Complicated Urinary tract infections (cUTI) MedDRA version: 14.0 Level: LLT Classification code 10046574 Term: Urinary tract infection NOS System Organ Class: 10021881 - Infections and infestations MedDRA version: 14.0 Level: LLT Classification code 10037606 Term: Pyelonephritis, unspecified System Organ Class: 10021881 - Infections and infestations
Conditions
Sponsors
GlaxoSmithKline Research and Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. Italian female subjects: female subject will be eligible for inclusion in this study only if they are of non-childbearing potential. 1. Adult subjects aged at least 18 years. N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraindicated to enrol females of childbearing potential, however, they must have a negative pregnancy test at study entry and must have practiced adequate contraception for at least 30 days prior to study entry. Additionally, the subject agrees to one of the methods listed in the protocol for avoidance of pregnancy during the entire study treatment period. 2. Subject requires hospitalisation and has clinical signs and symptoms of lower cUTI or pyelonephritis (complicated or uncomplicated) as defined below, that requires parenteral treatment only with a treatment course of a minimum of 5 days and a maximum of 14 days: a. Lower cUTI – subjects must have documented fever defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours, exceptions would be: i. Afebrile subjects with lower cUTI who have a white blood cell count (WBC) =15,000 cells/mm3 ii. Afebrile subjects with a lower cUTI following requiring parenteral therapy due to a specific indication e.g. • Before and during an operative procedure, when oral antibiotics are not indicated • Or in cases where the cUTI is suspected to be due to a pathogen resistant to current oral antibiotics, and at least two of the following UTI symptoms including dysuria, frequency, urgency or suprapubic pain, with the presence of a complicating factor: iii. Male gender; iv. Current bladder instrumentation or indwelling urinary catheter that has to be removed two days before the end of IV study drug administration; v. Obstructive uropathy that is expected to be medically or surgically treated during the course of IV study drug administration; vi. Urogenital surgery within 7 days preceding administration of the first dose of study drug; vii. Functional or anatomical abnormality of the urogenital tract including anatomic malformations or neurogenic bladder with voiding disturbance of at least 100 mL residual urine. b. Acute pyelonephritis (complicated or uncomplicated): subjects must have documented fever defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours and flank pain or costovertebral angle tenderness (CVA). Complicating factors for pyelonephritis are the same as for complicated UTI. 3. Subject has pyuria (white blood cell [WBC] count > 10/µL (or >5/high-power field [HPF] in a conventional urinalysis) in unspun clean-catch midstream urine (MSU) or catheter urine sample or = 10 WBC/HPF in spun MSU or catheter urine). 4. Subject has Gram-negative organism(s) on direct examination of a Gram-stained specimen from unspun or spun MSU or catheter urine sample. 5. Subject has provided a pre-therapy urine specimen obtained within 48 hours prior to the start of therapy, which when cultured has grown at least one and not more than two Gram-negative uropathogens at =10 to the power 5 CFU/mL. a. A subject may be enrolled before the results of the pre-therapy urine culture is known, but the subject should be withdrawn from the study if the culture does not yield at least one but not more than two qualifying Gram-negative urop
Exclusion criteria
Exclusion criteria: 1. Concomitant infection requiring systemic antibacterial therapy other than study drugs at the time of randomisation. 2. Subject is known to have one or more of the following: a. A urinary catheter that is not being removed during the study (or with an expectation that a catheter would be inserted during therapy with study drug and subsequently not removed during the study period; (intermittent straight catheterisation is acceptable) b. Complete permanent obstruction of the urinary tract; c. A permanent indwelling catheter or comparable instrumentation including nephrostomy that will not be removed during IV study drug administration; d. Suspected or confirmed prostatitis; e. Suspected or confirmed perinephric or intrarenal abscess; f. A UTI suspected or confirmed to be fungal in origin (with = 10 to the power 3 fungal CFU/mL); g. A UTI suspected or confirmed to be due to a Gram-positive uropathogen(s), with =10 to the power 5 Gram-positive organism CFU/mL; h. A UTI known at study entry to be caused by a pathogen(s) resistant to the study antimicrobial agent; i. Known ileal loops or vesico-ureteral reflux ; j. Polycystic kidney disease. 3. Subject has an APACHE II score >20. 4. Subject has known moderate to severe impairment of renal function including: a calculated creatinine clearance (CrCl) of =50 mL/min; requirement for peritoneal dialysis, haemodialysis, or haemofiltration; oliguria (less than 20 mL urine output per hour over 24 hours); 5. Subject with an intractable lower cUTI requiring more than 14 Days IV treatment. 6. Subjects with asymptomatic lower cUTI, such as subjects with spinal cord injury with lower cUTI who are not able to perceive symptoms due to their injury. 7. Subject with lower cUTI or pyelonephritis (complicated and uncomplicated) who has received any amount of a potentially therapeutic antibiotic within the 96 h before providing the baseline urine culture specimen or prior to the start of the study. 8. Subject has Gram-positive organism(s) on direct examination of a Gram-stained specimen of spun/unspun MSU or catheter urine. 9. Subject is considered unlikely to survive the 4 6 week study period or has any rapidly progressing disease or immediately life-threatening illness (including acute hepatic failure, respiratory failure or septic shock). 10. Subject has evidence of known or pre-existing severe hepatic disease (Child-Pugh score of B or C). 11. Subject has a known baseline haemoglobin less than 10 g/dL ,haematocrit less than 30% and/or a known reticulocyte count of >5% (i.e., reticulocytes >5% of total RBC mass) 12. Subject has known neutropenia or is anticipated to develop neutropenia during the course of the study (i.e., new chemotherapy subject), with absolute neutrophil count less than 1000 cells/mm3. 13. Subject has a known platelet count less than 75,000 cells /mm3 (subjects with platelet counts as low as 50,000 cells /mm3 are eligible if the reduction is historically stable). 14. Subject has an immunocompromising illness; including known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), organ (including bone marrow) transplantation, hematological malignancy, and/or immunosuppressive therapy , including high-dose corticosteroids (e.g., greater than 40 mg prednisone or equivalent per day for greater than two weeks). 15. Subject has participated in any investigational drug or device study within 30 days of study entry or within 5 hal
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of GSK2251052 in the treatment of adult subjects with lower cUTI and pyelonephritis (complicated and uncomplicated). To evaluate the clinical and microbiological efficacy of GSK2251052 in microbiologically evaluable adult subjects with lower cUTI and pyelonephritis (complicated and uncomplicated). ;Secondary Objective: To compare the clinical and bacteriological efficacy of GSK2251052 to imipenem-cilastatin in microbiologically evaluable adult subjects with lower cUTI and acute pyelonephritis (complicated and uncomplicated). To evaluate the pharmacokinetics of GSK2251052 and to characterise the pharmacokinetic/pharmacodynamic relationship in this study population. ;Primary end point(s): The primary endpoints are: Safety evaluation of data from clinical laboratory tests, urinalysis, spontaneous/elicited adverse event reporting, ECGs and vital signs in all subjects who had at least one dose of study medication. Primary efficacy outcome measure is the therapeutic response (combined per-subject clinical and microbiological response) at the Test of Cure visit in subjects who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy. ;Timepoint(s) of evaluation of this end point: The primary end point is to be evaluated at the test of cure visit (5 to 9 days post IV treatment) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Microbiological response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit. • Clinical response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit • Therapeutic response (combined clinical and microbiological response) at the End of IV Visit and Late Follow-Up Visit, • GSK2251052 pharmacokinetics and population PK/PD in the patient population ;Timepoint(s) of evaluation of this end point: Secondary end points are to be evaluated at the test of cure visit (5 to 9 days post IV treatment), End of IV therapy visit and Late follow-up visit (21 -28 days post IV treatment) | — |
Countries
Germany, Greece, Hungary, Russian Federation, South Africa, Spain, United States
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline Research and Development Ltd
Outcome results
None listed