Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens

NCT02714595 | Completed Phase 3 Results DMC

• 2 other identifiers: 1424R21312015-004703-23
• Study Type: interventional
• Target: 152
• Locations: 16 countries
• Sites: 85

Brief Summary

This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.

Conditions

Healthcare-associated Pneumonia (HCAP); Bloodstream Infections (BSI); Hospital Acquired Pneumonia (HAP); Complicated Urinary Tract Infection (cUTI); Sepsis; Ventilator Associated Pneumonia (VAP)

Keywords

cefiderocol; Bloodstream infections (BSI); Complicated urinary tract infection (cUTI); Ventilator associated pneumonia (VAP); Hospital acquired pneumonia (HAP); Sepsis; multi-drug resistant pathogens; S-649266; Gram-negative pathogens; Healthcare-associated pneumonia (HCAP); carbapenem resistant pathogens

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Clinical Cure at Test of Cure (TOC) in Participants With HAP/VAP/HCAP or BSI/Sepsis

  Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. Participants with missing data were considered as non-responders.

  Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21

• Percentage of Participants With Microbiologic Eradication at TOC in Participants With cUTI

  Microbiological outcome per Baseline pathogen was determined by the sponsor as defined for each infection site. For cUTI eradication was defined as a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ colony-forming units (CFU)/mL was reduced to \< 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.

  Test of cure, defined as 7 days after the end of treatment, equivalent to Study Days 14 to 21

Secondary Outcomes (40)

• Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With HAP/VAP/HCAP or BSI/Sepsis

  End of treatment, Day 7 to 14

• Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) in Participants With HAP/VAP/HCAP or BSI/Sepsis

  Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28

• Percentage of Participants With Clinical Cure at Test of Cure in Participants With cUTI

  Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21

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

  End of treatment, Day 7 to 14

• Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With cUTI

  Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28

Study Arms (2)

Cefiderocol

EXPERIMENTAL

Participants will receive cefiderocol 2 g administered intravenously over 3 hours, every 8 hours for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.

Drug: Cefiderocol

Best Available Therapy (BAT)

ACTIVE COMPARATOR

Best available therapy (BAT) will be chosen by the investigator and may include up to three antibacterial agents for carbapenem resistant Gram-negative bacteria, intravenously administered per country-specific guidelines for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.

Drug: Best Available Therapy

Interventions

Cefiderocol DRUG

2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days, or 2 g every 6 hours for participants with creatinine clearance \>120 mL/min.

Also known as: S-649266, Fetroja ®

Cefiderocol

Best Available Therapy DRUG

Standard of care with either a polymyxin-based or non-polymyxin-based regimen as determined by the investigator and consisting of one to three marketed antibacterial agent(s).

Best Available Therapy (BAT)

Eligibility Criteria

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

You may qualify if:

• Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem resistance
• Patients who have been treated previously with an empiric antibiotic regiment and failed treatment, both clinically and microbiologically, are eligible for the study, if they have an identified carbapenem-resistant Gram-negative pathogen which has either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the empiric antibiotic regimen or been grown from a culture performed after at least 2 days of the empiric antibiotic regimen
• Patient is male (no contraception required) or female and meets one of the following criteria:
• Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery
• Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for 6 months and confirmed by a follicle-stimulating hormone level of \> 40 mIU/mL, or amenorrhea for at least 12 months)
• Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS) for the entire duration of the study
• Of childbearing potential and practice abstinence as a preferred and usual lifestyle, and agrees to continue practicing abstinence from Screening and for the entire duration of the study
• Of childbearing potential, whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study
• Patients meeting specific criteria for each infection site

You may not qualify if:

• Patients who have a history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
• Patients who need more than 3 systemic antibiotics as part of best available therapy (BAT) for the treatment of the Gram-negative infection (patients with mixed Gram-positive or anaerobic infections may receive appropriate concomitant narrow spectrum antibiotics \[eg, vancomycin, linezolid, metronidazole, clindamycin\])
• Patients with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
• Patients who have central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection)
• Patients with infection requiring \> 3 weeks of antibiotic treatment (eg, bone and joint infection, endocarditis)
• Patients with cystic fibrosis or moderate to severe bronchiectasis
• Patients in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of Randomization
• Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) \< 100 cells/μL
• Female patients who have a positive pregnancy test at Screening or who are lactating
• Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score \> 30
• Patients who have received a potentially effective antibiotic regimen for the carbapenem-resistant Gram-negative infection for a continuous duration of more than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 72 hours leading to Randomization
• Patients with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of the study data
• Patients who have received another investigational drug or device within 30 days prior to study entry
• Patients who have previously been randomized in this study or received S-649266
• Patients receiving peritoneal dialysis

Sponsors & Collaborators

• Shionogi: lead

Study Sites (85)

Shionogi Research Site

Hartford, Connecticut, 06102, United States

Location

Shionogi Research Site

Newark, Delaware, 19718, United States

Location

Shionogi Research Site

Chicago, Illinois, 60611, United States

Location

Shionogi Research Site

New Orleans, Louisiana, 70121, United States

Location

Shionogi Research Site

Detroit, Michigan, 48202, United States

Location

Shionogi Research Site

Pittsburgh, Pennsylvania, 15213, United States

Location

Shionogi Research Site

Salvador, Estado de Bahia, 41810-011, Brazil

Location

Shionogi Research Site

Curitiba, Paraná, 80050, Brazil

Location

Shionogi Research Site

Passo Fundo, Rio Grande do Sul, 99010-080, Brazil

Location

Shionogi Research Site

Porto Alegre, Rio Grande do Sul, 90035-074, Brazil

Location

Shionogi Research Site

Porto Alegre, Rio Grande do Sul, 90035-903, Brazil

Location

Shionogi Research Site

Santa Maria, Rio Grande do Sul, 97105-900, Brazil

Location

Shionogi Research Site

São José do Rio Preto, São Paulo, 15090, Brazil

Location

Shionogi Research Site

São Paulo, São Paulo, 04378-000, Brazil

Location

Shionogi Research Site

Rijeka, Primorje-Gorski Kotar County, 51000, Croatia

Location

Shionogi Research Site

Split, 21000, Croatia

Location

Shionogi Research Site

Zagreb, 10000, Croatia

Location

Shionogi Research Site

La Tronche, Auvergne-Rhône-Alpes, 38043, France

Location

Shionogi Research Site

Paris, Île-de-France Region, 75018, France

Location

Shionogi Research Site

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Shionogi Research Site

Bonn, North Rhine-Westphalia, 53105, Germany

Location

Shionogi Research Site

Berlin, 12351, Germany

Location

Shionogi Research Site

Athens, Attica, 11526, Greece

Location

Shionogi Research Site

Athens, Attica, 12462, Greece

Location

Shionogi Research Site

Patra, Peloponnese, 26504, Greece

Location

Shionogi Research Site

Larissa, Thessaly, 41110, Greece

Location

Shionogi Research Site

Larissa, Thessaly, 41221, Greece

Location

Shionogi Research Site

Guatemala City, Guatemala

Location

Shionogi Research Site

Beersheba, Beersheba, 84101, Israel

Location

Shionogi Research Site

Be’er Ya‘aqov, Rehoboth, 70300, Israel

Location

Shionogi Research Site

Tel Aviv, Tel Aviv, 64239, Israel

Location

Shionogi Research Site

Tel Litwinsky, Tel Aviv, 52621, Israel

Location

Shionogi Research Site

Safed, Zefat, 13100, Israel

Location

Shionogi Research Site

Hadera, 38100, Israel

Location

Shionogi Research Site

Haifa, 31048, Israel

Location

Shionogi Research Site

Haifa, 3109601, Israel

Location

Shionogi Research Site

Holon, 58100, Israel

Location

Shionogi Research Site

Jerusalem, 91120, Israel

Location

Shionogi Research Site

Cisanello, PISA, 56124, Italy

Location

Shionogi Research Site

Milan, 20122, Italy

Location

Shionogi Research Site

Milan, 20132, Italy

Location

Shionogi Research Site

Milan, 20162, Italy

Location

Shionogi Research Site

Modena, 41124, Italy

Location

Shionogi Research Site

Udine, 33100, Italy

Location

Shionogi Research Site

Nagakute, Aichi-ken, 480-1195, Japan

Location

Shionogi Research Site

Shinagawa-ku, Tokyo, 142-8999, Japan

Location

Shionogi Research Site

Nagasaki, 852-8501, Japan

Location

Shionogi Research Site

Wŏnju, Gangwon-do, 26426, South Korea

Location

Shionogi Research Site

Seoul, Gwangjin-gu, 5030, South Korea

Location

Shionogi Research Site

Daegu, 41931, South Korea

Location

Shionogi Research Site

Daegu, 41944, South Korea

Location

Shionogi Research Site

Seoul, 06591, South Korea

Location

Shionogi Research Site

Seoul, 06973, South Korea

Location

Shionogi Research Site

Seoul, 07441, South Korea

Location

Shionogi Research Site

Seoul, 135-710, South Korea

Location

Shionogi Research Site

Terrassa, Barcelona, 08035, Spain

Location

Shionogi Research Site

Córdoba, Cordoba, 14004, Spain

Location

Shionogi Research Site

Lleida, Lleida, 25198, Spain

Location

Shionogi Research Site

Barcelona, 08003, Spain

Location

Shionogi Research Site

Barcelona, 08025, Spain

Location

Shionogi Research Site

Barcelona, 08036, Spain

Location

Shionogi Research Site

Ciudad Real, 13005, Spain

Location

Shionogi Research Site

Girona, 17007, Spain

Location

Shionogi Research Site

Madrid, 28046, Spain

Location

Shionogi Research Site

Málaga, 29010, Spain

Location

Shionogi Research Site

Seville, 41009, Spain

Location

Shionogi Research Site

Valencia, 46015, Spain

Location

Shionogi Research Site

Zaragoza, 50009, Spain

Location

Shionogi Research Site

Hualien City, Hualien, 97002, Taiwan

Location

Shionogi Research Site

Taichung, ROC, 40705, Taiwan

Location

Shionogi Research Site

Taipei City, Taipei, 10002, Taiwan

Location

Shionogi Research Site

Kaohsiung City, 81362, Taiwan

Location

Shionogi Research Site

Taichung, 40447, Taiwan

Location

Shionogi Research Site

Bangkok, 10700, Thailand

Location

Shionogi Research Site

Muang Nonthaburi, 11000, Thailand

Location

Shionogi Research Site

Muang, 40002, Thailand

Location

Shionogi Research Site

Bornova, İzmir, 35100, Turkey (Türkiye)

Location

Shionogi Research Site

Ankara, Turkey (Türkiye)

Location

Shionogi Research Site

Istanbul, 34098, Turkey (Türkiye)

Location

Shionogi Research Site

Istanbul, 34214, Turkey (Türkiye)

Location

Shionogi Research Site

Trabzon, Turkey (Türkiye)

Location

Shionogi Research Site

London, England, SE1 7EH, United Kingdom

Location

Shionogi Research Site

London, England, W 120NN, United Kingdom

Location

Shionogi Research Site

London, England, W12 0HS, United Kingdom

Location

Shionogi Research Site

London, England, United Kingdom

Location

Related Publications (5)

• 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

• 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

• Naseer S, Weinstein EA, Rubin DB, Suvarna K, Wei X, Higgins K, Goodwin A, Jang SH, Iarikov D, Farley J, Nambiar S. US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja(R)). Clin Infect Dis. 2021 Jun 15;72(12):e1103-e1111. doi: 10.1093/cid/ciaa1799.

  PMID: 33393598 DERIVED

• Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, Lodise TP, Naas T, Niki Y, Paterson DL, Portsmouth S, Torre-Cisneros J, Toyoizumi K, Wunderink RG, Nagata TD. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240. doi: 10.1016/S1473-3099(20)30796-9. Epub 2020 Oct 12.

  PMID: 33058795 DERIVED

• Bassetti M, Ariyasu M, Binkowitz B, Nagata TD, Echols RM, Matsunaga Y, Toyoizumi K, Doi Y. Designing A Pathogen-Focused Study To Address The High Unmet Medical Need Represented By Carbapenem-Resistant Gram-Negative Pathogens - The International, Multicenter, Randomized, Open-Label, Phase 3 CREDIBLE-CR Study. Infect Drug Resist. 2019 Nov 21;12:3607-3623. doi: 10.2147/IDR.S225553. eCollection 2019.

  PMID: 31819544 DERIVED

MeSH Terms

Conditions

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

Interventions

Cefiderocol

Condition Hierarchy (Ancestors)

Cross Infection; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Systemic Inflammatory Response Syndrome; Inflammation

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

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: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 21, 2016
• Study Start: September 7, 2016
• Primary Completion: April 1, 2019
• Study Completion: April 22, 2019
• Last Updated: January 12, 2021
• Results First Posted: December 17, 2020

Record last verified: 2020-12

Locations

DE (3); IL (10); JP (3); ES (13); IT (6); CR (3); GR (5); KR (8); GB (4); US (6); BR (8); TW (5); FR (2); TU (5); TH (3); GU (1)