Clinical trial NCT01381549: GSK2251052 in Complicated Urinary Tract Infection
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Infections, Urinary Tract
Keywords: Gram-negative
uropathogens
complicated lower urinary tract infection
pyelonephritis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-06-27
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Change From Baseline in Clinical Laboratory Parameters- Albumin and Total Protein
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Clinical Laboratory Parameters- Creatinine Clearance, Estimated (CCE)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Clinical Laboratory Parameters- Creatinine, Direct Bilirubin and Total Bilirubin
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Clinical Laboratory Parameters- Calcium, Carbon-dioxide (C02) Content/Bicarbonate, Chloride, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Clinical Laboratory Parameters- Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase and Gamma Glutamyl Transferase (GGT)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 28 days post-therapy
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to Late Follow-up Visit (21 to 28 days post-IV therapy)
measure: Summary of Vital Signs: Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Up to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Summary of Vital Signs- Mean Heart Rate
timeFrame: Up to Late Follow-up Visit (21 to 28 days post-IV therapy)
measure: Summary of Vital Signs- Mean Respiration Rate
timeFrame: Up to Late Follow-up Visit (21 to 28 days post-IV therapy)
measure: Summary of Vital Signs- Mean Temperature
timeFrame: Up to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Therapeutic Response at the Test of Cure Visit
timeFrame: Test of Cure Visit (5 to 9 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Hematocrit
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Mean Corpuscle Hemoglobin (MCH)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Mean Corpuscle Volume (MCV)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Red Blood Cell (RBC) Count and Reticulocytes
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
measure: Change From Baseline in Hematology Parameters- Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Total Neutrophils and White Blood Cell Count (WBC)
timeFrame: Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy)
Secondary outcomes:
measure: Microbiological Response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit
timeFrame: End of IV therapy (0-24 hours post-therapy), Test of Cure Visit (5 to 9 days post-IV therapy) and Late Follow-up (21-28 days post-therapy)
measure: Clinical Response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit
timeFrame: End of IV therapy (0-24 hours post-therapy), Test of Cure Visit (5 to 9 days post-IV therapy) and Late Follow-up (21-28 days post-therapy)
measure: Therapeutic Response (Combined Clinical and Microbiological Response) at the End of IV Visit and Late Follow-Up Visit
timeFrame: End of IV therapy (0-24 hours post-therapy) and Late Follow-up (21-28 days post-therapy)
measure: Maximum Plasma Concentration (Cmax) of GSK2251052
timeFrame: 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
measure: Area Under the Concentration Time Curve (AUC) of GSK2251052
timeFrame: 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
measure: Time to Cmax (Tmax) of GSK2251052
timeFrame: 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
measure: Cmax of GSK2251052 Using Non-intensive PK Sampling
timeFrame: 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
measure: AUC of GSK2251052 Using Non-intensive PK Sampling
timeFrame: 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
measure: Tmax of GSK2251052 Using Non-intensive PK Sampling
timeFrame: 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
measure: Cmax of GSK2251052 Using Intensive PK Sampling
timeFrame: 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
measure: AUC of GSK2251052 Using Intensive PK Sampling
timeFrame: 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
measure: Tmax of GSK2251052 Using Intensive PK Sampling
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Council Bluffs
country: United States
facility: GSK Investigational Site
state: Iowa
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: Corsicana
country: United States
facility: GSK Investigational Site
state: Texas
city: Chicoutimi
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Suresnes
country: France
facility: GSK Investigational Site
city: Toulouse cedex 9
country: France
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Chaidari
country: Greece
facility: GSK Investigational Site
city: Goudi, Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Irkutsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Rostov-on-Don
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St'Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Elche (Alicante)
country: Spain
facility: GSK Investigational Site
city: Getafe/Madrid
country: Spain
facility: GSK Investigational Site
city: Granada
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Pama de Mallorca
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: O'Dwyer K, Spivak AT, Ingraham K, Min S, Holmes DJ, Jakielaszek C, Rittenhouse S, Kwan AL, Livi GP, Sathe G, Thomas E, Van Horn S, Miller LA, Twynholm M, Tomayko J, Dalessandro M, Caltabiano M, Scangarella-Oman NE, Brown JR. Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob Agents Chemother. 2015 Jan;59(1):289-98. doi: 10.1128/AAC.03774-14. Epub 2014 Oct 27.