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

NCT02321800 | Completed Phase 2 Results DMC

• 1 other identifier: 1409R2121
• Study Type: interventional
• Target: 452
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Urinary Tract Infections

Keywords

S-649266; complicated urinary tract infection; cefiderocol; acute uncomplicated pyelonephritis; Gram-negative pathogens; imipenem/cilastatin

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure

  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.

  Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)

Secondary Outcomes (22)

• Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment

  Early assessment (EA; Day 4)

• Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment

  End of treatment (EOT; Day 7 to 14)

• 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)

• Percentage of Participants With Microbiological Eradication at Test of Cure

  Test of cure (7 days after end of treatment, Day 14 to 21)

• Percentage of Participants With Microbiological Eradication at Early Assessment

  Early assessment, Day 4

Study Arms (2)

Cefiderocol

EXPERIMENTAL

Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.

Drug: Cefiderocol

Imipenem/cilastatin

ACTIVE COMPARATOR

Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.

Drug: Imipenem/cilastatin

Interventions

Cefiderocol DRUG

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.

Also known as: FETROJA®, S-649266

Cefiderocol

Imipenem/cilastatin DRUG

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.

Also known as: PRIMAXIN®

Imipenem/cilastatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• Shionogi: lead

Related Publications (4)

• 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.

  PMID: 30509675 RESULT

• 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.

  PMID: 34868583 DERIVED

• 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.

  PMID: 34792787 DERIVED

• 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.

  PMID: 33393598 DERIVED

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

Cefiderocol; Cilastatin, Imipenem Drug Combination

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Imipenem; Thienamycins; Carbapenems; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Shionogi Clinical Trials Administrator
• Organization: Shionogi Inc.

shionogiclintrials-admin@shionogi.co.jp

800-849-9707

Study Officials

• Shionogi Clinical Trials Administrator Clinical Support Help Line

  Shionogi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 11, 2014
• First Posted: December 22, 2014
• Study Start: February 5, 2015
• Primary Completion: July 26, 2016
• Study Completion: August 16, 2016
• Last Updated: December 12, 2019
• Results First Posted: December 12, 2019

Record last verified: 2019-11