GSK2251052 in Complicated Urinary Tract Infection

This study has been terminated.
(Microbiological findings of resistance on therapy in patients with complicated urinary tract infection)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01381549
First received: June 9, 2011
Last updated: February 13, 2014
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Infections, Urinary Tract
Drug: GSK2251052
Drug: imipenem-cilastatin
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomised, Double-blind, Dose-finding, Multicenter Study of the Safety, Tolerability, and Efficacy of GSK2251052 Therapy Compared to Imipenem-cilastatin in the Treatment of Adult Subjects With Febrile Complicated Lower Urinary Tract Infections and Acute Pyelonephritis

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety outcome On Therapy [ Time Frame: On therapy (days 1-14) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, ECGs and vital signs in all enrolled subjects who had at least one dose of study medication

  • Safety outcome at End of Therapy [ Time Frame: End of therapy (0-24 hours post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, ECGs and vital signs in all enrolled subjects who had at least one dose of study medication

  • Safety outcome at Test of Cure [ Time Frame: Test of cure (5-9 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, ECGs and vital signs in all enrolled subjects who had at least 3 days of study medication

  • Safety outcome at Early Follow-up [ Time Frame: Early Follow-up (14-17 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, ECGs and vital signs in all enrolled subjects who had at 3 days of study medication

  • Safety outcome at Follow-up [ Time Frame: Follow-up (21-28 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, ECGs and vital signs in all enrolled subjects who had at least one dose of study medication

  • Efficacy Outcome - Therapeutic Response [ Time Frame: Test of cure (5-9 days post-therapy) ] [ Designated as safety issue: No ]
    Therapeutic response (combined per-subject clinical and microbiological response) in subjects who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy

  • Safety outcome at Hematology Safety Visit [ Time Frame: Hematology Safety (2-4 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of data from clinical laboratory tests, spontaneous/elicited adverse event reporting, in all enrolled subjects who had at least 3 days of study medication


Secondary Outcome Measures:
  • Microbiological response [ Time Frame: End of IV therapy (0-24 hours post-therapy) ] [ Designated as safety issue: No ]
    Microbiological success or failure in subjects who have a qualifying Gram-negative uropathogen at Baseline and who have a minimum of 5 days of IV therapy

  • Clinical Response [ Time Frame: End of IV therapy (0-24 hours post-therapy); Test of cure (5-9 days post-therapy); Late Follow-up (21-28 days post-therapy) ] [ Designated as safety issue: No ]
    Clinical success or failure in subjects who have a qualifying Gram-negative uropathogen at Baseline and who have a minimum of 5 days of IV therapy

  • Therapeutic response [ Time Frame: End of IV therapy (0-24 hours post-therpay; Late Follow-up (21-28 days post-therapy) ] [ Designated as safety issue: No ]
    Combined per-subject clinical and microbiological response in subjects who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy

  • Maximum plasma concentration (Cmax) of GSK2251052 [ Time Frame: Day 3: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Pharmcokinetics (PK) in all subjects

  • Area under the concentration time curve (AUC) of GSK2251052 [ Time Frame: Day 3: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    PK in all subjects

  • Time to Cmax (Tmax) of GSK2251052 [ Time Frame: Day 3: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    PK in all subjects

  • Cmax of GSK2251052 using Non-intensive PK sampling [ Time Frame: Day 4: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • AUC of GSK2251052 using Non-intensive PK sampling [ Time Frame: Day 4: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • Tmax of GSK2251052 using Non-intensive PK sampling [ Time Frame: Day 4: Pre- dose (just prior to the start of the first infusion of the day) and 1 hour (just prior to the end of the infusion), 2, 4, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • Cmax of GSK2251052 using intensive PK sampling [ Time Frame: Day 4: Pre-dose (just prior to the start of the first infusion of the day) 0.5, 1 hour (just prior to the end of the infusion), 1.25, 1.5, 2, 3, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients

  • AUC of GSK2251052 using intensive PK sampling [ Time Frame: Day 4: Pre-dose (just prior to the start of the first infusion of the day) 0.5, 1 hour (just prior to the end of the infusion), 1.25, 1.5, 2, 3, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients

  • Tmax of GSK2251052 using intensive PK sampling [ Time Frame: Day 4: Pre-dose (just prior to the start of the first infusion of the day) 0.5, 1 hour (just prior to the end of the infusion), 1.25, 1.5, 2, 3, 4, 8 and 12 hours post-dose ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients


Enrollment: 20
Study Start Date: June 2011
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2251052 750mg
q12h administered via IV infusion, plus saline placebo
Drug: GSK2251052
Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion
Other: Placebo
saline placebo
Experimental: GSK2251052 1500mg
q12h administered via IV infusion, plus saline placebo
Drug: GSK2251052
Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion
Other: Placebo
saline placebo
Active Comparator: imipenem-cilastatin
500 mg imipenem monohydrate and 500 mg cilastatin sodium; q6h administered via IV infusion, plus saline placebo
Drug: imipenem-cilastatin
Prepare as per prescribing information instructions in 100 mL bag of 0.9% NaCl and administered via IV infusion
Other Name: Primaxin® (Manufacturer: Merck)
Other: Placebo
saline placebo

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01381549

Locations
United States, California
GSK Investigational Site
Los Angeles, California, United States, 90033
United States, Iowa
GSK Investigational Site
Council Bluffs, Iowa, United States, 51503
United States, Kansas
GSK Investigational Site
Topeka, Kansas, United States, 66604
United States, Texas
GSK Investigational Site
Corsicana, Texas, United States, 75110
Canada, Quebec
GSK Investigational Site
Chicoutimi, Quebec, Canada, G7H 5H6
GSK Investigational Site
Sherbrooke, Quebec, Canada, J1H 5N4
France
GSK Investigational Site
Suresnes, France, 92151
GSK Investigational Site
Toulouse cedex 9, France, 31059
Greece
GSK Investigational Site
Athens, Greece, 11527
GSK Investigational Site
Chaidari, Greece, 12462
GSK Investigational Site
Goudi, Athens, Greece, 11527
GSK Investigational Site
Thessaloniki, Greece, 56429
Russian Federation
GSK Investigational Site
Irkutsk, Russian Federation, 664079
GSK Investigational Site
Moscow, Russian Federation, 125367
GSK Investigational Site
Rostov-on-Don, Russian Federation, 344022
GSK Investigational Site
Smolensk, Russian Federation, 214018
GSK Investigational Site
St'Petersburg, Russian Federation, 194354
Spain
GSK Investigational Site
Alicante, Spain, 03010
GSK Investigational Site
Elche (Alicante), Spain, 03203
GSK Investigational Site
Getafe/Madrid, Spain, 28905
GSK Investigational Site
Granada, Spain, 18003
GSK Investigational Site
Madrid, Spain, 28040
GSK Investigational Site
Murcia, Spain
GSK Investigational Site
Pama de Mallorca, Spain, 07010
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01381549     History of Changes
Other Study ID Numbers: 114688
Study First Received: June 9, 2011
Last Updated: February 13, 2014
Health Authority: Italy: AIFA - Italian Ministry of Health
Romania: Ministry of Health and Family
India: Ministry of Health
Poland: Ministerstwo Zdrowia
Hungary: National Institute of Pharmacy
Spain: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
United States: Food and Drug Administration
Hong Kong: Department of Health
South Africa: Department of Health
Israel: Ministry of Health
Russian Federation: Ministry of Health and social development of Russian Federation, Federal
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Greece: National Drug Organisation

Keywords provided by GlaxoSmithKline:
Gram-negative
uropathogens
complicated lower urinary tract infection
pyelonephritis

Additional relevant MeSH terms:
Pyelonephritis
Urinary Tract Infections
Nephritis, Interstitial
Nephritis
Kidney Diseases
Urologic Diseases
Pyelitis
Infection
Cilastatin
Imipenem
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 24, 2014