Clinical trial NCT03032380: Clinical Study of Cefiderocol (S-649266) for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Healthcare-associated Pneumonia (HCAP)
Hospital Acquired Pneumonia (HAP)
Ventilator Associated Pneumonia (VAP)
Keywords: Hospital-acquired pneumonia (HAP)
S-649266
linezolid
meropenem
Healthcare-associated pneumonia (HCAP)
nosocomial pneumonia
Ventilator-associated pneumonia (VAP)
Gram-negative pathogens
pneumonia
cefiderocol
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2017-01-26
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to compare all-cause mortality at Day 14 in participants receiving cefiderocol with participants receiving the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens.


Eligibility 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.

Primary outcomes:
measure: All-cause Mortality Rate at Day 14
timeFrame: From first dose of study drug to Day 14
Secondary outcomes:
measure: Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC)
timeFrame: Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)
measure: Percentage of Participants With Clinical Cure at Test of Cure
timeFrame: Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)
measure: Percentage of Participants With Clinical Cure at Early Assessment (EA)
timeFrame: Early assessment (Day 3-4 after the start of treatment)
measure: Percentage of Participants With Clinical Cure at End of Treatment (EOT)
timeFrame: End of treatment (Day 7 to 14)
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up (FU)
timeFrame: Follow-up (14 days after the end of treatment; Day 21 to 28)
measure: Percentage of Participants With Microbiologic Eradication at Early Assessment
timeFrame: Early Assessment, Days 3 to 4
measure: Percentage of Participants With Microbiologic Eradication at End of Treatment
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up
timeFrame: Follow-up (14 days after the end of treatment, Days 21 to 28)
measure: All-cause Mortality Rate at Day 28
timeFrame: From first dose of study drug to Day 28
measure: All-cause Mortality Rate at the End of Study
timeFrame: From first dose of study drug through end of study (28 days after end of treatment, up to 42 days)
measure: Total Hospitalization Time
timeFrame: 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)
measure: Number of Participants With Treatment-Emergent Adverse Events
timeFrame: From first dose of study drug through the end of study, up to 42 days.
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Shionogi Research Site
state: Connecticut
city: DeLand
country: United States
facility: Shionogi Research Site
state: Florida
city: Chicago
country: United States
facility: Shionogi Research Site
state: Illinois
city: Council Bluffs
country: United States
facility: Shionogi Research Site
state: Iowa
city: Louisville
country: United States
facility: Shionogi Research Site
state: Kentucky
city: Baton Rouge
country: United States
facility: Shionogi Research Site
state: Louisiana
city: Shreveport
country: United States
facility: Shionogi Research Site
state: Louisiana
city: Annapolis
country: United States
facility: Shionogi Research Site
state: Maryland
city: Detroit
country: United States
facility: Shionogi Research Site
state: Michigan
city: Saint Louis
country: United States
facility: Shionogi Research Site
state: Missouri
city: Cleveland
country: United States
facility: Shionogi Research Site
state: Ohio
city: Columbus
country: United States
facility: Shionogi Research Site
state: Ohio
city: Bethlehem
country: United States
facility: Shionogi Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Shionogi Research Site
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Shionogi Research Site
state: Utah
city: Brussels
country: Belgium
facility: Shionogi Research Site
city: Brussels
country: Belgium
facility: Shionogi Research Site
city: Halifax
country: Canada
facility: Shionogi Research Site
state: Nova Scotia
city: Kingston
country: Canada
facility: Shionogi Research Site
state: Ontario
city: Brno
country: Czechia
facility: Shionogi Research Site
city: Hradec Kralove
country: Czechia
facility: Shionogi Research Site
city: Kolin
country: Czechia
facility: Shionogi Research Site
city: Kyjov
country: Czechia
facility: Shionogi Research Site
city: Ostrava-Poruba
country: Czechia
facility: Shionogi Research Site
city: Prague
country: Czechia
facility: Shionogi Research Site
city: Pribram
country: Czechia
facility: Shionogi Research Site
city: Kohtla-Jarve
country: Estonia
facility: Shionogi Research Site
city: Parnu
country: Estonia
facility: Shionogi Research Site
city: Tallin
country: Estonia
facility: Shionogi Research Site
city: Tartu
country: Estonia
facility: Shionogi Research Site
city: Angers
country: France
facility: Shionogi Research Site
city: Argenteuil
country: France
facility: Shionogi Research Site
city: Bron
country: France
facility: Shionogi Research Site
city: LaRoche-sur-Yon
country: France
facility: Shionogi Research Site
city: Lyon Cedex
country: France
facility: Shionogi Research Site
city: Nice
country: France
facility: Shionogi Research Site
city: Paris Cedex
country: France
facility: Shionogi Research Site
city: Batumi
country: Georgia
facility: Shionogi Research Site
city: Kutaisi
country: Georgia
facility: Shionogi Research Site
city: Kutaisi
country: Georgia
facility: Shionogi Research Site
city: Tbilisi
country: Georgia
facility: Shionogi Research Site
city: Bonn
country: Germany
facility: Shionogi Research Site
city: Hamburg
country: Germany
facility: Shionogi Research Site
city: Heidelberg
country: Germany
facility: Shionogi Research Site
city: Leipzig
country: Germany
facility: Shionogi Research Site
city: Budapest
country: Hungary
facility: Shionogi Research Site
city: Budapest
country: Hungary
facility: Shionogi Research Site
city: Debrecen
country: Hungary
facility: Shionogi Research Site
city: Fehergyarmat
country: Hungary
facility: Shionogi Research Site
city: Szekesfehervar
country: Hungary
facility: Shionogi Research Site
city: Holon
country: Israel
facility: Shionogi Research Site
city: Jerusalem
country: Israel
facility: Shionogi Research Site
city: Tel Aviv
country: Israel
facility: Shionogi Research Site
city: Tel Hashomer
country: Israel
facility: Shionogi Research Site
city: Tikva
country: Israel
facility: Shionogi Research Site
city: Maebashi
country: Japan
facility: Shionogi Research Site
state: Gunma
city: Tsuchiura
country: Japan
facility: Shionogi Research Site
state: Ibaraki
city: Tsu-city
country: Japan
facility: Shionogi Research Site
state: Mie
city: Shimajiri-gun
country: Japan
facility: Shionogi Research Site
state: Okinawa
city: Itabashi-ku
country: Japan
facility: Shionogi Research Site
state: Tokyo
city: Kumamoto
country: Japan
facility: Shionogi Research Site
city: Daugavpils
country: Latvia
facility: Shionogi Research Site
city: Liepaja
country: Latvia
facility: Shionogi Research Site
city: Riga
country: Latvia
facility: Shionogi Research Site
city: Saldus Novads
country: Latvia
facility: Shionogi Research Site
city: Jaro
country: Philippines
facility: Shionogi Research Site
state: Iloilo City
city: Tondo
country: Philippines
facility: Shionogi Research Site
state: Manila
city: Caloocan
country: Philippines
facility: Shionogi Research Site
state: Metro Manila
city: Quezon City
country: Philippines
facility: Shionogi Research Site
state: Metro Manila
city: Quezon City
country: Philippines
facility: Shionogi Research Site
state: Metro Manila
city: Caloocan City
country: Philippines
facility: Shionogi Research Site
city: Iloilo City
country: Philippines
facility: Shionogi Research Site
city: Manila
country: Philippines
facility: Shionogi Research Site
city: San Juan
country: Puerto Rico
facility: Shionogi Research Site
city: Barnaul
country: Russian Federation
facility: Shionogi Research Site
city: Barnaul
country: Russian Federation
facility: Shionogi Research Site
city: Chelyabinsk
country: Russian Federation
facility: Shionogi Research Site
city: Krasnodar
country: Russian Federation
facility: Shionogi Research Site
city: Moscow
country: Russian Federation
facility: Shionogi Research Site
city: Moscow
country: Russian Federation
facility: Shionogi Research Site
city: Moscow
country: Russian Federation
facility: Shionogi Research Site
city: Novosibirsk
country: Russian Federation
facility: Shionogi Research Site
city: Novosibirsk
country: Russian Federation
facility: Shionogi Research Site
city: Sait-Petersburg
country: Russian Federation
facility: Shionogi Research Site
city: Smolensk
country: Russian Federation
facility: Shionogi Research Site
city: St. Petersburg
country: Russian Federation
facility: Shionogi Research Site
city: St. Petersburg
country: Russian Federation
facility: Shionogi Research Site
city: St. Petersburg
country: Russian Federation
facility: Shionogi Research Site
city: St. Petersburg
country: Russian Federation
facility: Shionogi Research Site
city: Tomsk
country: Russian Federation
facility: Shionogi Research Site
city: Belgrade
country: Serbia
facility: Shionogi Research Site
city: Kragujev Ac
country: Serbia
facility: Shionogi Research Site
city: Sremska Kamenica
country: Serbia
facility: Shionogi Research Site
city: Alicante
country: Spain
facility: Shionogi Research Site
city: Barcelona
country: Spain
facility: Shionogi Research Site
city: Barcelona
country: Spain
facility: Shionogi Research Site
city: Barcelona
country: Spain
facility: Shionogi Research Site
city: Madrid
country: Spain
facility: Shionogi Research Site
city: Madrid
country: Spain
facility: Shionogi Research Site
city: Torrejon de Ardoz
country: Spain
facility: Shionogi Research Site
city: Torrevieja
country: Spain
facility: Shionogi Research Site
city: Valencia
country: Spain
facility: Shionogi Research Site
city: New Taipei City
country: Taiwan
facility: Shionogi Research Site
city: Taichung
country: Taiwan
facility: Shionogi Research Site
city: Taipei
country: Taiwan
facility: Shionogi Research Site
city: Taipei
country: Taiwan
facility: Shionogi Research Site
city: Chernivtsi
country: Ukraine
facility: Shionogi Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Shionogi Research Site
city: Ivano Frankivsk
country: Ukraine
facility: Shionogi Research Site
city: Kharkiv
country: Ukraine
facility: Shionogi Research Site
city: Kharkiv
country: Ukraine
facility: Shionogi Research Site
city: Kherson
country: Ukraine
facility: Shionogi Research Site
city: Kiev
country: Ukraine
facility: Shionogi Research Site
city: Kiev
country: Ukraine
facility: Shionogi Research Site
city: Kremenchuk
country: Ukraine
facility: Shionogi Research Site
city: Poltava
country: Ukraine
facility: Shionogi Research Site
city: Sumy
country: Ukraine
facility: Shionogi Research Site
city: Vinnitsya
country: Ukraine
facility: Shionogi Research Site
city: Zaporizhzhya
country: Ukraine
facility: Shionogi Research Site
Study officials:
affiliation: Shionogi
name: Shionogi Clinical Trials Administrator Clinical Support Help Line
role: STUDY_DIRECTOR
References:
citation: Nordmann P, Shields RK, Doi Y, Takemura M, Echols R, Matsunaga Y, Yamano Y. Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials. Microb Drug Resist. 2022 Apr;28(4):398-407. doi: 10.1089/mdr.2021.0180. Epub 2022 Jan 24.
citation: Skaar EP, Echols R, Matsunaga Y, Menon A, Portsmouth S. Iron serum levels and iron homeostasis parameters in patients with nosocomial pneumonia treated with cefiderocol: post hoc analysis of the APEKS-NP study. Eur J Clin Microbiol Infect Dis. 2022 Mar;41(3):467-476. doi: 10.1007/s10096-021-04399-9. Epub 2022 Jan 13.
citation: Wenzler E, Butler D, Tan X, Katsube T, Wajima T. Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy. Clin Pharmacokinet. 2022 Apr;61(4):539-552. doi: 10.1007/s40262-021-01086-y. Epub 2021 Nov 18.
citation: 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. 2021 Feb;21(2):213-225. doi: 10.1016/S1473-3099(20)30731-3. Epub 2020 Oct 12.