Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02321800
Recruitment Status : Completed
First Posted : December 22, 2014
Results First Posted : December 12, 2019
Last Update Posted : December 12, 2019
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Brief Summary:
The purpose of this study was to determine the efficacy and safety of intravenous cefiderocol (S-649266) in hospitalized adults with complicated urinary tract infections caused by Gram-negative pathogens.

Condition or disease Intervention/treatment Phase
Urinary Tract Infections Drug: Cefiderocol Drug: Imipenem/cilastatin Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 452 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of Intravenous S-649266 in Complicated Urinary Tract Infections With or Without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens in Hospitalized Adults in Comparison With Intravenous Imipenem/Cilastatin
Actual Study Start Date : February 5, 2015
Actual Primary Completion Date : July 26, 2016
Actual Study Completion Date : August 16, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cefiderocol
Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.
Drug: Cefiderocol
2000 mg intravenously every 8 hours for 7 to 14 days; dose adjustments for participants with reduced renal function (estimated CrCl ≤ 70 mL/minute) and/or body weight (< 70 kg) included every 6-hour dosing intervals and/or reduced doses.
Other Names:
  • FETROJA®
  • S-649266

Active Comparator: Imipenem/cilastatin
Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Drug: Imipenem/cilastatin
1000 mg of each intravenously every 8 hours for 7 to 14 days; dose adjustments for participants with reduced renal function (estimated CrCl ≤ 70 mL/minute) and/or body weight (< 70 kg) included every 6-hour dosing intervals and/or reduced doses.
Other Name: PRIMAXIN®




Primary Outcome Measures :
  1. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure [ Time Frame: Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21) ]

    The primary efficacy endpoint was the composite outcome of clinical response and microbiological response at the test of cure assessment, defined as 7 days (±2 days) after the end of antibiotic treatment.

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.



Secondary Outcome Measures :
  1. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment [ Time Frame: Early assessment (EA; Day 4) ]

    A composite outcome of clinical response and microbiological response at the early assessment, defined as Day 4 of antibiotic treatment.

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.


  2. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment [ Time Frame: End of treatment (EOT; Day 7 to 14) ]

    A composite outcome of clinical response and microbiological response at the end of treatment, defined as the end of the last infusion of antibiotic treatment.

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.


  3. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up [ Time Frame: Follow-up (FUP; 14 days after end of treatment, Day 21 to 28) ]

    A composite response of clinical response and microbiological response at the follow-up assessment, defined as 14 days after the end of treatment.

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug.

    Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, showed that the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.


  4. Percentage of Participants With Microbiological Eradication at Test of Cure [ Time Frame: Test of cure (7 days after end of treatment, Day 14 to 21) ]
    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

  5. Percentage of Participants With Microbiological Eradication at Early Assessment [ Time Frame: Early assessment, Day 4 ]
    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

  6. Percentage of Participants With Microbiological Eradication at End of Treatment [ Time Frame: End of treatment, Day 7 to 14 ]
    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

  7. Percentage of Participants With Microbiological Eradication at Follow-up [ Time Frame: Follow-up, 14 days after end of treatment, Day 21 to 28 ]
    Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.

  8. Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen [ Time Frame: Test of cure; 7 days after end of treatment, Day 14 to 21 ]

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

    Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.


  9. Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen [ Time Frame: Early assessment, Day 4 ]

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

    Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.


  10. Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen [ Time Frame: End of treatment, Day 7 to 14 ]

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

    Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.


  11. Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen [ Time Frame: Follow-up, 14 days after the end of treatment, Day 21 to 28 ]

    Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.

    Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.


  12. Percentage of Participants With Clinical Response at Test of Cure [ Time Frame: Test of cure, 7 days after end of treatment, Day 14 to 21 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

  13. Percentage of Participants With Clinical Response at Early Assessment [ Time Frame: Early assessment, Day 4 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

  14. Percentage of Participants With Clinical Response at End of Treatment [ Time Frame: End of treatment, Day 7 to 14 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

  15. Percentage of Participants With Clinical Response at Follow-up [ Time Frame: Follow-up, 14 days after end of treatment, Day 21 to 28 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI showing no evidence of recurrence after administration of the last dose of study drug.

  16. Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen [ Time Frame: Test of cure, 7 days after end of treatment, Day 14 to 21 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

  17. Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen [ Time Frame: Early assessment, Day 4 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

  18. Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen [ Time Frame: End of treatment, Day 7 to 14 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

  19. Percentage of Participants With Clinical Response at Follow-up Per Uropathogen [ Time Frame: Follow-up, 14 days after the end of treatment, Day 21 to 28 ]
    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

  20. Plasma Concentration of Cefiderocol [ Time Frame: On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion ]
  21. Urine Concentration of Cefiderocol [ Time Frame: Day 3, 2 hours and 6 hours after end of infusion ]
  22. Number of Participants With Adverse Events [ Time Frame: From first dose of study drug until 28 days after end of treatment; Day 35 to 42 ]

    A serious adverse event was defined by regulation as any adverse event (AE) occurring at any dose that resulted in any of the following outcomes:

    • Death
    • Life-threatening condition
    • Hospitalization or prolongation of existing hospitalization
    • Persistent or significant disability/incapacity
    • Congenital anomaly/birth defect
    • Other medically important condition.

    The relationship of an event to the study drug was determined by the investigator based on whether the AE could be reasonably explained as being caused by the study drug.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Hospitalized male and female patients ≥ 18 years
  • Clinical diagnosis of either complicated urinary tract infections (cUTI) with or without pyelonephritis or acute uncomplicated pyelonephritis
  • cUTI diagnosed with a history of ≥ 1 of the following:

    • Indwelling urinary catheter or recent instrumentation of the urinary tract
    • Urinary retention (caused by benign prostatic hypertrophy)
    • Urinary retention of at least 100 mL or more of residual urine after voiding (neurogenic bladder)
    • Obstructive uropathy
    • Azotemia caused by intrinsic renal disease (blood urea nitrogen and creatinine values greater than normal laboratory values) OR Pyelonephritis and normal urinary tract anatomy, ie, acute uncomplicated pyelonephritis AND

At least 2 of the following signs or symptoms:

  • Chills or rigors or warmth associated with fever (temperature greater than or equal to 38 degrees Celsius)
  • Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI)
  • Nausea or vomiting
  • Dysuria, urinary frequency, or urinary urgency
  • Costo-vertebral angle tenderness on physical examination AND

All subjects had to have urinalysis evidence of pyuria demonstrated by 1 of the following:

  • Dipstick analysis positive for leukocyte esterase
  • ≥ 10 white blood cells (WBCs) per μL in unspun urine, or ≥ 10 WBCs per high power field in spun urine

    • Positive urine culture within 48 hours prior to randomization containing ≥10^5 colony forming unit (CFU)/mL of a Gram-negative uropathogen likely to be susceptible to imipenem (IPM)
    • Patients who were treated previously with an empiric antibiotic other than the study drugs but failed treatment, both clinically and microbiologically, were eligible for the study if they had an identified Gram-negative uropathogen that was not susceptible to the previously used empiric treatment and likely to be susceptible to IPM
    • Subjects receiving antibiotic prophylaxis for UTI who present with signs and symptoms consistent with an active new UTI

Exclusion Criteria:

  • Urine culture identifies only a Gram-positive pathogen and/or a Gram-negative uropathogen resistant to IPM
  • Urine culture at study entry isolates more than 2 uropathogens or patient has a confirmed fungal UTI
  • Asymptomatic bacteriuria, the presence of >10^5 CFU/mL of a uropathogen and pyuria but without local or systemic symptoms
  • Patient is receiving hemodialysis or peritoneal dialysis

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): NCT02321800


Sponsors and Collaborators
Shionogi
Investigators
Layout table for investigator information
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi
Publications of Results:
Layout table for additonal information
Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT02321800    
Other Study ID Numbers: 1409R2121
First Posted: December 22, 2014    Key Record Dates
Results First Posted: December 12, 2019
Last Update Posted: December 12, 2019
Last Verified: November 2019
Keywords provided by Shionogi Inc. ( Shionogi ):
S-649266
complicated urinary tract infection
cefiderocol
acute uncomplicated pyelonephritis
Gram-negative pathogens
imipenem/cilastatin
Additional relevant MeSH terms:
Layout table for MeSH terms
Infection
Communicable Diseases
Urinary Tract Infections
Pyelonephritis
Urologic Diseases
Nephritis, Interstitial
Nephritis
Kidney Diseases
Pyelitis
Imipenem
Cilastatin
Anti-Bacterial Agents
Anti-Infective Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action