 17 | 5 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 6 | 7 |
| Overall Study | Withdrawal by Subject | 11 | 7 |
| Overall Study | Withdrawal parent/guardian | 0 | 1 |
Baseline characteristics
| Characteristic | PIP/TAZ | Total | IMI/REL |
|---|---|---|---|
| Age, Continuous | 58.9 Years STANDARD_DEVIATION 18.4 | 59.7 Years STANDARD_DEVIATION 17.7 | 60.4 Years STANDARD_DEVIATION 17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 55 Participants | 111 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 205 Participants | 414 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 12 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 37 Participants | 79 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 10 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 209 Participants | 417 Participants | 208 Participants |
| Sex: Female, Male Female | 78 Participants | 164 Participants | 86 Participants |
| Sex: Female, Male Male | 191 Participants | 373 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 266 | 58 / 269 |
| other Total, other adverse events | 98 / 266 | 105 / 269 |
| serious Total, serious adverse events | 71 / 266 | 86 / 269 |
Outcome results
Primary
Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population
The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time frame: Up to 28 days
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline lower respiratory tract (LRT) specimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population | 15.9 Percentage of participants |
| PIP/TAZ | Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population | 21.3 Percentage of participants |
Comparison: Adjusted difference in all-cause mortalityp-value: <0.00195% CI: [-11.9, 1.2]t-test, 1 sided
Secondary
Percentage of Participants Discontinuing Study Therapy Due to an AE
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 14 days
Population: All participants who received ≥1 dose of study therapy are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants Discontinuing Study Therapy Due to an AE | 5.6 Percentage of participants |
| PIP/TAZ | Percentage of Participants Discontinuing Study Therapy Due to an AE | 8.2 Percentage of participants |
95% CI: [-7.1, 1.8]
Secondary
Percentage of Participants in the CE Population With a FCR at Day 28
The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: Day 28
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 28 clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the CE Population With a FCR at Day 28 | 70.5 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the CE Population With a FCR at Day 28 | 75.6 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-14.3, 7.5]
Secondary
Percentage of Participants in the CE Population With a FCR at EFU Visit
The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: Up to 16 days after end of therapy (up to Day 30)
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EFU clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the CE Population With a FCR at EFU Visit | 74.3 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the CE Population With a FCR at EFU Visit | 79.4 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-13.6, 6.4]
Secondary
Percentage of Participants in the CE Population With a FCR at EOT Visit
The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required) or improved (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: From Day 7 to Day 14
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EOT clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the CE Population With a FCR at EOT Visit | 84.7 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the CE Population With a FCR at EOT Visit | 85.3 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-8.1, 7.4]
Secondary
Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6)
The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 6 (OTX2)
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 6 clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) | 85.5 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) | 87.8 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-9.8, 5.5]
Secondary
Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10)
The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 10 (OTX3)
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 10 clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) | 89.6 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) | 83.6 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-4.6, 18.4]
Secondary
Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3]
The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 3 (OTX1)
Population: The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 3 clinical response data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] | 70.8 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] | 72.8 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-11.3, 7.8]
Secondary
Percentage of Participants in the ME Population With a FMR at EFU Visit
The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved).
Time frame: Up to 16 days after end of therapy (up to Day 30)
Population: The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EFU data and LRT culture available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the ME Population With a FMR at EFU Visit | 89.9 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the ME Population With a FMR at EFU Visit | 86.4 Percentage of participants |
Comparison: Adjusted difference in favorable microbiological response95% CI: [-4, 14.1]
Secondary
Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit
The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved).
Time frame: From Day 7 to Day 14
Population: The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EOT data and LRT culture available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit | 87.1 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit | 85.5 Percentage of participants |
Comparison: Adjusted difference in favorable microbiological response95% CI: [-5.5, 11]
Secondary
Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit
The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: Up to 16 days after end of therapy (up to 30 days)
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline LRT specimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit | 61.0 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit | 55.8 Percentage of participants |
Comparison: Adjusted difference in FCRp-value: <0.00195% CI: [-3.2, 13.2]t-test, 1 sided
Secondary
Percentage of Participants in the MITT Population With a FCR at Day 28
The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either sustained cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] with no evidence of resurgence and no additional antibiotics are required) or cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: Day 28
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 28 data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a FCR at Day 28 | 51.9 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a FCR at Day 28 | 50.6 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-7.2, 9.4]
Secondary
Percentage of Participants in the MITT Population With a FCR at EOT
The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either cure (all pre-therapy signs and symptoms of the index infection have resolved \[or returned to pre-infection status\] and no additional antibiotics are required) or improved (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\] and no additional antibiotics are required).
Time frame: From Day 7 to Day 14
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have EOT data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a FCR at EOT | 74.2 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a FCR at EOT | 69.7 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-3.1, 12]
Secondary
Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3)
The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 3 (OTX1)
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 3 data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) | 68.0 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) | 64.7 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-4.6, 11.6]
Secondary
Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6)
The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 6 (OTX2)
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 6 data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) | 83.5 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) | 83.1 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-6.3, 7.4]
Secondary
Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10)
The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as improved (majority of pre-therapy signs and symptoms of the index infection have improved or resolved \[or returned to pre-infection status\]).
Time frame: Day 10 (OTX3)
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 10 data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) | 83.5 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) | 80.4 Percentage of participants |
Comparison: Adjusted difference in favorable clinical response95% CI: [-7.1, 14.2]
Secondary
Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit
The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved).
Time frame: From Day 7 to Day 14
Population: The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EOT data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit | 77.2 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit | 67.9 Percentage of participants |
Comparison: Adjusted difference in favorable microbiological response95% CI: [1.6, 17.9]
Secondary
Percentage of Participants in the mMITT Population With a FMR at EFU Visit
The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either eradication (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or presumed eradication (no specimen collected because the participant deemed clinically cured or improved).
Time frame: Up to 16 days after end of therapy (up to Day 30)
Population: The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EFU data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants in the mMITT Population With a FMR at EFU Visit | 67.9 Percentage of participants |
| PIP/TAZ | Percentage of Participants in the mMITT Population With a FMR at EFU Visit | 61.9 Percentage of participants |
Comparison: Adjusted difference in favorable microbiological response95% CI: [-2.7, 15]
Secondary
Percentage of Participants With ≥1 Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 30 days
Population: All participants who received ≥1 dose of study therapy are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants With ≥1 Adverse Event (AE) | 85.0 Percentage of participants |
| PIP/TAZ | Percentage of Participants With ≥1 Adverse Event (AE) | 86.6 Percentage of participants |
95% CI: [-7.7, 4.3]
Secondary
Percentage of Participants With ACM at EFU in the MITT Population
The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time frame: Up to 16 days after end of therapy (up to 30 days)
Population: The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline specimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants With ACM at EFU in the MITT Population | 14.8 Percentage of participants |
| PIP/TAZ | Percentage of Participants With ACM at EFU in the MITT Population | 19.5 Percentage of participants |
Comparison: Adjusted difference in all-cause mortality95% CI: [-11, 1.7]
Secondary
Percentage of Participants With ACM at EFU in the mMITT Population
The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time frame: Up to 16 days after end of therapy (up to 30 days)
Population: The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants With ACM at EFU in the mMITT Population | 15.3 Percentage of participants |
| PIP/TAZ | Percentage of Participants With ACM at EFU in the mMITT Population | 18.3 Percentage of participants |
Comparison: Adjusted difference in all-cause mortality95% CI: [-10.2, 3.8]
Secondary
Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population
The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time frame: Up to 28 days
Population: The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMI/REL | Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population | 16.7 Percentage of participants |
| PIP/TAZ | Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population | 20.2 Percentage of participants |
Comparison: Adjusted difference in all-cause mortality95% CI: [-10.9, 3.6]