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

Phase 2

Completed

• Conditions: Urinary Tract Infections
• Interventions: Drug: Imipenem/cilastatin; Drug: Cefiderocol

• Registration Number: NCT02321800
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-11-11
• Study First Submitted QC: 2014-12-16
• Study First Posted: 2014-12-22
• Study Start: 2015-02-05
• Primary Completion: 2016-07-26
• Study Completion: 2016-08-16
• Disposition First Submitted: 2017-07-11
• Disposition First Submitted QC: 2017-07-11
• Disposition First Posted: 2017-07-13
• Status Verified: 2019-11
• Results First Submitted: 2019-11-20
• Results First Submitted QC: 2019-11-20
• Last Update Submitted: 2019-11-20
• Results First Posted: 2019-12-12
• Last Update Posted: 2019-12-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 452

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Imipenem/cilastatin	Imipenem/cilastatin	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Cefiderocol	Cefiderocol	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure	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

Name	Time	Method
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment	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.
Percentage of Participants With Microbiological Eradication at Early Assessment	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.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment	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.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up	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.
Percentage of Participants With Microbiological Eradication at Follow-up	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.
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen	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.
Percentage of Participants With Microbiological Eradication at Test of Cure	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.
Percentage of Participants With Microbiological Eradication at End of Treatment	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.
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen	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.
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen	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.
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen	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.
Percentage of Participants With Clinical Response at Test of Cure	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.
Percentage of Participants With Clinical Response at End of Treatment	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.
Percentage of Participants With Clinical Response at Follow-up	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.
Percentage of Participants With Clinical Response at Early Assessment	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.
Plasma Concentration of Cefiderocol	On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion
Urine Concentration of Cefiderocol	Day 3, 2 hours and 6 hours after end of infusion
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen	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.
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen	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.
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen	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.
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen	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.
Number of Participants With Adverse Events	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.