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

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ClinicalTrials.gov Identifier: NCT03032380
Recruitment Status : Completed
First Posted : January 26, 2017
Last Update Posted : February 27, 2020
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Tracking Information
First Submitted Date  ICMJE January 17, 2017
First Posted Date  ICMJE January 26, 2017
Last Update Posted Date February 27, 2020
Actual Study Start Date  ICMJE October 24, 2017
Actual Primary Completion Date February 26, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2017)
All-cause Mortality at Day 14 [ Time Frame: Day 14 ]
The mortality from all-causes in each arm of the study by the fourteenth day after the start of treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2017)
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at Test of Cure (TOC) [ Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days) ]
    Clinical outcome will be assessed by the investigator as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at TOC [ Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days) ]
    The microbiological outcome by baseline pathogen at TOC will be determined by the sponsor as either: eradication, persistence, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at Early Assessment (EA) [ Time Frame: Early assessment, defined as 3-4 days after the start of treatment. ]
    Clinical outcome at EA will be assessed as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at End of Treatment (EOT) [ Time Frame: End of treatment, defined as the last day of study treatment (7-14 days) ]
    Clinical outcome will be assessed by the investigator at EOT as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Sustained Clinical Cure at Follow-up (FU) [ Time Frame: Follow-up, defined as 14 days after the end of treatment (treatment duration is 7-14 days) ]
    Clinical outcome will be assessed by the investigator at FU as either: Sustained clinical cure, relapse, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at EA [ Time Frame: Early assessment, defined as 3-4 days after the start of treatment. ]
    The microbiological outcome by baseline pathogen will be determined by the sponsor at EA as either: eradication, persistence, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at EOT [ Time Frame: End of treatment, defined as the last day of study treatment (7-14 days) ]
    The microbiological outcome by baseline pathogen will be determined by the sponsor at EOT as either: eradication, persistence or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Sustained Eradication at FU [ Time Frame: Follow-up, defined as 14 days after the end of treatment (treatment duration is 7-14 days) ]
    Microbiological outcome by baseline pathogen will be determined by the sponsor at FU as either: Sustained eradication, recurrence, or indeterminate.
  • All-cause Mortality at Day 28 [ Time Frame: Day 28 ]
    The mortality from all-causes in each arm of the study by the twenty-eighth day after the start of treatment.
  • All-cause Mortality Over the Full Duration of the Study [ Time Frame: From start of treatment through study completion (up to 42 days) ]
    The mortality from all-causes in each arm of the study for the full duration of the study.
  • Number of 24-hour Days Associated with the Treatment of the Infection [ Time Frame: Treatment period (7-14 days) ]
    Resource utilization
  • Number of Participants with Adverse Events [ Time Frame: From baseline through study completion (up to 42 days) ]
    Incidence and severity of adverse events in each arm of the study.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2017)
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at Test of Cure (TOC) [ Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days) ]
    Clinical outcome will be assessed by the investigator as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at TOC [ Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days) ]
    The microbiological outcome by baseline pathogen at TOC will be determined by the sponsor as either: eradication, persistence, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at Early Assessment (EA) [ Time Frame: Early assessment, defined as 3-4 days after the start of treatment. ]
    Clinical outcome at EA will be assessed as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Clinical Cure at End of Treatment (EOT) [ Time Frame: End of treatment, defined as the last day of study treatment (7-14 days) ]
    Clinical outcome will be assessed by the investigator at EOT as either: clinical cure, clinical failure, or indeterminate.
  • Percentage of Participants with a Clinical Outcome of Sustained Clinical Cure at Follow-up (FUP) [ Time Frame: Follow-up, defined as 14 days after the end of treatment (treatment duration is 7-14 days) ]
    Clinical outcome will be assessed by the investigator at FUP as either: Sustained clinical cure, relapse, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at EA [ Time Frame: Early assessment, defined as 3-4 days after the start of treatment. ]
    The microbiological outcome by baseline pathogen will be determined by the sponsor at EA as either: eradication, persistence, or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Eradication at EOT [ Time Frame: End of treatment, defined as the last day of study treatment (7-14 days) ]
    The microbiological outcome by baseline pathogen will be determined by the sponsor at EOT as either: eradication, persistence or indeterminate.
  • Percentage of Participants with a Microbiologic Outcome of Sustained Eradication at FUP [ Time Frame: Follow-up, defined as 14 days after the end of treatment (treatment duration is 7-14 days) ]
    Microbiological outcome by baseline pathogen will be determined by the sponsor at FUP as either: Sustained eradication, recurrence, or indeterminate.
  • All-cause Mortality at Day 28 [ Time Frame: Day 28 ]
    The mortality from all-causes in each arm of the study by the twenty-eighth day after the start of treatment.
  • All-cause Mortality Over the Full Duration of the Study [ Time Frame: From start of treatment through study completion (up to 42 days) ]
    The mortality from all-causes in each arm of the study for the full duration of the study.
  • Number of 24-hour Days Associated with the Treatment of the Infection [ Time Frame: Treatment period (7-14 days) ]
    Resource utilization
  • Number of Participants with Adverse Events [ Time Frame: From baseline through study completion (up to 42 days) ]
    Incidence and severity of adverse events in each arm of the study.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens
Official Title  ICMJE 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
Brief Summary To compare all-cause mortality at Day 14 in participants receiving S-649266 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Healthcare-associated Pneumonia (HCAP)
  • Hospital Acquired Pneumonia (HAP)
  • Ventilator Associated Pneumonia (VAP)
Intervention  ICMJE
  • Drug: S-649266
    2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)
    Other Name: Cefiderocol
  • 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 will be administered intravenously over 30 minutes to 2 hours, every 12 hours.
    Other Name: Zyvox®
Study Arms  ICMJE
  • Experimental: S-649266
    Participants will receive 2 g S-649266 administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.
    Interventions:
    • Drug: S-649266
    • Drug: Linezolid
  • 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.
    Interventions:
    • Drug: Meropenem
    • Drug: Linezolid
Publications * Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye KS, Kollef M, Menon A, Pogue JM, Shorr AF, Timsit JF, Zeitlinger M, Nagata TD. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2020 Oct 12. pii: S1473-3099(20)30731-3. doi: 10.1016/S1473-3099(20)30731-3. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 23, 2017)
300
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 1, 2019
Actual Primary Completion Date February 26, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   Estonia,   France,   Georgia,   Germany,   Hungary,   Israel,   Japan,   Latvia,   Philippines,   Puerto Rico,   Russian Federation,   Serbia,   Spain,   Taiwan,   Ukraine,   United States
Removed Location Countries Colombia
 
Administrative Information
NCT Number  ICMJE NCT03032380
Other Study ID Numbers  ICMJE 1615R2132
2016-003020-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Shionogi Inc. ( Shionogi )
Study Sponsor  ICMJE Shionogi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi
PRS Account Shionogi Inc.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP