| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary tract infections (cUTI) |
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| E.1.1.1 | Medical condition in easily understood language |
| a urinary infection or kidney infection (also known as pyelonephritis) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046574 |
| E.1.2 | Term | Urinary tract infection NOS |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037606 |
| E.1.2 | Term | Pyelonephritis, unspecified |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
French subjects: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 off 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 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 ≥105 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 uropathogens at ≥105 CFU/mL or if the culture yields Gram-positive uropathogens
b.A subject with lower cUTI or pyelonephritis(complicated or uncomplicated)who has failed a previous antibacterial treatment regimen is eligible provided a urine specimen is positive for one and not more than two bacterial Gram-negative uropathogens at ≥105 CFU/mL.Subjects who are treatment failures due to imipenem-cilastatin should not be enrolled
6.QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
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 ≥ 103 fungal CFU/mL);
g. A UTI suspected or confirmed to be due to a Gram-positive uropathogen(s), with ≥105 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 or with a neurogenic bladder that are not able to perceive symptoms or subjects with symptoms of neurogenic hyper-reflexive bladder 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 Gramstained 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 half-lives, whichever is longer.
16. Subject has previously received treatment with GSK2251052.
17. Subject has a prior history of seizures or has a CNS abnormality predisposing them to seizures or has a lowered seizure threshold and/or is using concomitant medications with seizure potential.
18. Subject requires probenicid or valproic acid medications.
19. Subject with a history of moderate or severe hypersensitivity to β-lactam antibiotics.
20. Subject is pregnant or nursing.
21. Subject, in the opinion of the investigator may be significantly compromised by a potential drop in haemoglobin ≥2.5g/dl which is not related to the condition under study.
French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days.
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| E.5 End points |
| E.5.1 | 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.
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| E.5.1.1 | 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) |
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| E.5.2 | 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
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| E.5.2.1 | 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) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Hong Kong |
| India |
| Israel |
| Russian Federation |
| South Africa |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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