GSK2251052 in Complicated Urinary Tract Infection
Condition: Infections, Urinary Tract
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis
Intervention: GSK2251052; imipenem-cilastatin; Placebo
Intervention description: Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion; Prepare as per prescribing information instructions in 100 mL bag of 0.9% NaCl and administered via IV infusion; saline placebo
Intervention MeSH terms: Imipenem; Cilastatin, Imipenem Drug Combination; Cilastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gram-negative; uropathogens; complicated lower urinary tract infection; pyelonephritis

Summary:

      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.
    

Eligibility 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