A randomized study in hospitalised patients with complicated urinary tract infections caused by Gram-negative bacteria to compare the efficacy and safety of S-649266 to Imipenem/Cilastin, both administered by intravenous infusion

• Register: EUCTR
• Last refreshed on: 19 September 2016
• Main ID: EUCTR2014-000914-76-HU
• Date of registration: 12/08/2014
• Prospective Registration: Yes
• Primary sponsor: Shionogi Inc.
• Public title: A randomized study in hospitalised patients with complicated urinary tract infections caused by Gram-negative bacteria to compare the efficacy and safety of S-649266 to Imipenem/Cilastin, both administered by intravenous infusion
• Scientific 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
• Date of first enrolment: 30/09/2014
• Target sample size: 450
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000914-76
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Chile, Colombia, Croatia, Czech Republic, Ecuador, Georgia, Germany, Guatemala, Hungary, Italy, Japan, Latvia, Peru, Poland, Romania, Russian Federation, Spain, United States

Contacts

• Name: Guido Moesker
• Affiliation: Medpace UK

• Name: Guido Moesker
• Affiliation: Medpace UK

Key inclusion & exclusion criteria

Inclusion criteria:
1. Hospitalized patients who have a clinical diagnosis of either cUTI with or without pyelonephritis or acute uncomplicated pyelonephritis, and who have provided written informed consent or informed consent provided by legal guardian. (Note: Country specific rules and local Ethics Committee approval for legal guardian informed consent will determine whether or not a patient unable to comprehend or sign the informed consent is allowed to be enrolled in the study).
The specific clinical diagnosis will include:

cUTI with a history of at least one of the following:
•Indwelling urinary catheter or recent instrumentation of the urinary tract (within 14 days prior to screening)
•Urinary retention caused by benign prostatic hypertrophy
• Urine retention of at least 100 millileters (mL) or more of residual urine after voiding (neurogenic bladder)
•Obstructive uropathy (nephrolithiasis, fibrosis, etc.)
•Azotemia caused by intrinsic renal disease (BUN and creatinine values greater than normal laboratory values)
OR
Pyelonephritis and normal urinary tract anatomy, ie, acute uncomplicated pyelonephritis

AND
All patients must have at least two 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
Urinalysis evidence of pyuria demonstrated by:
•Dipstick analysis positive for leukocyte esterase
•Or =10 WBCs per µL in unspun urine, or =10 WBCs per high power field in spun urine)
2. Patients who had a positive urine culture obtained within 48 hours prior to randomization containing = 100000CFU/mL of a Gram-negative uropathogen likely to be susceptible to imipenem are eligible for this study (Note: patients may be enrolled prior to the results of the urine culture being available)
3. Patients, who have been treated previously with an empiric antibiotic other than the study medications, but failed treatment, both clinically and microbiologically, are eligible for the study if they have an identified uropathogen which is non-susceptible to the empiric treatment and is a Gram-negative uropathogen likely to be susceptible to imipenem (or alternative carbapenem antibiotic).
4. Female patients can participate if they are surgically sterile or have completed menopause, or if they are capable of having children, are not pregnant or nursing and they agree not to attempt pregnancy from the screening until end of study (EOS) (approximately 28 days following EOT) or according to country specific requirements, whichever is longer.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 202
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 248

Exclusion criteria:
1. Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other ß-lactam antibiotics
2. Patient's urine culture at study entry isolates more than 2 uropathogens, regardless of colony count, or patient has a confirmed fungal UTI.
3. Patients with asymptomatic bacteriuria, the presence of =100000CFU/mL of a uropathogen and pyuria but without local or systemic symptoms
4. Patient is receiving hemodialysis or peritoneal dialysis. Impairment of renal function with an estimated CrCl < 21 mL/min, requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Complicated Urinary Tract Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis caused by Gram-negative Pathogens
MedDRA version: 19.0 Level: HLT Classification code 10046577 Term: Urinary tract infections System Organ Class: 100000004862

Intervention(s)

Product Code: S-649266
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: NA
Other descriptive name: S-649266
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Tienam
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Imipenem
CAS Number: 74431-23-5
Other descriptive name: IMIPENEM MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
INN or Proposed INN: Cilastatin
Other descriptive name: CILASTATIN SODIUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Primary Outcome(s)

Secondary Objective: ? To assess the safety of S-649266 in a patient population with the potential to have MDR bacterial infections.
? To compare the clinical and microbiologic responses of S-649266 with IPM/CS in a patient population at risk for MDR Gram-negative pathogens at early assessment (EA), EOT, and at Follow-Up (FUP) as defined in the Acceptable Time Windows
? To assess microbiologic response per pathogen at EA, EOT, TOC, and FUP
? To assess microbiologic response per patient at EA, EOT, TOC, and FUP
? To assess clinical response per pathogen at EA, EOT, TOC, and FUP
? To assess clinical response per patient at EA, EOT, TOC, and FUP
? To determine plasma and urine drug concentrations at specified times post dose in a population of patients with acute infection.

Timepoint(s) of evaluation of this end point: Test of cure (TOC) - EOT + 7 days

Main Objective: To compare the composite outcome of clinical cure and microbiologic eradication of S-649266 with those of imipenem/cilastatin (IPM/CS) in a patient population at risk for multidrug resistant (MDR) Gram-negative pathogens originating from complicated urinary tract infection (cUTI) with or without pyelonephritis or acute uncomplicated pyelonephritis at the test of cure (TOC) (approximately 7 days following the end of treatment (EOT); (EOT is defined as the last day of study drug treatment).

Primary end point(s): Clinical and microbiologic response: Clinical cure in clinical outcomes (resolution of the signs and symptoms of cUTI or return to pre-infection baseline if known) and Eradication in microbiological outcomes (microbiological success) at the Test of Cure (TOC).

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Early assessment (EA) - Day 4
End of treatment (EOT) - last day of study drug ie up to 14 days
Test of cure (TOC) - EOT + 7 days
Follow-up (FUP) - EOT + 14 days

PK Days 3-5: plasma-prior to, just before the end and 1 hour post infusion; urine 2 and 6 hours after the start of the infusion

Secondary end point(s): Microbiologic response per pathogen and patient at EA, EOT, TOC, and FUP
Clinical response per patient and pathogen at EA, EOT, TOC, and FUP
Pharmacokinetic and safety profile

Secondary ID(s)

2014-000914-76-CZ

1409R2121

Source(s) of Monetary Support

Shionogi Inc.