GSK2251052 in Complicated Urinary Tract Infection

GlaxoSmithKline (GSK)

Status and phase: Terminated; Phase 2

Conditions: Infections, Urinary Tract

Treatments: Other: Placebo; Drug: imipenem-cilastatin; Drug: GSK2251052

Study type: Interventional

Funder types: Industry

Identifiers

NCT01381549

114688

Details and patient eligibility

About

This study is being conducted to evaluate the safety, efficacy (clinical and microbiological), pharmacokinetics/pharmacodynamics of GSK2251052 and to assess whether it would be a suitable antibiotic for the treatment for febrile lower cUTI and pyelonephritis(complicated and uncomplicated). GSK2251052 will be compared to imipenem-cilastatin, which is an antibiotic commonly used to treat serious cUTI infections. GSK2251052 has a spectrum of microbiological activity that includes pathogens responsible for cUTI.

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Adult subjects least 18 years of age.

N.B. Females of non-childbearing or childbearing potential may be enrolled. Females of childbearing potential 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 following methods for avoidance of pregnancy during the entire study treatment period:

• Abstinence; or,
• Oral Contraceptive, either combined estrogen/progesterone or progesterone alone, PLUS an additional barrier method [ie, condom, occlusive cap (diaphragm or cervical/vault caps) or vaginal spermicidal agent (foam/gel/film/cream/suppository)]; or,
• Injectable progesterone; or
• Implants of levonorgestrel; or,
• Estrogenic vaginal ring; or,
• Percutaneous contraceptive patches; or
• Intrauterine device (IUD) or intrauterine system (IUS) showing that failure rate is less than 1% in the IUD or IUS product label; or,
• Has a male partner who is sterilized (vasectomy with documentation of azoospermia).
• Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
• Females are considered to be of non-childbearing potential if they have documented tubal ligation or hysterectomy; or are postmenopausal, defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]
• 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:
• 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:
• Afebrile subjects with lower cUTI who have a white blood cell count (WBC) ≥15,000 cells/mm3
• 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:
• Male gender;
• Current bladder instrumentation or indwelling urinary catheter that has to be removed two days before the end of IV study drug administration;
• Obstructive uropathy that is expected to be medically or surgically treated during the course of IV study drug administration;
• Urogenital surgery within 7 days preceding administration of the first dose of study drug;
• Functional or anatomical abnormality of the urogenital tract including anatomic malformations or neurogenic bladder with voiding disturbance of at least 100 mL residual urine.
• 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.
• 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).
• Subject has Gram-negative organism(s) on direct examination of a Gram-stained specimen from unspun or spun MSU or catheter urine sample.
• 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 >=10^5 CFU/mL.
• 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 >=10^5 CFU/mL or if the culture yields Gram-positive uropathogens.
• 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 >=10^5 CFU/mL. Subjects who are treatment failures due to imipenem-cilastatin should not be enrolled.
• QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block
• Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

• Concomitant infection requiring systemic antibacterial therapy other than study drugs at the time of randomisation.
• Subject is known to have one or more of the following:
• 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)
• Complete permanent obstruction of the urinary tract;
• A permanent indwelling catheter or comparable instrumentation including nephrostomy that will not be removed during IV study drug administration
• Suspected or confirmed prostatitis
• Suspected or confirmed perinephric or intrarenal abscess
• A UTI suspected or confirmed to be fungal in origin (with >= 10^3 fungal CFU/mL)
• A UTI suspected or confirmed to be due to a Gram-positive uropathogen(s), with >= 10^5 Gram-positive organism CFU/mL;
• A UTI known at study entry to be caused by a pathogen(s) resistant to the study antimicrobial agent;
• Known ileal loops or vesico-ureteral reflux ;
• Polycystic kidney disease.
• Subject has an APACHE II score >20
• Subject has known severe impairment of renal function including: a calculated creatinine clearance (CrCl) of less than 50 mL/min; requirement for peritoneal dialysis, haemodialysis, or haemofiltration; oliguria (less than 20 mL urine output per hour over 24 hours);
• Subject with an intractable lower cUTI requiring more than 14 Days IV treatment.
• 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.
• 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.
• Subject has Gram-positive organism(s) on direct examination of a Gram-stained specimen of spun/unspun MSU or catheter urine.
• 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).
• Subject has evidence of known or pre-existing severe hepatic disease (Child-Pugh score of B or C).
• 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)
• 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
• 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).
• 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)
• Subject has participated in any investigational drug or device study within 30 days of study entry or within 5 half-lives, whichever is longer.
• Subject has previously received treatment with GSK2251052.
• 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.
• Subject requires probenicid or valproic acid medications.
• Subject has a history of moderate or severe hypersensitivity to beta-lactam antibiotics.
• Subject is pregnant or nursing
• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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20 participants in 3 patient groups

GSK2251052 750mg

Experimental group

Description:

q12h administered via IV infusion, plus saline placebo

Treatment:

Other: Placebo

Drug: GSK2251052

GSK2251052 1500mg

Experimental group

Description:

q12h administered via IV infusion, plus saline placebo

Treatment:

Other: Placebo

Drug: GSK2251052

imipenem-cilastatin

Active Comparator group

Description:

500 mg imipenem monohydrate and 500 mg cilastatin sodium; q6h administered via IV infusion, plus saline placebo

Treatment:

Other: Placebo

Drug: imipenem-cilastatin