Clinical trial NCT02321800: A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urinary Tract Infections
Keywords: S-649266
complicated urinary tract infection
cefiderocol
acute uncomplicated pyelonephritis
Gram-negative pathogens
imipenem/cilastatin
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2014-12-22
Enrollment: 452
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure
timeFrame: Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)
Secondary outcomes:
measure: Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment
timeFrame: Early assessment (EA; Day 4)
measure: Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment
timeFrame: End of treatment (EOT; Day 7 to 14)
measure: Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up
timeFrame: Follow-up (FUP; 14 days after end of treatment, Day 21 to 28)
measure: Percentage of Participants With Microbiological Eradication at Test of Cure
timeFrame: Test of cure (7 days after end of treatment, Day 14 to 21)
measure: Percentage of Participants With Microbiological Eradication at Early Assessment
timeFrame: Early assessment, Day 4
measure: Percentage of Participants With Microbiological Eradication at End of Treatment
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiological Eradication at Follow-up
timeFrame: Follow-up, 14 days after end of treatment, Day 21 to 28
measure: Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen
timeFrame: Test of cure; 7 days after end of treatment, Day 14 to 21
measure: Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen
timeFrame: Early assessment, Day 4
measure: Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen
timeFrame: Follow-up, 14 days after the end of treatment, Day 21 to 28
measure: Percentage of Participants With Clinical Response at Test of Cure
timeFrame: Test of cure, 7 days after end of treatment, Day 14 to 21
measure: Percentage of Participants With Clinical Response at Early Assessment
timeFrame: Early assessment, Day 4
measure: Percentage of Participants With Clinical Response at End of Treatment
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Clinical Response at Follow-up
timeFrame: Follow-up, 14 days after end of treatment, Day 21 to 28
measure: Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen
timeFrame: Test of cure, 7 days after end of treatment, Day 14 to 21
measure: Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen
timeFrame: Early assessment, Day 4
measure: Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen
timeFrame: End of treatment, Day 7 to 14
measure: Percentage of Participants With Clinical Response at Follow-up Per Uropathogen
timeFrame: Follow-up, 14 days after the end of treatment, Day 21 to 28
measure: Plasma Concentration of Cefiderocol
timeFrame: On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion
measure: Urine Concentration of Cefiderocol
timeFrame: Day 3, 2 hours and 6 hours after end of infusion
measure: Number of Participants With Adverse Events
timeFrame: From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Other outcomes:
Locations:
Study officials:
affiliation: Shionogi
name: Shionogi Clinical Trials Administrator Clinical Support Help Line
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.