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Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens (CREDIBLE - CR)

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: NCT02714595
Recruitment Status : Completed
First Posted : March 21, 2016
Results First Posted : December 17, 2020
Last Update Posted : January 12, 2021
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Brief Summary:
This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.

Condition or disease Intervention/treatment Phase
Healthcare-associated Pneumonia (HCAP) Bloodstream Infections (BSI) Hospital Acquired Pneumonia (HAP) Complicated Urinary Tract Infection (cUTI) Sepsis Ventilator Associated Pneumonia (VAP) Drug: Cefiderocol Drug: Best Available Therapy Phase 3

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

Detailed Description:
This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients with either hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI)/sepsis caused by carbapenem-resistant Gram-negative pathogens.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
Actual Study Start Date : September 7, 2016
Actual Primary Completion Date : April 1, 2019
Actual Study Completion Date : April 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cefiderocol
Participants will receive cefiderocol 2 g administered intravenously over 3 hours, every 8 hours for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.
Drug: Cefiderocol
2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days, or 2 g every 6 hours for participants with creatinine clearance >120 mL/min.
Other Names:
  • S-649266
  • Fetroja ®

Active Comparator: Best Available Therapy (BAT)
Best available therapy (BAT) will be chosen by the investigator and may include up to three antibacterial agents for carbapenem resistant Gram-negative bacteria, intravenously administered per country-specific guidelines for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.
Drug: Best Available Therapy
Standard of care with either a polymyxin-based or non-polymyxin-based regimen as determined by the investigator and consisting of one to three marketed antibacterial agent(s).




Primary Outcome Measures :
  1. Percentage of Participants With Clinical Cure at Test of Cure (TOC) in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    HAP/VAP/HCAP: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    Participants with missing data were considered as non-responders.


  2. Percentage of Participants With Microbiologic Eradication at TOC in Participants With cUTI [ Time Frame: Test of cure, defined as 7 days after the end of treatment, equivalent to Study Days 14 to 21 ]

    Microbiological outcome per Baseline pathogen was determined by the sponsor as defined for each infection site. For cUTI eradication was defined as a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ colony-forming units (CFU)/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.



Secondary Outcome Measures :
  1. Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: End of treatment, Day 7 to 14 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    HAP/VAP/HCAP: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.


  2. Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    Sustained clinical cure for HAP/VAP/HCAP: 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.

    BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC.


  3. Percentage of Participants With Clinical Cure at Test of Cure in Participants With cUTI [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


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

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  5. Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With cUTI [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    Sustained clinical cure for cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.


  6. Percentage of Participants With Clinical Cure at End of Treatment in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: End of treatment, Day 7 to 14 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  7. Percentage of Participants With Clinical Cure at Test of Cure in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  8. Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    Sustained clinical cure for HAP/VAP/HCAP: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy is required for the treatment of pneumonia in a participant assessed as cured at TOC.

    BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy is required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC.

    cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.


  9. Percentage of Participants With Clinical Cure at End of Treatment By Baseline Pathogen [ Time Frame: End of treatment, Day 7 to 14 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis:

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  10. Percentage of Participants With Clinical Cure at Test of Cure By Baseline Pathogen [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  11. Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Pathogen [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    Sustained clinical cure for HAP/VAP/HCAP: 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.

    BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC.

    cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.


  12. Percentage of Participants With Clinical Cure at EOT By Baseline Carbapenem-resistant Pathogen [ Time Frame: End of treatment, Day 7 to 14 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis:

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  13. Percentage of Participants With Clinical Cure at TOC By Baseline Carbapenem-resistant Pathogen [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis:

    HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection.

    BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.

    cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.


  14. Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Carbapenem-resistant Pathogen [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis.

    Sustained clinical cure for HAP/VAP/HCAP: 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.

    BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC.

    cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.


  15. Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: End of treatment, Day 7 to 14 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria established for each infection site:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen 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 to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  16. Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria established for each infection site:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen 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 to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  17. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP or BSI/Sepsis [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC. If an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable. For sepsis, if the participant has a successful clinical outcome after TOC and an appropriate clinical culture could not be obtained, the response was presumed sustained eradication.

    Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.


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

    Microbiological outcome per Baseline pathogen was determined by the sponsor as defined for each infection site. For cUTI eradication was defined as a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  19. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With cUTI [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Microbiological outcome per Baseline pathogen at follow-up was determined by the sponsor as defined for each infection site.

    For cUTI sustained eradication was defined as a culture taken any time after documented eradication at TOC and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained <10³ CFU/mL.

    Overall per-participant sustained eradication was defined as sustained eradication of all Baseline Gram-negative pathogens.


  20. Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: End of treatment, Day 7 to 14 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  21. Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  22. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable.

    For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication.

    cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL.

    Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.


  23. Percentage of Participants With Microbiologic Eradication at EOT By Baseline Pathogen [ Time Frame: End of treatment, Day 7 to 14 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  24. Percentage of Participants With Microbiologic Eradication at TOC By Baseline Pathogen [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  25. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Pathogen [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable.

    For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication.

    cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL.

    Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.


  26. Percentage of Participants With Microbiologic Eradication at EOT By Baseline Carbapenem-resistant Pathogen [ Time Frame: End of treatment, Day 7 to 14 ]

    Microbiological outcome per Baseline carbapenem-resistant pathogen were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  27. Percentage of Participants With Microbiologic Eradication at TOC By Baseline Carbapenem-resistant Pathogen [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]

    Microbiological outcome per Baseline carbapenem-resistant pathogen were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication.

    cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL.

    Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.


  28. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Carbapenem-resistant Pathogen [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]

    Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis:

    HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC.

    BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable.

    For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication.

    cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL.

    Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.


  29. Percentage of Participants With Microbiologic Eradication at EOT in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia [ Time Frame: End of treatment, Day 7 to 14 ]
    The percentage of participants who experienced eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture.

  30. Percentage of Participants With Microbiologic Eradication at TOC in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]
    The percentage of participants who experienced eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture.

  31. Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]
    The percentage of participants who experienced sustained eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture after TOC.

  32. Percentage of Participants With a Composite Clinical and Microbiological Response at EOT [ Time Frame: End of treatment, Day 7 to 14 ]
    The composite clinical and microbiological response rate is defined as the percentage of participants with both clinical cure and microbiologic eradication, as defined above for each site of infection.

  33. Percentage of Participants With a Composite Clinical and Microbiological Response at TOC [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]
    The composite clinical and microbiological response rate is defined as the percentage of participants with both clinical cure and microbiologic eradication, as defined above for each site of infection.

  34. Percentage of Participants With a Composite Clinical and Microbiological Response at Follow-up [ Time Frame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28 ]
    The composite clinical and microbiological response rate is defined as the percentage of participants with both sustained clinical cure and sustained microbiologic eradication, as defined above for each site of infection.

  35. All-cause Mortality at Day 14 and Day 28 [ Time Frame: Day 14 and Day 28 ]
    The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants who experienced mortality regardless of the cause at or before Day 14 and Day 28, respectively.

  36. Percentage of Participants Alive and With No Change in Antibiotic Treatment Due to Either Lack of Therapeutic Benefit or Drug-related Toxicity at TOC [ Time Frame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21 ]
  37. Survival Time [ Time Frame: Days 1 to 10, 11 to 20, 21 to 30, 31 to 40, 41-50, and 51 to 60. ]
    Survival time was analyzed by Kaplan-Meier survival curve. The table below presents deaths that occurred in10-day time intervals through the end of study

  38. Change From Baseline in Clinical Pulmonary Infection Score (CPIS) in Participants With Pneumonia (HAP/VAP/HCAP) [ Time Frame: Baseline, end of treatment (Day 7-14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28) ]
    Clinical pulmonary infection score (CPIS) is a surrogate for diagnosis and treatment response. Points (0, 1, or 2) are assigned for observed findings for 5 variables including body temperature, white blood cell count, tracheal secretions, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), and chest radiograph infiltrates. The total score ranges from 0 to 10, where higher scores may indicate a higher likelihood of mortality; a negative change from Baseline indicates improvement

  39. Change From Baseline in Sequential Organ Failure Assessment (SOFA) [ Time Frame: Baseline, end of treatment (Day 7 to 14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28) ]
    The SOFA score is a scoring system to determine the extent of a patient's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each score is from 0 to 4, and the total score ranges from 0 to 24, where higher scores indicate a higher likelihood of mortality. A negative change from Baseline score indicates improvement.

  40. Number of Participants With Adverse Events [ Time Frame: From first dose of study drug up to 28 days after last dose; maximum treatment duration was 29 days in the cefiderocol group and 22 days in the BAT group. ]

    The severity of each adverse event (AE) was graded by the investigator according to the following definitions:

    • Mild: Symptom or finding 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 interruption of usual daily activities or has a clinically significant effect

    The relationship of AEs to study treatment was determined by the investigator according to the following definition:

    ● Related: An AE which can be reasonably explained as having been caused by the study treatment.

    A serious AE is defined as any AE that resulted in any of the following outcomes:

    • Death
    • Life-threatening condition
    • Hospitalization or prolongation of existing hospitalization
    • 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:

  • Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem resistance
  • Patients who have been treated previously with an empiric antibiotic regiment and failed treatment, both clinically and microbiologically, are eligible for the study, if they have an identified carbapenem-resistant Gram-negative pathogen which has either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the empiric antibiotic regimen or been grown from a culture performed after at least 2 days of the empiric antibiotic regimen
  • Patient is male (no contraception required) or female and meets one of the following criteria:

    • Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery
    • Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for 6 months and confirmed by a follicle-stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months)
    • Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS) for the entire duration of the study
    • Of childbearing potential and practice abstinence as a preferred and usual lifestyle, and agrees to continue practicing abstinence from Screening and for the entire duration of the study
    • Of childbearing potential, whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study
  • Patients meeting specific criteria for each infection site

Exclusion Criteria:

  1. Patients who have a history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
  2. Patients who need more than 3 systemic antibiotics as part of best available therapy (BAT) for the treatment of the Gram-negative infection (patients with mixed Gram-positive or anaerobic infections may receive appropriate concomitant narrow spectrum antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin])
  3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
  4. Patients who have central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection)
  5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and joint infection, endocarditis)
  6. Patients with cystic fibrosis or moderate to severe bronchiectasis
  7. Patients in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of Randomization
  8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) < 100 cells/μL
  9. Female patients who have a positive pregnancy test at Screening or who are lactating
  10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 30
  11. Patients who have received a potentially effective antibiotic regimen for the carbapenem-resistant Gram-negative infection for a continuous duration of more than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 72 hours leading to Randomization
  12. Patients with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of the study data
  13. Patients who have received another investigational drug or device within 30 days prior to study entry
  14. Patients who have previously been randomized in this study or received S-649266
  15. Patients receiving peritoneal dialysis
  16. Patients meeting specific exclusion criteria for each infection site

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): NCT02714595


Locations
Show Show 85 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] June 27, 2019
Study Protocol  [PDF] November 16, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT02714595    
Other Study ID Numbers: 1424R2131
2015-004703-23 ( EudraCT Number )
First Posted: March 21, 2016    Key Record Dates
Results First Posted: December 17, 2020
Last Update Posted: January 12, 2021
Last Verified: December 2020
Keywords provided by Shionogi Inc. ( Shionogi ):
cefiderocol
Bloodstream infections (BSI)
Complicated urinary tract infection (cUTI)
Ventilator associated pneumonia (VAP)
Hospital acquired pneumonia (HAP)
Sepsis
multi-drug resistant pathogens
S-649266
Gram-negative pathogens
Healthcare-associated pneumonia (HCAP)
carbapenem resistant pathogens
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Urinary Tract Infections
Pneumonia, Ventilator-Associated
Healthcare-Associated Pneumonia
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Pathologic Processes
Urologic Diseases
Cross Infection
Iatrogenic Disease
Disease Attributes