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

NCT ID: NCT03032380

Last Updated: 2020-11-13

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

300 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-10-24

Study Completion Date

2019-04-01

Brief Summary

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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.

Detailed Description

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Conditions

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

Keywords

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Hospital-acquired pneumonia (HAP) S-649266 linezolid meropenem Healthcare-associated pneumonia (HCAP) nosocomial pneumonia Ventilator-associated pneumonia (VAP) Gram-negative pathogens pneumonia cefiderocol

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Cefiderocol

Participants will receive 2 g cefiderocol administered intravenously every 8 hours for 7 to 14 days and 600 mg linezolid administered intravenously every 12 hours for at least 5 days.

Group Type EXPERIMENTAL

Cefiderocol

Intervention Type DRUG

2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)

Linezolid

Intervention Type DRUG

600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.

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.

Group Type ACTIVE_COMPARATOR

Meropenem

Intervention Type DRUG

2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function)

Linezolid

Intervention Type DRUG

600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.

Interventions

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Cefiderocol

2000 mg intravenously every 8 hours for a period of 7 to14 days (dosage adjustment is necessary based on renal function)

Intervention Type DRUG

Meropenem

2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function)

Intervention Type DRUG

Linezolid

600 mg of linezolid administered intravenously over 30 minutes to 2 hours, every 12 hours.

Intervention Type DRUG

Other Intervention Names

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S-649266 Merrem® Zyvox®

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Shionogi

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Shionogi Clinical Trials Administrator Clinical Support Help Line

Role: STUDY_DIRECTOR

Shionogi

Locations

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Shionogi Research Site

New Haven, Connecticut, United States

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DeLand, Florida, United States

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Chicago, Illinois, United States

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Council Bluffs, Iowa, United States

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Louisville, Kentucky, United States

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Baton Rouge, Louisiana, United States

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Shreveport, Louisiana, United States

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Annapolis, Maryland, United States

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Detroit, Michigan, United States

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St Louis, Missouri, United States

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Cleveland, Ohio, United States

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Columbus, Ohio, United States

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Bethlehem, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Salt Lake City, Utah, United States

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Brussels, , Belgium

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Brussels, , Belgium

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Halifax, Nova Scotia, Canada

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Kingston, Ontario, Canada

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Brno, , Czechia

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Hradec Králové, , Czechia

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Kolín, , Czechia

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Kyjov, , Czechia

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Ostrava-Poruba, , Czechia

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Prague, , Czechia

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Příbram, , Czechia

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Kohtla-Järve, , Estonia

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Pärnu, , Estonia

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Tallinn, , Estonia

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Tartu, , Estonia

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Angers, , France

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Argenteuil, , France

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Bron, , France

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LaRoche-sur-Yon, , France

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Lyon, , France

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Nice, , France

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Paris, , France

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Batumi, , Georgia

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Kutaisi, , Georgia

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Kutaisi, , Georgia

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Tbilisi, , Georgia

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Bonn, , Germany

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Hamburg, , Germany

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Heidelberg, , Germany

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Leipzig, , Germany

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Budapest, , Hungary

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Budapest, , Hungary

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Debrecen, , Hungary

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Fehérgyarmat, , Hungary

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Székesfehérvár, , Hungary

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Holon, , Israel

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Jerusalem, , Israel

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Tel Aviv, , Israel

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Tel Litwinsky, , Israel

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Tikva, , Israel

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Maebashi, Gunma, Japan

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Tsuchiura, Ibaraki, Japan

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Tsu, Mie-ken, Japan

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Shimajiri-gun, Okinawa, Japan

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Itabashi-ku, Tokyo, Japan

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Kumamoto, , Japan

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Daugavpils, , Latvia

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Liepāja, , Latvia

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Riga, , Latvia

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Saldus Novads, , Latvia

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Jaro, Iloilo City, Philippines

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Tondo, Manila, Philippines

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Caloocan City, National Capital Region, Philippines

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Quezon City, National Capital Region, Philippines

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Quezon City, National Capital Region, Philippines

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Caloocan City, , Philippines

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Iloilo City, , Philippines

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Manila, , Philippines

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San Juan, , Puerto Rico

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Barnaul, , Russia

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Barnaul, , Russia

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Chelyabinsk, , Russia

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Krasnodar, , Russia

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Moscow, , Russia

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Moscow, , Russia

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Moscow, , Russia

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Novosibirsk, , Russia

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Novosibirsk, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Saint Petersburg, , Russia

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Sait-Petersburg, , Russia

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Smolensk, , Russia

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Tomsk, , Russia

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Belgrade, , Serbia

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Kamenitz, , Serbia

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Kragujevac, , Serbia

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Alicante, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Torrejón de Ardoz, , Spain

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Torrevieja, , Spain

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Valencia, , Spain

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New Taipei City, , Taiwan

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Taichung, , Taiwan

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Taipei, , Taiwan

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Taipei, , Taiwan

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Chernivtsi, , Ukraine

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Dnipropetrovsk, , Ukraine

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Ivano-Frankivsk, , Ukraine

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Kharkiv, , Ukraine

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Kharkiv, , Ukraine

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Kherson, , Ukraine

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Kiev, , Ukraine

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Kiev, , Ukraine

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Kremenchuk, , Ukraine

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Poltava, , Ukraine

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Sumy, , Ukraine

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Vinnitsya, , Ukraine

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Zaporizhzhya, , Ukraine

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Countries

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

References

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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.

Reference Type DERIVED
PMID: 35076335 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35025025 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34792787 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33058798 (View on PubMed)

Provided Documents

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Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

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2016-003020-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1615R2132

Identifier Type: -

Identifier Source: org_study_id