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

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ClinicalTrials.gov Identifier: NCT02321800
Recruitment Status : Completed
First Posted : December 22, 2014
Last Update Posted : July 13, 2017
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )

Study Description
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Brief Summary:
To determine the efficacy and safety of intravenous 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: S-649266 Drug: Imipenem/cilastatin Phase 2

Detailed Description:
The purpose of this study is to determine the efficacy and safety of intravenous S 649266 versus intravenous imipenem/cilastatin in hospitalized adults with complicated urinary tract infections with or without pyelonephritis or acute uncomplicated pyelonephritis caused by Gram-negative pathogens.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 450 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
Study Start Date : December 1, 2014
Actual Primary Completion Date : July 26, 2016
Actual Study Completion Date : August 16, 2016

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Arms and Interventions
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Arm Intervention/treatment
Experimental: S-649266 Drug: S-649266
2000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function and body weight)
Other Name: cefiderocol
Active Comparator: Imipenem/cilastatin Drug: Imipenem/cilastatin
1000 mg intravenously every 8 hours for a period of 7 to 14 days (dosage adjustment is necessary based on renal function and body weight)


Outcome Measures
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Primary Outcome Measures :
  1. Composite of Clinical Cure and Microbiologic Eradication [ Time Frame: Baseline and at Test of Cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14-21) ]
    Clinical and Microbiologic Response: Resolution or improvement of the symptoms of cUTI present at trial entry (and no new symptoms) and the demonstration that the bacterial pathogen found at trial entry is reduced to fewer than 10^4 CFU/mL on urine culture at the TOC (microbiological success).


Secondary Outcome Measures :
  1. Microbiologic response per pathogen and per patient at early assessment (EA), EOT, TOC, and follow-up (FUP) [ Time Frame: Baseline and Early Assessment (EA; Day 4), EOT (Day 7-14), TOC (Day 14-21), and at Follow-up (FUP; 14 days after end of treatment; equivalent to Study Days 21-28) ]
    Eradication in microbiological outcomes (microbiological success), where eradication is defined as a urine culture that shows the bacterial uropathogen(s) found at entry at ≥ 10^5 CFU/mL are reduced to < 10^4 CFU/mL. A microbiological response per pathogen will be determined for each pathogen isolated at baseline. A microbiological response per patient will be determined for each patient based on individual responses.

  2. Clinical response per pathogen and per patient at EA, EOT, TOC, and FUP [ Time Frame: Baseline and EA (Day 4), EOT (Day 7-14), TOC (Day 14-21), and FUP (Days 21-28) ]
    Clinical cure in clinical outcomes (resolution of the signs and symptoms of complicated urinary tract infection [cUTI] or return to pre-infection baseline if known). A clinical response per pathogen will be determined for each pathogen isolated at baseline. A clinical response per patient will be determined for each patient based on individual responses.

  3. Plasma concentration of S-649266 [ Time Frame: On Day 3 of dosing; plasma sampling prior to infusion, within 15 minutes prior to end of infusion, and at 2 hours post infusion ]
    Plasma concentration of S-649266 at steady state

  4. Urine concentrations of S-649266 [ Time Frame: Urine sampling 2 hours and 6 hours after end of infusion ]
    Urine concentration of S-649266 at steady state

  5. Number of participants with adverse events [ Time Frame: From Baseline to the Safety Follow-up visit 28 days after end of treatment; equivalent to study Day 35 to 42 ]

Eligibility Criteria
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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, and azotemia caused by intrinsic renal disease (blood urea nitrogen and creatinine values greater than normal laboratory values)
  • 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, and costo-vertebral angle tenderness on physical examination
  • Urinalysis evidence of pyuria demonstrated by dipstick analysis positive for leukocyte esterase or ≥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 with an effective antibiotic for no more than 24 hours during the previous 72 hours
  • Patients who failed treatment, both clinically and microbiologically, and have an identified uropathogen which is non-susceptible to the empiric treatment and is a Gram-negative uropathogen 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02321800


Sponsors and Collaborators
Shionogi
Investigators
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi
More Information
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Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT02321800     History of Changes
Other Study ID Numbers: 1409R2121
First Posted: December 22, 2014    Key Record Dates
Last Update Posted: July 13, 2017
Last Verified: July 2017

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:
Infection
Communicable Diseases
Urinary Tract Infections
Pyelonephritis
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