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

• Sponsor: Shionogi
• Information provided by (Responsible Party): Shionogi Inc. ( Shionogi )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Healthcare-associated Pneumonia (HCAP); Hospital Acquired Pneumonia (HAP); Ventilator Associated Pneumonia (VAP)	Drug: S-649266; Drug: Meropenem; Drug: Linezolid	Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
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.	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: Linezolid; 600 mg of Linezolid will be 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 will be administered intravenously over 30 minutes to 2 hours, every 12 hours.; Other Name: Zyvox®

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. Number of 24-hour Days Associated with the Treatment of the Infection [ Time Frame: Treatment period (7-14 days) ]
    Resource utilization
12. 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.

Eligibility Criteria

• 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.

Contacts and Locations

  Show 119 Study Locations

Sponsors and Collaborators

Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line; Shionogi

More Information

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT03032380 History of Changes
• Other Study ID Numbers: 1615R2132; 2016-003020-23 ( EudraCT Number )
• First Posted: January 26, 2017
• Last Update Posted: April 4, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Pneumonia; Pneumonia, Ventilator-Associated; Healthcare-Associated Pneumonia; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Cross Infection; Infection; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Linezolid; Meropenem; Cephalosporins; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action