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

NCT03032380 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 1615R21322016-003020-23
• Study Type: interventional
• Target: 300
• Locations: 18 countries
• Sites: 115

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC)

  Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)

• Percentage of Participants With Clinical Cure at Test of Cure

  Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)

• Percentage of Participants With Clinical Cure at Early Assessment (EA)

  Early assessment (Day 3-4 after the start of treatment)

• Percentage of Participants With Clinical Cure at End of Treatment (EOT)

  End of treatment (Day 7 to 14)

• Percentage of Participants With Sustained Clinical Cure at Follow-up (FU)

  Follow-up (14 days after the end of treatment; Day 21 to 28)

Study Arms (2)

Cefiderocol

EXPERIMENTAL

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.

Drug: Cefiderocol; Drug: Linezolid

Meropenem

ACTIVE COMPARATOR

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; Drug: Linezolid

Interventions

Cefiderocol DRUG

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

Also known as: S-649266

Cefiderocol

Meropenem DRUG

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

Also known as: Merrem®

Meropenem

Linezolid DRUG

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

Also known as: Zyvox®

Cefiderocol; Meropenem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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 \[PaO2/FiO2\])
• 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
• 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:
• Documented fever (ie, core body temperature \[tympanic, rectal, esophageal\] ≥ 38°C \[100.4°F\], oral temperature ≥ 37.5°C, or axillary temperature ≥ 37°C)
• Hypothermia (ie, core body temperature \[tympanic, rectal, esophageal\] ≤ 35°C \[95.0°F\], oral temperature ≤ 35.5°C and axillary temperature ≤ 36°C)
• Leukocytosis with a total peripheral white blood cell (WBC) count ≥ 10,000 cells/mm³
• Leukopenia with total peripheral WBC count ≤ 4500 cells/mm³
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Shionogi: lead

Study Sites (119)

Shionogi Research Site

New Haven, Connecticut, 06511, United States

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DeLand, Florida, 32720, United States

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Chicago, Illinois, 60612, United States

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Council Bluffs, Iowa, 51503, United States

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Louisville, Kentucky, 40202, United States

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Baton Rouge, Louisiana, 70808, United States

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Shreveport, Louisiana, 71103, United States

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Annapolis, Maryland, 21404, United States

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Detroit, Michigan, 48201, United States

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St Louis, Missouri, 63110-0250, United States

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Cleveland, Ohio, 44106, United States

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Columbus, Ohio, 43210-1267, United States

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Bethlehem, Pennsylvania, 18105, United States

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Philadelphia, Pennsylvania, 19141, United States

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Salt Lake City, Utah, 84132, United States

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Brussels, 1020, Belgium

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Brussels, 1070, Belgium

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Halifax, Nova Scotia, B3H3A7, Canada

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Kingston, Ontario, K7L 2V7, Canada

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Brno, 65693, Czechia

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Hradec Králové, 50005, Czechia

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Kolín, 28000, Czechia

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Kyjov, 69701, Czechia

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Ostrava-Poruba, 708 52, Czechia

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Prague, 15006, Czechia

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Příbram, 26101, Czechia

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Kohtla-Järve, 31025, Estonia

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Pärnu, 80010, Estonia

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Tallinn, 13419, Estonia

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Tartu, 51014, Estonia

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Angers, 49933, France

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Argenteuil, 95100, France

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Bron, 69677, France

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LaRoche-sur-Yon, 85925, France

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Lyon, 69437, France

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Nice, 06202, France

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Paris, 75018, France

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Batumi, 6010, Georgia

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Kutaisi, 4600, Georgia

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Kutaisi, 4601, Georgia

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Tbilisi, 0160, Georgia

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Bonn, 53127, Germany

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Hamburg, 20246, Germany

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Heidelberg, 69120, Germany

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Leipzig, 04103, Germany

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Budapest, 1121, Hungary

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Budapest, 1125, Hungary

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Debrecen, H-4031, Hungary

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Fehérgyarmat, 4900, Hungary

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Székesfehérvár, 8000, Hungary

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Holon, 58100, Israel

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Jerusalem, 9103102, Israel

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Tel Aviv, 64239, Israel

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Tel Litwinsky, 52621, Israel

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Tikva, 49100, Israel

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Maebashi, Gunma, 371-8511, Japan

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Tsuchiura, Ibaraki, 300-8585, Japan

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Tsu, Mie-ken, 514-8507, Japan

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Shimajiri-gun, Okinawa, 901-1193, Japan

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Itabashi-ku, Tokyo, 173-8610, Japan

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Kumamoto, 860-0008, Japan

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Daugavpils, LV-5417, Latvia

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Liepāja, LV-3414, Latvia

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Riga, LV-1006, Latvia

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Saldus Novads, LV-1002, Latvia

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Jaro, Iloilo City, 5000, Philippines

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Tondo, Manila, 1012, Philippines

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Caloocan, National Capital Region, 1400, Philippines

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Quezon City, National Capital Region, 1104, Philippines

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Quezon City, National Capital Region, 1109, Philippines

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Caloocan, 1427, Philippines

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Iloilo City, 5000, Philippines

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Manila, 1000, Philippines

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San Juan, 00921, Puerto Rico

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Barnaul, 656024, Russia

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Barnaul, 656045, Russia

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Chelyabinsk, 454000, Russia

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Krasnodar, 350012, Russia

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Moscow, 105203, Russia

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Moscow, 115280, Russia

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Moscow, 127015, Russia

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Novosibirsk, 630051, Russia

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Novosibirsk, 630075, Russia

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Saint Petersburg, 192242, Russia

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Saint Petersburg, 196247, Russia

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Saint Petersburg, 197706, Russia

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Saint Petersburg, 454091, Russia

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Sait-Petersburg, 194354, Russia

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Smolensk, 214019, Russia

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Tomsk, 634063, Russia

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Belgrade, 11000, Serbia

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Kamenitz, 21204, Serbia

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Kragujevac, 34000, Serbia

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Alicante, 03010, Spain

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Barcelona, 08003, Spain

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Barcelona, 08026, Spain

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Barcelona, 8036, Spain

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Madrid, 28007, Spain

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Madrid, 28922, Spain

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Torrejón de Ardoz, 28850, Spain

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Torrevieja, 03186, Spain

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Valencia, 46010, Spain

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New Taipei City, 235, Taiwan

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Taichung, 40705, Taiwan

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Taipei, 10002, Taiwan

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Taipei, 11696, Taiwan

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Chernivtsi, 58001, Ukraine

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Dnipropetrovsk, 49000, Ukraine

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Ivano-Frankivsk, 76008, Ukraine

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Kharkiv, 61037, Ukraine

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Kharkiv, 61103, Ukraine

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Kherson, 73000, Ukraine

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Kiev, 01133, Ukraine

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Kiev, 041112, Ukraine

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Kremenchuk, 39617, Ukraine

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Poltava, 36038, Ukraine

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Sumy, 40031, Ukraine

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Vinnitsya, 21029, Ukraine

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Zaporizhzhya, 69035, Ukraine

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Related Publications (4)

• 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.

  PMID: 35076335 DERIVED

• 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.

  PMID: 35025025 DERIVED

• 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.

  PMID: 34792787 DERIVED

• 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.

  PMID: 33058798 DERIVED

MeSH Terms

Conditions

Healthcare-Associated Pneumonia; Pneumonia, Ventilator-Associated; Pneumonia

Interventions

Cefiderocol; Meropenem; Linezolid

Condition Hierarchy (Ancestors)

Cross Infection; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thienamycins; Carbapenems; Acetamides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Shionogi Clinical Trials Administrator
• Organization: Shionogi Inc.

shionogiclintrials-admin@shionogi.co.jp

800-849-9707

Study Officials

• Shionogi Clinical Trials Administrator Clinical Support Help Line

  Shionogi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: January 17, 2017
• First Posted: January 26, 2017
• Study Start: October 24, 2017
• Primary Completion: February 26, 2019
• Study Completion: April 1, 2019
• Last Updated: November 13, 2020
• Results First Posted: November 13, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

JP (6); SE (3); IL (5); ES (9); HU (5); PH (8); RU (16); BE (2); DE (4); CZ (7); LA (4); US (15); FR (7); CA (2); PR (1); TW (4); UA (13); GE (4)