GSK2251052 in Complicated Urinary Tract Infection

Infections, Urinary Tract Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01381549
• Other study ID #: 114688
• Status: Terminated
• Phase: Phase 2
• First received: June 9, 2011
• Last updated: July 24, 2014
• Start date: June 2011
• Est. completion date: March 2012

Study information

• Verified date: February 2014
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: AIFA - Italian Ministry of HealthRomania: Ministry of Health and FamilyIndia: Ministry of HealthPoland: Ministerstwo ZdrowiaHungary: National Institute of PharmacySpain: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesUnited States: Food and Drug AdministrationHong Kong: Department of HealthSouth Africa: Department of HealthIsrael: Ministry of HealthRussian Federation: Ministry of Health and social development of Russian Federation, FederalCanada: Health CanadaFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Greece: National Drug Organisation
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: March 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Infections, Urinary Tract
• Urinary Tract Infections

Intervention

Drug:
• GSK2251052
Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion
• imipenem-cilastatin
Prepare as per prescribing information instructions in 100 mL bag of 0.9% NaCl and administered via IV infusion

Other:
• Placebo
saline placebo

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Chicoutimi	Quebec
Canada	GSK Investigational Site	Sherbrooke	Quebec
France	GSK Investigational Site	Suresnes
France	GSK Investigational Site	Toulouse cedex 9
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Chaidari
Greece	GSK Investigational Site	Goudi, Athens
Greece	GSK Investigational Site	Thessaloniki
Russian Federation	GSK Investigational Site	Irkutsk
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Rostov-on-Don
Russian Federation	GSK Investigational Site	Smolensk
Russian Federation	GSK Investigational Site	St'Petersburg
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Elche (Alicante)
Spain	GSK Investigational Site	Getafe/Madrid
Spain	GSK Investigational Site	Granada
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Murcia
Spain	GSK Investigational Site	Pama de Mallorca
United States	GSK Investigational Site	Corsicana	Texas
United States	GSK Investigational Site	Council Bluffs	Iowa
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Topeka	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada,  France,  Greece,  Russian Federation,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety outcome On Therapy	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	On therapy (days 1-14)	Yes
Primary	Safety outcome at End of Therapy	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	End of therapy (0-24 hours post-therapy)	Yes
Primary	Safety outcome at Test of Cure	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	Test of cure (5-9 days post-therapy)	Yes
Primary	Safety outcome at Early Follow-up	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	Early Follow-up (14-17 days post-therapy)	Yes
Primary	Safety outcome at Follow-up	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	Follow-up (21-28 days post-therapy)	Yes
Primary	Efficacy Outcome - Therapeutic Response	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	Test of cure (5-9 days post-therapy)	No
Primary	Safety outcome at Hematology Safety Visit	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	Hematology Safety (2-4 days post-therapy)	Yes
Secondary	Microbiological response	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	End of IV therapy (0-24 hours post-therapy)	No
Secondary	Clinical Response	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	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)	No
Secondary	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	End of IV therapy (0-24 hours post-therpay; Late Follow-up (21-28 days post-therapy)	No
Secondary	Maximum plasma concentration (Cmax) of GSK2251052	Pharmcokinetics (PK) in all subjects	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	No
Secondary	Area under the concentration time curve (AUC) of GSK2251052	PK in all subjects	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	No
Secondary	Time to Cmax (Tmax) of GSK2251052	PK in all subjects	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	No
Secondary	Cmax of GSK2251052 using Non-intensive PK sampling	Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling	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	No
Secondary	AUC of GSK2251052 using Non-intensive PK sampling	Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling	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	No
Secondary	Tmax of GSK2251052 using Non-intensive PK sampling	Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling	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	No
Secondary	Cmax of GSK2251052 using intensive PK sampling	Sub-set of approximately 15 patients	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	No
Secondary	AUC of GSK2251052 using intensive PK sampling	Sub-set of approximately 15 patients	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	No
Secondary	Tmax of GSK2251052 using intensive PK sampling	Sub-set of approximately 15 patients	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	No