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

Ventilator Associated Pneumonia (VAP) Clinical Trial

— APEKS-NP  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03032380
• Other study ID #: 1615R2132
• Secondary ID: 2016-003020-23
• Status: Completed
• Phase: Phase 3
• Start date: October 24, 2017
• Est. completion date: April 1, 2019

Study information

• Verified date: October 2020
• Source: Shionogi Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: April 1, 2019
• Est. primary completion date: February 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Healthcare-Associated Pneumonia
• Healthcare-associated Pneumonia (HCAP)
• Hospital Acquired Pneumonia (HAP)
• Pneumonia
• Pneumonia, Ventilator-Associated
• Ventilator Associated Pneumonia (VAP)

Intervention

Drug:
• Cefiderocol
2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)
• Meropenem
2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function)
• Linezolid
600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.

Locations

Country	Name	City	State
Belgium	Shionogi Research Site	Brussels
Belgium	Shionogi Research Site	Brussels
Canada	Shionogi Research Site	Halifax	Nova Scotia
Canada	Shionogi Research Site	Kingston	Ontario
Czechia	Shionogi Research Site	Brno
Czechia	Shionogi Research Site	Hradec Kralove
Czechia	Shionogi Research Site	Kolin
Czechia	Shionogi Research Site	Kyjov
Czechia	Shionogi Research Site	Ostrava-Poruba
Czechia	Shionogi Research Site	Prague
Czechia	Shionogi Research Site	Pribram
Estonia	Shionogi Research Site	Kohtla-Jarve
Estonia	Shionogi Research Site	Parnu
Estonia	Shionogi Research Site	Tallin
Estonia	Shionogi Research Site	Tartu
France	Shionogi Research Site	Angers
France	Shionogi Research Site	Argenteuil
France	Shionogi Research Site	Bron
France	Shionogi Research Site	LaRoche-sur-Yon
France	Shionogi Research Site	Lyon Cedex
France	Shionogi Research Site	Nice
France	Shionogi Research Site	Paris Cedex
Georgia	Shionogi Research Site	Batumi
Georgia	Shionogi Research Site	Kutaisi
Georgia	Shionogi Research Site	Kutaisi
Georgia	Shionogi Research Site	Tbilisi
Germany	Shionogi Research Site	Bonn
Germany	Shionogi Research Site	Hamburg
Germany	Shionogi Research Site	Heidelberg
Germany	Shionogi Research Site	Leipzig
Hungary	Shionogi Research Site	Budapest
Hungary	Shionogi Research Site	Budapest
Hungary	Shionogi Research Site	Debrecen
Hungary	Shionogi Research Site	Fehergyarmat
Hungary	Shionogi Research Site	Szekesfehervar
Israel	Shionogi Research Site	Holon
Israel	Shionogi Research Site	Jerusalem
Israel	Shionogi Research Site	Tel Aviv
Israel	Shionogi Research Site	Tel Hashomer
Israel	Shionogi Research Site	Tikva
Japan	Shionogi Research Site	Itabashi-ku	Tokyo
Japan	Shionogi Research Site	Kumamoto
Japan	Shionogi Research Site	Maebashi	Gunma
Japan	Shionogi Research Site	Shimajiri-gun	Okinawa
Japan	Shionogi Research Site	Tsu-city	Mie
Japan	Shionogi Research Site	Tsuchiura	Ibaraki
Latvia	Shionogi Research Site	Daugavpils
Latvia	Shionogi Research Site	Liepaja
Latvia	Shionogi Research Site	Riga
Latvia	Shionogi Research Site	Saldus Novads
Philippines	Shionogi Research Site	Caloocan	Metro Manila
Philippines	Shionogi Research Site	Caloocan City
Philippines	Shionogi Research Site	Iloilo City
Philippines	Shionogi Research Site	Jaro	Iloilo City
Philippines	Shionogi Research Site	Manila
Philippines	Shionogi Research Site	Quezon City	Metro Manila
Philippines	Shionogi Research Site	Quezon City	Metro Manila
Philippines	Shionogi Research Site	Tondo	Manila
Puerto Rico	Shionogi Research Site	San Juan
Russian Federation	Shionogi Research Site	Barnaul
Russian Federation	Shionogi Research Site	Barnaul
Russian Federation	Shionogi Research Site	Chelyabinsk
Russian Federation	Shionogi Research Site	Krasnodar
Russian Federation	Shionogi Research Site	Moscow
Russian Federation	Shionogi Research Site	Moscow
Russian Federation	Shionogi Research Site	Moscow
Russian Federation	Shionogi Research Site	Novosibirsk
Russian Federation	Shionogi Research Site	Novosibirsk
Russian Federation	Shionogi Research Site	Sait-Petersburg
Russian Federation	Shionogi Research Site	Smolensk
Russian Federation	Shionogi Research Site	St. Petersburg
Russian Federation	Shionogi Research Site	St. Petersburg
Russian Federation	Shionogi Research Site	St. Petersburg
Russian Federation	Shionogi Research Site	St. Petersburg
Russian Federation	Shionogi Research Site	Tomsk
Serbia	Shionogi Research Site	Belgrade
Serbia	Shionogi Research Site	Kragujev Ac
Serbia	Shionogi Research Site	Sremska Kamenica
Spain	Shionogi Research Site	Alicante
Spain	Shionogi Research Site	Barcelona
Spain	Shionogi Research Site	Barcelona
Spain	Shionogi Research Site	Barcelona
Spain	Shionogi Research Site	Madrid
Spain	Shionogi Research Site	Madrid
Spain	Shionogi Research Site	Torrejon de Ardoz
Spain	Shionogi Research Site	Torrevieja
Spain	Shionogi Research Site	Valencia
Taiwan	Shionogi Research Site	New Taipei City
Taiwan	Shionogi Research Site	Taichung
Taiwan	Shionogi Research Site	Taipei
Taiwan	Shionogi Research Site	Taipei
Ukraine	Shionogi Research Site	Chernivtsi
Ukraine	Shionogi Research Site	Dnipropetrovsk
Ukraine	Shionogi Research Site	Ivano Frankivsk
Ukraine	Shionogi Research Site	Kharkiv
Ukraine	Shionogi Research Site	Kharkiv
Ukraine	Shionogi Research Site	Kherson
Ukraine	Shionogi Research Site	Kiev
Ukraine	Shionogi Research Site	Kiev
Ukraine	Shionogi Research Site	Kremenchuk
Ukraine	Shionogi Research Site	Poltava
Ukraine	Shionogi Research Site	Sumy
Ukraine	Shionogi Research Site	Vinnitsya
Ukraine	Shionogi Research Site	Zaporizhzhya
United States	Shionogi Research Site	Annapolis	Maryland
United States	Shionogi Research Site	Baton Rouge	Louisiana
United States	Shionogi Research Site	Bethlehem	Pennsylvania
United States	Shionogi Research Site	Chicago	Illinois
United States	Shionogi Research Site	Cleveland	Ohio
United States	Shionogi Research Site	Columbus	Ohio
United States	Shionogi Research Site	Council Bluffs	Iowa
United States	Shionogi Research Site	DeLand	Florida
United States	Shionogi Research Site	Detroit	Michigan
United States	Shionogi Research Site	Louisville	Kentucky
United States	Shionogi Research Site	New Haven	Connecticut
United States	Shionogi Research Site	Philadelphia	Pennsylvania
United States	Shionogi Research Site	Saint Louis	Missouri
United States	Shionogi Research Site	Salt Lake City	Utah
United States	Shionogi Research Site	Shreveport	Louisiana

Sponsors (1)

Lead Sponsor	Collaborator
Shionogi

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  Estonia,  France,  Georgia,  Germany,  Hungary,  Israel,  Japan,  Latvia,  Philippines,  Puerto Rico,  Russian Federation,  Serbia,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	From first dose of study drug to Day 14
Secondary	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.	Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)
Secondary	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.	Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)
Secondary	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.	Early assessment (Day 3-4 after the start of treatment)
Secondary	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.	End of treatment (Day 7 to 14)
Secondary	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.	Follow-up (14 days after the end of treatment; Day 21 to 28)
Secondary	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.	Early Assessment, Days 3 to 4
Secondary	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.	End of treatment, Day 7 to 14
Secondary	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.	Follow-up (14 days after the end of treatment, Days 21 to 28)
Secondary	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.	From first dose of study drug to Day 28
Secondary	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.	From first dose of study drug through end of study (28 days after end of treatment, up to 42 days)
Secondary	Total Hospitalization Time	The length of hospital stay attributable to the study-qualifying infection.	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)
Secondary	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	From first dose of study drug through the end of study, up to 42 days.