Clinical trial NCT02714595: Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
Official title: A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2016-03-21
Enrollment: 152
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: 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.

Detailed description: This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients with either hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI)/sepsis caused by carbapenem-resistant Gram-negative pathogens.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

1. 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)
2. 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 \[eg, vancomycin, linezolid, metronidazole, clindamycin\])
3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
4. Patients who have central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection)
5. Patients with infection requiring \> 3 weeks of antibiotic treatment (eg, bone and joint infection, endocarditis)
6. Patients with cystic fibrosis or moderate to severe bronchiectasis
7. Patients in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of Randomization
8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) \< 100 cells/μL
9. Female patients who have a positive pregnancy test at Screening or who are lactating
10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score \> 30
11. 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
12. 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
13. Patients who have received another investigational drug or device within 30 days prior to study entry
14. Patients who have previously been randomized in this study or received S-649266
15. Patients receiving peritoneal dialysis
16. Patients meeting specific exclusion criteria for each infection site

Primary outcomes:
measure: Percentage of Participants With Clinical Cure at Test of Cure (TOC) in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Microbiologic Eradication at TOC in Participants With cUTI
timeFrame: Test of cure, defined as 7 days after the end of treatment, equivalent to Study Days 14 to 21
Secondary outcomes:
measure: Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Clinical Cure at Test of Cure in Participants With cUTI
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With cUTI
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With cUTI
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Clinical Cure at End of Treatment in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Clinical Cure at Test of Cure in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Clinical Cure at End of Treatment By Baseline Pathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Clinical Cure at Test of Cure By Baseline Pathogen
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Pathogen
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Clinical Cure at EOT By Baseline Carbapenem-resistant Pathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Clinical Cure at TOC By Baseline Carbapenem-resistant Pathogen
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Carbapenem-resistant Pathogen
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP or BSI/Sepsis
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT in Participants With cUTI
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With cUTI
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT By Baseline Pathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiologic Eradication at TOC By Baseline Pathogen
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Pathogen
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT By Baseline Carbapenem-resistant Pathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiologic Eradication at TOC By Baseline Carbapenem-resistant Pathogen
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Carbapenem-resistant Pathogen
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With Microbiologic Eradication at EOT in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiologic Eradication at TOC in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: Percentage of Participants With a Composite Clinical and Microbiological Response at EOT
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With a Composite Clinical and Microbiological Response at TOC
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Percentage of Participants With a Composite Clinical and Microbiological Response at Follow-up
timeFrame: Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
measure: All-cause Mortality at Day 14 and Day 28
timeFrame: Day 14 and Day 28
measure: Percentage of Participants Alive and With No Change in Antibiotic Treatment Due to Either Lack of Therapeutic Benefit or Drug-related Toxicity at TOC
timeFrame: Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
measure: Survival Time
timeFrame: Days 1 to 10, 11 to 20, 21 to 30, 31 to 40, 41-50, and 51 to 60.
measure: Change From Baseline in Clinical Pulmonary Infection Score (CPIS) in Participants With Pneumonia (HAP/VAP/HCAP)
timeFrame: Baseline, end of treatment (Day 7-14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28)
measure: Change From Baseline in Sequential Organ Failure Assessment (SOFA)
timeFrame: Baseline, end of treatment (Day 7 to 14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28)
measure: Number of Participants With Adverse Events
timeFrame: From first dose of study drug up to 28 days after last dose; maximum treatment duration was 29 days in the cefiderocol group and 22 days in the BAT group.
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Shionogi Research Site
state: Connecticut
city: Newark
country: United States
facility: Shionogi Research Site
state: Delaware
city: Chicago
country: United States
facility: Shionogi Research Site
state: Illinois
city: New Orleans
country: United States
facility: Shionogi Research Site
state: Louisiana
city: Detroit
country: United States
facility: Shionogi Research Site
state: Michigan
city: Pittsburgh
country: United States
facility: Shionogi Research Site
state: Pennsylvania
city: Salvador
country: Brazil
facility: Shionogi Research Site
state: Bahia
city: Curitiba
country: Brazil
facility: Shionogi Research Site
state: Parana
city: Passo Fundo
country: Brazil
facility: Shionogi Research Site
state: RIO Grande DO SUL
city: Porto Alegre
country: Brazil
facility: Shionogi Research Site
state: RIO Grande DO SUL
city: Porto Alegre
country: Brazil
facility: Shionogi Research Site
state: RIO Grande DO SUL
city: Santa Maria
country: Brazil
facility: Shionogi Research Site
state: RIO Grande DO SUL
city: São José do Rio Preto
country: Brazil
facility: Shionogi Research Site
state: SAO Paulo
city: São Paulo
country: Brazil
facility: Shionogi Research Site
state: SAO Paulo
city: Rijeka
country: Croatia
facility: Shionogi Research Site
state: Primorje-Gorski Kotar
city: Split
country: Croatia
facility: Shionogi Research Site
city: Zagreb
country: Croatia
facility: Shionogi Research Site
city: Paris
country: France
facility: Shionogi Research Site
state: Ile-de-france
city: La Tronche
country: France
facility: Shionogi Research Site
state: Rhone-alpes
city: Heidelberg
country: Germany
facility: Shionogi Research Site
state: Baden-wuerttemberg
city: Bonn
country: Germany
facility: Shionogi Research Site
state: Nordrhein-westfalen
city: Berlin
country: Germany
facility: Shionogi Research Site
city: Athens
country: Greece
facility: Shionogi Research Site
state: Attica
city: Athens
country: Greece
facility: Shionogi Research Site
state: Attica
city: Patra
country: Greece
facility: Shionogi Research Site
state: Peloponnese
city: Larisa
country: Greece
facility: Shionogi Research Site
state: Thessaly
city: Larisa
country: Greece
facility: Shionogi Research Site
state: Thessaly
city: Ciudad de Guatemala
country: Guatemala
facility: Shionogi Research Site
city: Beer-Sheva
country: Israel
facility: Shionogi Research Site
state: Beersheba
city: Be'er Ya'akov
country: Israel
facility: Shionogi Research Site
state: Rehoboth
city: Tel Hashomer
country: Israel
facility: Shionogi Research Site
state: Tel Aviv
city: Tel-Aviv
country: Israel
facility: Shionogi Research Site
state: Tel Aviv
city: Safed
country: Israel
facility: Shionogi Research Site
state: Zefat
city: Hadera
country: Israel
facility: Shionogi Research Site
city: Haifa
country: Israel
facility: Shionogi Research Site
city: Haifa
country: Israel
facility: Shionogi Research Site
city: Holon
country: Israel
facility: Shionogi Research Site
city: Jerusalem
country: Israel
facility: Shionogi Research Site
city: Cisanello
country: Italy
facility: Shionogi Research Site
state: Pisa
city: Milano
country: Italy
facility: Shionogi Research Site
city: Milano
country: Italy
facility: Shionogi Research Site
city: Milano
country: Italy
facility: Shionogi Research Site
city: Modena
country: Italy
facility: Shionogi Research Site
city: Udine
country: Italy
facility: Shionogi Research Site
city: Nagakute
country: Japan
facility: Shionogi Research Site
state: Aichi
city: Shinagawa-ku
country: Japan
facility: Shionogi Research Site
state: Tokyo
city: Nagasaki
country: Japan
facility: Shionogi Research Site
city: Wonju-si
country: Korea, Republic of
facility: Shionogi Research Site
state: Gangwon-Do
city: Seoul
country: Korea, Republic of
facility: Shionogi Research Site
state: Gwangjin-gu
city: Daegu
country: Korea, Republic of
facility: Shionogi Research Site
city: Daegu
country: Korea, Republic of
facility: Shionogi Research Site
city: Seoul
country: Korea, Republic of
facility: Shionogi Research Site
city: Seoul
country: Korea, Republic of
facility: Shionogi Research Site
city: Seoul
country: Korea, Republic of
facility: Shionogi Research Site
city: Seoul
country: Korea, Republic of
facility: Shionogi Research Site
city: Terrassa
country: Spain
facility: Shionogi Research Site
state: Barcelona
city: Córdoba
country: Spain
facility: Shionogi Research Site
state: Cordoba
city: Lérida
country: Spain
facility: Shionogi Research Site
state: Lleida
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: Ciudad Real
country: Spain
facility: Shionogi Research Site
city: Gerona
country: Spain
facility: Shionogi Research Site
city: Madrid
country: Spain
facility: Shionogi Research Site
city: Malaga
country: Spain
facility: Shionogi Research Site
city: Sevilla
country: Spain
facility: Shionogi Research Site
city: Valencia
country: Spain
facility: Shionogi Research Site
city: Zaragoza
country: Spain
facility: Shionogi Research Site
city: Taichung
country: Taiwan
facility: Shionogi Research Site
state: ROC
city: Taipei City
country: Taiwan
facility: Shionogi Research Site
state: Taipei
city: Hualien
country: Taiwan
facility: Shionogi Research Site
city: Kaohsiung
country: Taiwan
facility: Shionogi Research Site
city: Taichung
country: Taiwan
facility: Shionogi Research Site
city: Bangkok
country: Thailand
facility: Shionogi Research Site
city: Muang Nonthaburi
country: Thailand
facility: Shionogi Research Site
city: Muang
country: Thailand
facility: Shionogi Research Site
city: Bornova
country: Turkey
facility: Shionogi Research Site
state: Izmir
city: Ankara
country: Turkey
facility: Shionogi Research Site
city: Istanbul
country: Turkey
facility: Shionogi Research Site
city: Istanbul
country: Turkey
facility: Shionogi Research Site
city: Trabzon
country: Turkey
facility: Shionogi Research Site
city: London
country: United Kingdom
facility: Shionogi Research Site
state: England
city: London
country: United Kingdom
facility: Shionogi Research Site
state: England
city: London
country: United Kingdom
facility: Shionogi Research Site
state: England
city: London
country: United Kingdom
facility: Shionogi Research Site
state: England
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: 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: 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.
citation: 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.
citation: 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.