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NCT02321800: APEKS-cUTI

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

Completed Phase 2 Results posted Last updated 12 December 2019
What this trial tests

Phase 2 trial testing Cefiderocol in Urinary Tract Infections in 452 participants. Completed in 16 August 2016.

Timeline
5 February 2015
Primary endpoint
26 July 2016
16 August 2016

Quick facts

Lead sponsorShionogi
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment452
Start date5 February 2015
Primary completion26 July 2016
Estimated completion16 August 2016

Drugs / interventions tested

Conditions studied

Sponsor

Shionogi — full company profile →

Who can join

18 and older, any sex, with Urinary Tract Infections. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure Primary · 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 pat

GroupValue95% CI
Cefiderocol72.6
Imipenem/Cilastatin54.6
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment Secondary · 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 C

GroupValue95% CI
Cefiderocol88.1
Imipenem/Cilastatin87.4
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment Secondary · 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/

GroupValue95% CI
Cefiderocol96.4
Imipenem/Cilastatin95.8
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up Secondary · 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 t

GroupValue95% CI
Cefiderocol54.4
Imipenem/Cilastatin39.5
Percentage of Participants With Microbiological Eradication at Test of Cure Secondary · 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.

GroupValue95% CI
Cefiderocol73.0
Imipenem/Cilastatin56.3
Percentage of Participants With Microbiological Eradication at Early Assessment Secondary · 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.

GroupValue95% CI
Cefiderocol92.1
Imipenem/Cilastatin90.8
Percentage of Participants With Microbiological Eradication at End of Treatment Secondary · 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.

GroupValue95% CI
Cefiderocol96.8
Imipenem/Cilastatin95.8
Percentage of Participants With Microbiological Eradication at Follow-up Secondary · 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.

GroupValue95% CI
Cefiderocol57.1
Imipenem/Cilastatin43.7
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen Secondary · 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.

Escherichia coli
GroupValue95% CI
Cefiderocol75.0
Imipenem/Cilastatin58.2
Klebsiella pneumoniae
GroupValue95% CI
Cefiderocol75.0
Imipenem/Cilastatin52.0
Pseudomonas aeruginosa
GroupValue95% CI
Cefiderocol44.4
Imipenem/Cilastatin60.0
Proteus mirabilis
GroupValue95% CI
Cefiderocol76.5
Imipenem/Cilastatin50.0
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen Secondary · 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.

Escherichia coli
GroupValue95% CI
Cefiderocol92.8
Imipenem/Cilastatin94.9
Klebsiella pneumoniae
GroupValue95% CI
Cefiderocol89.6
Imipenem/Cilastatin88.0
Pseudomonas aeruginosa
GroupValue95% CI
Cefiderocol94.4
Imipenem/Cilastatin80.0
Proteus mirabilis
GroupValue95% CI
Cefiderocol88.2
Imipenem/Cilastatin100.0
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen Secondary · 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.

Escherichia coli
GroupValue95% CI
Cefiderocol98.7
Imipenem/Cilastatin97.5
Klebsiella pneumoniae
GroupValue95% CI
Cefiderocol97.9
Imipenem/Cilastatin92.0
Pseudomonas aeruginosa
GroupValue95% CI
Cefiderocol88.9
Imipenem/Cilastatin100.0
Proteus mirabilis
GroupValue95% CI
Cefiderocol94.1
Imipenem/Cilastatin100.0
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen Secondary · 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.

Escherichia coli
GroupValue95% CI
Cefiderocol59.9
Imipenem/Cilastatin41.8
Klebsiella pneumoniae
GroupValue95% CI
Cefiderocol58.3
Imipenem/Cilastatin52.0
Pseudomonas aeruginosa
GroupValue95% CI
Cefiderocol27.8
Imipenem/Cilastatin20.0
Proteus mirabilis
GroupValue95% CI
Cefiderocol64.7
Imipenem/Cilastatin0

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug until 28 days after end of treatment; Day 35 to 42. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

S-649266
Serious: 14/300 (5%)
Deaths: 1/300
Imipenem/Cilastatin
Serious: 12/148 (8%)
Deaths: 0/148

Serious adverse events (35 terms)

ReactionSystemS-649266Imipenem/Cilastatin
Clostridium difficile colitisInfections and infestations——
AnaemiaBlood and lymphatic system disorders——
Haemorrhagic anaemiaBlood and lymphatic system disorders——
Cardiac failureCardiac disorders——
Cardiac failure acuteCardiac disorders——
Cardio-respiratory arrestCardiac disorders——
Myocardial ischaemiaCardiac disorders——
Congenital ureteric anomalyCongenital, familial and genetic disorders——
DiarrhoeaGastrointestinal disorders——
Duodenal ulcerGastrointestinal disorders——
Lower gastrointestinal haemorrhageGastrointestinal disorders——
Upper gastrointestinal haemorrhageGastrointestinal disorders——
PyrexiaGeneral disorders——
Gallbladder painHepatobiliary disorders——
AbscessInfections and infestations——
AscariasisInfections and infestations——
CellulitisInfections and infestations——
Device related infectionInfections and infestations——
PneumoniaInfections and infestations——
Prostatic abscessInfections and infestations——
PyelonephritisInfections and infestations——
Renal abscessInfections and infestations——
Urinary tract infectionInfections and infestations——
Alcohol poisoningInjury, poisoning and procedural complications——
Gastrointestinal injuryInjury, poisoning and procedural complications——
Other adverse events (15 terms — click to expand)

ReactionSystemS-649266Imipenem/Cilastatin
HypertensionVascular disorders——
DiarrhoeaGastrointestinal disorders——
ConstipationGastrointestinal disorders——
Infusion site painGeneral disorders——
HeadacheNervous system disorders——
NauseaGastrointestinal disorders——
CoughRespiratory, thoracic and mediastinal disorders——
VomitingGastrointestinal disorders——
Abdominal pain upperGastrointestinal disorders——
HypokalaemiaMetabolism and nutrition disorders——
Renal cystRenal and urinary disorders——
InsomniaPsychiatric disorders——
Infusion site erythemaGeneral disorders——
Clostridium difficile colitisInfections and infestations——
Vaginal infectionInfections and infestations——

Most-reported serious reactions: Clostridium difficile colitis, Anaemia, Haemorrhagic anaemia, Cardiac failure, Cardiac failure acute, Cardio-respiratory arrest, Myocardial ischaemia, Congenital ureteric anomaly.

Data from ClinicalTrials.gov NCT02321800 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. 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.
    Portsmouth S, van Veenhuyzen D, Echols R, Machida M, et al · · 2018 · cited 300× · PMID 30509675 · DOI 10.1016/s1473-3099(18)30554-1
  2. Iron metabolism: pathophysiology and pharmacology.
    Roemhild K, von Maltzahn F, Weiskirchen R, Knüchel R, et al · · 2021 · cited 188× · PMID 34090703 · DOI 10.1016/j.tips.2021.05.001
  3. Antibiotics in the clinical pipeline in October 2019.
    Butler MS, Paterson DL. · · 2020 · cited 174× · PMID 32152527 · DOI 10.1038/s41429-020-0291-8
  4. New β-Lactamase Inhibitors in the Clinic.
    Papp-Wallace KM, Bonomo RA. · · 2016 · cited 121× · PMID 27208767 · DOI 10.1016/j.idc.2016.02.007
  5. Cefiderocol Antimicrobial Susceptibility Testing against Multidrug-Resistant Gram-Negative Bacilli: a Comparison of Disk Diffusion to Broth Microdilution.
    Morris CP, Bergman Y, Tekle T, Fissel JA, et al · · 2020 · cited 84× · PMID 32938734 · DOI 10.1128/jcm.01649-20
  6. Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection.
    Kawaguchi N, Katsube T, Echols R, Wajima T. · · 2021 · cited 67× · PMID 33257454 · DOI 10.1128/aac.01437-20
  7. Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward 'molecularly targeted' therapy.
    El Chakhtoura NG, Saade E, Iovleva A, Yasmin M, et al · · 2018 · cited 60× · PMID 29310479 · DOI 10.1080/14787210.2018.1425139
  8. Defining the Role of Novel β-Lactam Agents That Target Carbapenem-Resistant Gram-Negative Organisms.
    Tamma PD, Hsu AJ. · · 2019 · cited 55× · PMID 30793757 · DOI 10.1093/jpids/piz002

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Trials by the same sponsor.

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing