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

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ClinicalTrials.gov Identifier: NCT02714595
Recruitment Status : Recruiting
First Posted : March 21, 2016
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Brief Summary:
This study is designed to provide evidence of efficacy of S-649266 in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.

Condition or disease Intervention/treatment Phase
Healthcare-associated Pneumonia (HCAP) Bloodstream Infections (BSI) Hospital Acquired Pneumonia (HAP) Complicated Urinary Tract Infection (cUTI) Sepsis Ventilator Associated Pneumonia (VAP) Drug: S-649266 Drug: Best Available Therapy Phase 3

Detailed Description:
This study is designed to provide evidence of efficacy of S-649266 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 7, 2016
Estimated Primary Completion Date : April 30, 2019
Estimated Study Completion Date : May 19, 2019

Arm Intervention/treatment
Experimental: S-649266
Participants will receive S-649266 2 g administered intravenously over 3 hours, every 8 hours for 7-14 days
Drug: S-649266
2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function).
Other Name: cefiderocol

Active Comparator: Best Available Therapy (BAT)
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.
Drug: Best Available Therapy
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).




Primary Outcome Measures :
  1. Clinical outcome per patient at test of cure (TOC) in patients with HAP/VAP/HCAP or BSI/sepsis [ Time Frame: Test of cure, defined as 7 days after end of treatment (treatment duration is 7-14 days) ]
    For HAP/VAP/HCAP, clinical cure is 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 is required for the treatment of the current infection. For BSI/sepsis clinical cure is the resolution or substantial improvement of baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy is required for the treatment of BSI/sepsis.

  2. Microbiologic outcome (for Gram-negative pathogen) per patient at TOC in patients with cUTI [ Time Frame: 7 days after end of treatment (7-14 days) ]
    Eradication is defined as a urine culture showing that the baseline Gram-negative uropathogen found at entry at ≥ 10^5 colony forming units (CFU)/mL are reduced to < 10^4 CFU/mL.


Secondary Outcome Measures :
  1. Clinical outcome per patient at end of treatment (EOT) and follow-up (FUP)(HAP/VAP/HCAP or BSI/sepsis) [ Time Frame: End of treatment (7-14 days) and 14 days after end of treatment (FUP) ]
  2. Clinical outcome per pathogen at EOT, TOC and FUP (HAP/VAP/HCAP or BSI/sepsis) [ Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP) ]
  3. Clinical outcome per patient/pathogen at EOT, TOC and FUP (cUTI) [ Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP) ]
  4. Microbiologic outcome (for Gram-negative pathogen) per patient/pathogen at EOT, TOC, and follow-up (FUP) (HAP/VAP/HCAP or BSI/sepsis) [ Time Frame: End of treatment, 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP) ]
  5. Microbiologic outcome (for Gram-negative pathogen) per patient at EOT, and FUP (cUTI) [ Time Frame: End of treatment (7-14 days) and 14 days after end of treatment (FUP) ]
  6. Microbiologic outcome (for Gram-negative pathogen) per pathogen at EOT, TOC, and FUP (cUTI) [ Time Frame: End of treatment (7-14 days) and at 7 days (TOC) and 14 days after end of treatment (FUP) ]
  7. Microbiologic outcome with documented carbapenem-resistant Gram-negative bacteremia (regardless of primary infection diagnosis) at EOT, TOC, and FUP [ Time Frame: End of treatment (7-14 days) and at 7 days (TOC)and 14 days after end of treatment (FUP) ]
  8. Participants with positive clinical and microbiologic outcome at EOT, TOC, and FUP [ Time Frame: End of treatment (7-14 days), 7 days after end of treatment (TOC), and 14 days after end of treatment (FUP) ]
  9. All-cause mortality at Day 14 and Day 28 for HAP/VAP/HCAP and BSI/sepsis [ Time Frame: Day 14 and Day 28 ]
  10. Composite endpoint of survival and no change in antibiotic treatment due to either lack of therapeutic benefit or drug-related toxicity at TOC [ Time Frame: 7 days after end of treatment (7-14 days) ]
  11. Survival time (HAP/VAP/HCAP, BSI/sepsis) [ Time Frame: Up to 28 days after the end of treatment (7-14 days) ]
  12. Clinical Pulmonary Infection Score (CPIS) at EOT and TOC (HAP/VAP/HCAP only) [ Time Frame: End of treatment (7-14 days) and 7 days after end of treatment ]
  13. Sequential Organ Failure Assessment (SOFA) score at EOT and TOC [ Time Frame: End of treatment and 7 days after end of treatment ]
  14. Number of participants with adverse events [ Time Frame: From Baseline to 28 days after end of treatment (7-14 days) ]
    Safety and tolerability profile



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02714595


Contacts
Contact: Shionogi Clinical Trials Administrator Clinical Support Help Line 800-849-9707 Shionogiclintrials-admin@shionogi.co.jp

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Sponsors and Collaborators
Shionogi
Investigators
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi

Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT02714595     History of Changes
Other Study ID Numbers: 1424R2131
2015-004703-23 ( EudraCT Number )
First Posted: March 21, 2016    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018

Keywords provided by Shionogi Inc. ( Shionogi ):
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

Additional relevant MeSH terms:
Infection
Communicable Diseases
Pneumonia
Sepsis
Urinary Tract Infections
Pneumonia, Ventilator-Associated
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Urologic Diseases
Cross Infection
Ventilator-Induced Lung Injury
Lung Injury
Anti-Bacterial Agents
Anti-Infective Agents