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

• 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: Shionogi
• Information provided by (Responsible Party): Shionogi Inc. ( Shionogi )

Study Description

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

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Study Design

• 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

Arms and Interventions

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®

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Sponsors and Collaborators

Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line; Shionogi

More Information

Publications of Results:

Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, Tenke P, Nagata TD. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1. Epub 2018 Oct 25.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Portsmouth S, Echols R, Toyoizumi K, Tillotson G, Nagata TD. Structured patient interview to assess clinical outcomes in complicated urinary tract infections in the APEKS-cUTI study: pilot investigation. Ther Adv Infect Dis. 2021 Nov 24;8:20499361211058257. doi: 10.1177/20499361211058257. eCollection 2021 Jan-Dec.

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. Erratum In: Clin Pharmacokinet. 2022 Jul;61(7):1069.

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.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT02321800
• Other Study ID Numbers: 1409R2121
• First Posted: December 22, 2014
• 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:

Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Disease Attributes; Pathologic Processes; 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