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Clinical Study of Cefiderocol (S-649266) for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens (APEKS-NP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03032380
Recruitment Status : Completed
First Posted : January 26, 2017
Results First Posted : November 13, 2020
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthcare-associated Pneumonia (HCAP) Hospital Acquired Pneumonia (HAP) Ventilator Associated Pneumonia (VAP) Drug: Cefiderocol Drug: Meropenem Drug: Linezolid Phase 3

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S-649266 Compared With Meropenem for the Treatment of Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens
Actual Study Start Date : October 24, 2017
Actual Primary Completion Date : February 26, 2019
Actual Study Completion Date : April 1, 2019


Arm Intervention/treatment
Experimental: Cefiderocol
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
2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)
Other Name: S-649266

Drug: Linezolid
600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.
Other Name: Zyvox®

Active Comparator: Meropenem
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
2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function)
Other Name: Merrem®

Drug: Linezolid
600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.
Other Name: Zyvox®




Primary Outcome Measures :
  1. All-cause Mortality Rate at Day 14 [ Time Frame: From first dose of study drug to 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


Secondary Outcome Measures :
  1. Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC) [ Time Frame: Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21) ]

    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.


  2. Percentage of Participants With Clinical Cure at Test of Cure [ Time Frame: Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21) ]

    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.


  3. Percentage of Participants With Clinical Cure at Early Assessment (EA) [ Time Frame: Early assessment (Day 3-4 after the start of treatment) ]

    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.


  4. Percentage of Participants With Clinical Cure at End of Treatment (EOT) [ Time Frame: End of treatment (Day 7 to 14) ]

    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.


  5. Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) [ Time Frame: Follow-up (14 days after the end of treatment; Day 21 to 28) ]

    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.


  6. Percentage of Participants With Microbiologic Eradication at Early Assessment [ Time Frame: Early Assessment, Days 3 to 4 ]

    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.


  7. Percentage of Participants With Microbiologic Eradication at End of Treatment [ Time Frame: End of treatment, Day 7 to 14 ]

    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.


  8. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up [ Time Frame: Follow-up (14 days after the end of treatment, Days 21 to 28) ]

    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.


  9. All-cause Mortality Rate at Day 28 [ Time Frame: From first dose of study drug to 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.

  10. All-cause Mortality Rate at the End of Study [ Time Frame: From first dose of study drug through end of study (28 days after end of treatment, up to 42 days) ]
    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.

  11. Total Hospitalization Time [ 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) ]
    The length of hospital stay attributable to the study-qualifying infection.

  12. Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: From first dose of study drug through the end of study, up to 42 days. ]

    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects 18 years or older at the time of signing informed consent
  • Subjects who have provided written informed consent or their informed consent has been provided by a legally authorized representative
  • Subjects who meet the clinical diagnosis criteria for hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP)
  • All subjects must fulfill at least 1 of the following clinical criteria at screening:

    1. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (eg, respiratory rate > 25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation
    2. Hypoxemia (eg, a partial pressure of oxygen [PaO2] < 60 mm Hg while the subject is breathing room air, as determined by arterial blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of inspired oxygen [PaO2/FiO2])
    3. Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure
    4. New onset of or increase in (quantity or characteristics) suctioned respiratory secretions, demonstrating evidence of inflammation and absence of contamination
  • All subjects must have at least 1 of the following signs:

    1. Documented fever (ie, core body temperature [tympanic, rectal, esophageal] ≥ 38°C [100.4°F], oral temperature ≥ 37.5°C, or axillary temperature ≥ 37°C)
    2. Hypothermia (ie, core body temperature [tympanic, rectal, esophageal] ≤ 35°C [95.0°F], oral temperature ≤ 35.5°C and axillary temperature ≤ 36°C)
    3. Leukocytosis with a total peripheral white blood cell (WBC) count ≥ 10,000 cells/mm³
    4. Leukopenia with total peripheral WBC count ≤ 4500 cells/mm³
    5. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear
  • All subjects must have a chest radiograph during screening showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography (CT) scan in the same time window showing the same findings could also be acceptable
  • All subjects must have a suspected Gram-negative infection involving the lower respiratory tract

Exclusion Criteria:

  • Subjects who have known or suspected community-acquired bacterial pneumonia (CABP), atypical pneumonia, viral pneumonia, or chemical pneumonia (including aspiration of gastric contents, inhalation injury)
  • Other exclusions based on the prescribing information of meropenem or linezolid, prior antibiotic usage, age, and pregnancy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03032380


Locations
Show Show 119 study locations
Sponsors and Collaborators
Shionogi
Investigators
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Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi
  Study Documents (Full-Text)

Documents provided by Shionogi Inc. ( Shionogi ):
Statistical Analysis Plan  [PDF] July 9, 2019
Study Protocol  [PDF] February 22, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT03032380    
Other Study ID Numbers: 1615R2132
2016-003020-23 ( EudraCT Number )
First Posted: January 26, 2017    Key Record Dates
Results First Posted: November 13, 2020
Last Update Posted: November 13, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shionogi Inc. ( Shionogi ):
Hospital-acquired pneumonia (HAP)
S-649266
linezolid
meropenem
Healthcare-associated pneumonia (HCAP)
nosocomial pneumonia
Ventilator-associated pneumonia (VAP)
Gram-negative pathogens
pneumonia
cefiderocol
Additional relevant MeSH terms:
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Pneumonia, Ventilator-Associated
Healthcare-Associated Pneumonia
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cross Infection
Infection
Iatrogenic Disease
Disease Attributes
Pathologic Processes
Meropenem
Linezolid
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action