Clinical Trials/NCT02714595

NCT02714595CompletedPhase 3

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

Shionogi1 site in 1 country152 target enrollmentStarted: September 7, 2016Last updated: January 12, 2021

Conditions

Interventions

Drugs

Trial Snapshot

Phase: Phase 3
Status: Completed
Sponsor
Enrollment: 152
Locations: 1
Primary Endpoint: Percentage of Participants With Clinical Cure at Test of Cure (TOC) in Participants With HAP/VAP/HCAP or BSI/Sepsis

Study Overview Study Design Eligibility Criteria Arms & Interventions Outcomes Investigators Sites Records & Identifiers Similar Trials Related News

Study Overview

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.

Study Design

Study Type: Interventional
Allocation: Randomized
Intervention Model: Parallel
Primary Purpose: Treatment
Masking: None

Eligibility Criteria

Ages: 18 Years to — (Adult, Older Adult)
Sex: All
Accepts Healthy Volunteers: No

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

•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
•Patients meeting specific exclusion criteria for each infection site

Arms & Interventions

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.

Intervention: Cefiderocol (Drug)

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.

Intervention: Best Available Therapy (Drug)

Outcomes

Primary Outcomes

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

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

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.

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

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

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.

Secondary Outcomes

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 Sustained Clinical Cure at Follow-up By Baseline Pathogen(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(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 End of Treatment (EOT) in Participants With HAP/VAP/HCAP or BSI/Sepsis(End of treatment, Day 7 to 14)
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)
Percentage of Participants With Clinical Cure at End of Treatment in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(End of treatment, Day 7 to 14)
Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP or BSI/Sepsis(End of treatment, Day 7 to 14)
Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP or BSI/Sepsis(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up 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 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 Sustained Clinical Cure at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(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 By Baseline Pathogen(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 Test of Cure in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(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 By Baseline Pathogen(End of treatment, Day 7 to 14)
Percentage of Participants With Clinical Cure at EOT By Baseline Carbapenem-resistant Pathogen(End of treatment, Day 7 to 14)
Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Carbapenem-resistant Pathogen(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(End of treatment, Day 7 to 14)
Percentage of Participants With Clinical Cure at TOC By Baseline Carbapenem-resistant Pathogen(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Percentage of Participants With Sustained Microbiologic Eradication 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)
Percentage of Participants With a Composite Clinical and Microbiological Response at EOT(End of treatment, Day 7 to 14)
All-cause Mortality at Day 14 and Day 28(Day 14 and Day 28)
Percentage of Participants With Microbiologic Eradication at EOT in Participants With cUTI(End of treatment, Day 7 to 14)
Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall(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 EOT By Baseline Pathogen(End of treatment, Day 7 to 14)
Percentage of Participants With Microbiologic Eradication at TOC By Baseline Pathogen(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Survival Time(Days 1 to 10, 11 to 20, 21 to 30, 31 to 40, 41-50, and 51 to 60.)
Change From Baseline in Clinical Pulmonary Infection Score (CPIS) in Participants With Pneumonia (HAP/VAP/HCAP)(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))
Number of Participants With Adverse Events(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.)
Percentage of Participants With Microbiologic Eradication at EOT By Baseline Carbapenem-resistant Pathogen(End of treatment, Day 7 to 14)
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Carbapenem-resistant Pathogen(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants With Microbiologic Eradication at TOC in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Percentage of Participants With a Composite Clinical and Microbiological Response at TOC(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Change From Baseline in Sequential Organ Failure Assessment (SOFA)(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))
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Pathogen(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants With Microbiologic Eradication at TOC By Baseline Carbapenem-resistant Pathogen(Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21)
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants With a Composite Clinical and Microbiological Response at Follow-up(Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28)
Percentage of Participants Alive and With No Change in Antibiotic Treatment Due to Either Lack of Therapeutic Benefit or Drug-related Toxicity at TOC(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 EOT in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia(End of treatment, Day 7 to 14)

Investigators

Sponsor

Shionogi

Sponsor Class

Industry

Responsible Party

Sponsor

Study Sites (1)

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