A Phase 3 interventional study of Cefiderocol and Meropenem in Healthcare-associated Pneumonia (HCAP), Hospital Acquired Pneumonia (HAP) and Ventilator Associated Pneumonia (VAP), sponsored by Shionogi. Completed at 119 sites in 19 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-11-13.
Sponsored by Shionogi · Phase 3, Interventional, and Treatment
The primary objective of this study is to compare all-cause mortality at Day 14 in participants receiving cefiderocol with participants receiving the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens.
2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.
This study's enrollment of 300 is above the median of 106 across 1,247 interventional studies indexed under Pneumonia.
Browse Pneumonia studies →Shionogi is the lead sponsor of 104 studies on the registry; 10 are open to participants now.
Of its 39 completed or terminated interventional studies of FDA-regulated products, 21 (54%) have results posted.
Counted across the registry records on this site, refreshed daily.
All subjects must fulfill at least 1 of the following clinical criteria at screening:
All subjects must have at least 1 of the following signs:
Exclusion Criteria:
Participants will receive 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Drug: Cefiderocol · Drug: Linezolid
Participants will receive 2 g meropenem administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
Drug: Meropenem · Drug: Linezolid
2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)
Also known as: S-649266
2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function)
Also known as: Merrem®
600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.
Also known as: Zyvox®
All-cause Mortality Rate at Day 14
The all-cause mortality (ACM) rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from the first infusion of study drug up to Day 14. The Modified Intent-to-Treat Population included all randomized participants who met either of the following criteria: * Evidence of Gram-negative infection of the lower respiratory tract based on a culture, Gram-stain, or other diagnostic test * Evidence of a lower respiratory tract infection but culture or other diagnostic tests did not provide a microbiologic diagnosis
Time frame: From first dose of study drug to Day 14
Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC)
Lower respiratory tract specimens (eg, sputum, endotracheal aspiration \[ETA\], endobronchial culture specimens collected by bronchoalveolar lavage \[BAL\], or protected specimen brush \[PSB\], lung biopsy tissue, pleural effusions, etc) were sent to the local microbiology laboratory for isolation and identification of pathogens. Microbiological outcome by Baseline pathogen at TOC was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, bronchoalveolar lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
Time frame: Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)
Percentage of Participants With Clinical Cure at Test of Cure
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
Time frame: Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)
Percentage of Participants With Clinical Cure at Early Assessment (EA)
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
Time frame: Early assessment (Day 3-4 after the start of treatment)
Percentage of Participants With Clinical Cure at End of Treatment (EOT)
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
Time frame: End of treatment (Day 7 to 14)
Percentage of Participants With Sustained Clinical Cure at Follow-up (FU)
Clinical outcome was assessed by the investigator at follow-up as either Sustained Clinical Cure, Relapse, or Indeterminate. Sustained Clinical Cure: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC.
Time frame: Follow-up (14 days after the end of treatment; Day 21 to 28)
Percentage of Participants With Microbiologic Eradication at Early Assessment
Microbiological outcome by Baseline pathogen at Early Assessment was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
Time frame: Early Assessment, Days 3 to 4
Percentage of Participants With Microbiologic Eradication at End of Treatment
Microbiological outcome by Baseline pathogen at End of Treatment was determined by the sponsor as either: Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
Time frame: End of treatment, Day 7 to 14
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up
Microbiological outcome by Baseline pathogen at Follow-up was determined by the sponsor as either Sustained Eradication, Persistence, Recurrence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Sustained eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy) after TOC. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical response after TOC, the response was presumed to be eradication.
Time frame: Follow-up (14 days after the end of treatment, Days 21 to 28)
All-cause Mortality Rate at Day 28
The all-cause mortality (ACM) rate at Day 28 was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first dose of study drug up to Day 28.
Time frame: From first dose of study drug to Day 28
All-cause Mortality Rate at the End of Study
The all-cause mortality rate during both the treatment and follow-up period (up to the end of study \[EOS\] visit) was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first infusion of study drug up to EOS. If a participant discontinued from the study before EOS and survival information was not available, then the survival status for this endpoint for the participant was considered unknown.
Time frame: From first dose of study drug through end of study (28 days after end of treatment, up to 42 days)
Total Hospitalization Time
The length of hospital stay attributable to the study-qualifying infection.
Time frame: From first dose of study drug to test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21) and to follow-up (14 days after the end of treatment; Day 21 to 28)
Number of Participants With Treatment-Emergent Adverse Events
The severity of each adverse event (AE) was graded by the investigator according to the following definitions: * Mild: A finding or symptom is minor and does not interfere with usual daily activities. * Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status. * Severe: The event causes an interruption of the participant's usual daily activities or has a clinically significant effect. The relationship of each AE to the study treatment was determined by the investigator based on whether the AE could be reasonably explained as having been caused by the study drug (treatment related AE \[TRAE\]). An SAE is defined as any AE occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening condition * Hospitalization or prolongation of existing hospitalization for treatment * Persistent or significant disability/incapacity * Congenital anomaly/birth defect * Other medically important condition
Time frame: From first dose of study drug through the end of study, up to 42 days.
The study population included participants with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative bacteria.
| Milestone | Cefiderocol | Meropenem |
|---|---|---|
| Started | 148 | 152 |
| Received treatment | 148 | 150 |
| Completed | 106 | 112 |
| Not completed | 42 | 40 |
| Withdrew: Adverse event | 0 | 1 |
| Withdrew: Lack of efficacy | 1 | 0 |
| Withdrew: Withdrawal by subject | 2 | 3 |
| Withdrew: Recovery | 0 | 1 |
| Withdrew: Death | 39 | 34 |
| Withdrew: Other - miscellaneous | 0 | 1 |
The all-cause mortality (ACM) rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from the first infusion of study drug up to Day 14. The Modified Intent-to-Treat Population included all randomized participants who met either of the following criteria: * Evidence of Gram-negative infection of the lower respiratory tract based on a culture, Gram-stain, or other diagnostic test * Evidence of a lower respiratory tract infection but culture or other diagnostic tests did not provide a microbiologic diagnosis
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| All-cause Mortality Rate at Day 14 | 12.4 | 11.6 |
Lower respiratory tract specimens (eg, sputum, endotracheal aspiration \[ETA\], endobronchial culture specimens collected by bronchoalveolar lavage \[BAL\], or protected specimen brush \[PSB\], lung biopsy tissue, pleural effusions, etc) were sent to the local microbiology laboratory for isolation and identification of pathogens. Microbiological outcome by Baseline pathogen at TOC was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, bronchoalveolar lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC) | 47.6 | 48.0 |
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Clinical Cure at Test of Cure | 64.8 | 66.7 |
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Clinical Cure at Early Assessment (EA) | 82.8 | 83.0 |
Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Clinical Cure at End of Treatment (EOT) | 77.2 | 81.0 |
Clinical outcome was assessed by the investigator at follow-up as either Sustained Clinical Cure, Relapse, or Indeterminate. Sustained Clinical Cure: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) | 57.9 | 57.8 |
Microbiological outcome by Baseline pathogen at Early Assessment was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Microbiologic Eradication at Early Assessment | 41.9 | 53.5 |
Microbiological outcome by Baseline pathogen at End of Treatment was determined by the sponsor as either: Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical outcome, the response was presumed as eradication.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Microbiologic Eradication at End of Treatment | 63.7 | 66.9 |
Microbiological outcome by Baseline pathogen at Follow-up was determined by the sponsor as either Sustained Eradication, Persistence, Recurrence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Sustained eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy) after TOC. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical response after TOC, the response was presumed to be eradication.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| Percentage of Participants With Sustained Microbiologic Eradication at Follow-up | 43.5 | 38.6 |
The all-cause mortality (ACM) rate at Day 28 was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first dose of study drug up to Day 28.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| All-cause Mortality Rate at Day 28 | 21.0 | 20.5 |
The all-cause mortality rate during both the treatment and follow-up period (up to the end of study \[EOS\] visit) was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first infusion of study drug up to EOS. If a participant discontinued from the study before EOS and survival information was not available, then the survival status for this endpoint for the participant was considered unknown.
| percentage of participants | Cefiderocol | Meropenem |
|---|---|---|
| All-cause Mortality Rate at the End of Study | 26.8 | 23.3 |
The length of hospital stay attributable to the study-qualifying infection.
| days | Cefiderocol | Meropenem |
|---|---|---|
| Test of Cure | 11.54 ± 7.81 | 11.47 ± 7.32 |
| Follow-up | 13.49 ± 10.06 | 12.98 ± 9.59 |
The severity of each adverse event (AE) was graded by the investigator according to the following definitions: * Mild: A finding or symptom is minor and does not interfere with usual daily activities. * Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status. * Severe: The event causes an interruption of the participant's usual daily activities or has a clinically significant effect. The relationship of each AE to the study treatment was determined by the investigator based on whether the AE could be reasonably explained as having been caused by the study drug (treatment related AE \[TRAE\]). An SAE is defined as any AE occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening condition * Hospitalization or prolongation of existing hospitalization for treatment * Persistent or significant disability/incapacity * Congenital anomaly/birth defect * Other medically important condition
| Participants | Cefiderocol | Meropenem |
|---|---|---|
| Any adverse event | 130 | 129 |
| Mild adverse events | 33 | 37 |
| Moderate adverse events | 41 | 47 |
| Severe adverse events | 56 | 45 |
| Treatment-related adverse events | 14 | 17 |
| Serious adverse events | 54 | 45 |
| Treatment-related serious adverse events | 3 | 5 |
| AEs leading to discontinuation of study drug | 12 | 14 |
| TRAE leading to discontinuation of study drug | 2 | 2 |
| Adverse events leading to death | 39 | 35 |
Collected over From first dose of study drug through the end of study, up to 42 days.. Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cefiderocol | 39/148 (26.4%) | 54/148 (36.5%) | 119/148 (80.4%) |
| Meropenem | 35/150 (23.3%) | 45/150 (30%) | 123/150 (82%) |
| Event | Cefiderocol | Meropenem |
|---|---|---|
| Cardiac arrestCardiac disorders | 7/148 | 5/150 |
| PneumoniaInfections and infestations | 6/148 | 3/150 |
| Acute respiratory failureRespiratory, thoracic and mediastinal disorders | 6/148 | 1/150 |
| Hepatic enzyme increasedInvestigations | 1/148 | 5/150 |
| Brain oedemaNervous system disorders | 1/148 | 5/150 |
| Multiple organ dysfunction syndromeGeneral disorders | 4/148 | 4/150 |
| Septic shockInfections and infestations | 4/148 | 1/150 |
| Cardio-respiratory arrestCardiac disorders | 3/148 | 2/150 |
| SepsisInfections and infestations | 3/148 | 2/150 |
| Pneumonia aspirationRespiratory, thoracic and mediastinal disorders | 3/148 | 2/150 |
| Event | Cefiderocol | Meropenem |
|---|---|---|
| HypokalaemiaMetabolism and nutrition disorders | 16/148 | 23/150 |
| Urinary tract infectionInfections and infestations | 22/148 | 15/150 |
| DiarrhoeaGastrointestinal disorders | 13/148 | 13/150 |
| AnaemiaBlood and lymphatic system disorders | 12/148 | 12/150 |
| HyponatraemiaMetabolism and nutrition disorders | 4/148 | 10/150 |
| Decubitus ulcerSkin and subcutaneous tissue disorders | 4/148 | 10/150 |
| Aspartate aminotransferase increasedInvestigations | 9/148 | 5/150 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 9/148 | 5/150 |
| HypotensionVascular disorders | 2/148 | 9/150 |
| Alanine aminotransferase increasedInvestigations | 8/148 | 6/150 |
The intent-to-treat (ITT) population included all randomized participants who received at least 1 dose of study treatment.
| Age, Continuous(years) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| Mean | 64.7 ± 14.5 | 65.6 ± 15.1 | 65.2 ± 14.8 |
| Age, Customized(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| < 65 years | 65 | 58 | 123 |
| >= 65 years | 83 | 92 | 175 |
| Sex: Female, Male(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| Female | 47 | 46 | 93 |
| Male | 101 | 104 | 205 |
| Ethnicity (NIH/OMB)(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| Hispanic or Latino | 4 | 3 | 7 |
| Not Hispanic or Latino | 140 | 139 | 279 |
| Unknown or Not Reported | 4 | 8 | 12 |
| Race/Ethnicity, Customized(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| White | 102 | 100 | 202 |
| Black or African American | 0 | 1 | 1 |
| Asian | 44 | 44 | 88 |
| American Indian or Alaska Native | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Other | 2 | 4 | 6 |
| Missing | 0 | 1 | 1 |
| Region(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| North America | 6 | 6 | 12 |
| South America | 0 | 0 | 0 |
| Europe | 99 | 100 | 199 |
| Asia-Pacific | 43 | 44 | 87 |
| Clinical Diagnosis(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| VABP | 60 | 65 | 125 |
| HABP | 60 | 61 | 121 |
| HCABP | 28 | 24 | 52 |
| Acute Physiology and Chronic Health Evaluation II (APACHE II) Score(Participants) | Cefiderocol | Meropenem | Total |
|---|---|---|---|
| <= 15 | 75 | 78 | 153 |
| 16 - 19 | 32 | 26 | 58 |
| >= 20 | 41 | 46 | 87 |
Showing the first 100 of 119 sites across 19 countries.
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