GSK2251052 in Complicated Urinary Tract Infection

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Infections, Urinary Tract

Intervention / Treatment
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* Drug: GSK2251052
* Drug: imipenem-cilastatin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2251052 750mg<br>q12h administered via IV infusion, plus saline placebo | Drug: GSK2251052<br>* Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion<br>Other: Placebo<br>* saline placebo<br>|
| Experimental: GSK2251052 1500mg<br>q12h administered via IV infusion, plus saline placebo | Drug: GSK2251052<br>* Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion<br>Other: Placebo<br>* saline placebo<br>|
| Active Comparator: imipenem-cilastatin<br>500 mg imipenem monohydrate and 500 mg cilastatin sodium; q6h administered via IV infusion, plus saline placebo | Drug: imipenem-cilastatin<br>* Prepare as per prescribing information instructions in 100 mL bag of 0.9% NaCl and administered via IV infusion<br>* Other names: Primaxin® (Manufacturer: Merck);Other: Placebo<br>* saline placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Laboratory Parameters- Albumin and Total Protein | Clinical laboratory parameters included albumin and total protein. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in albumin and total protein are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Clinical Laboratory Parameters- Creatinine Clearance, Estimated (CCE) | Clinical laboratory parameters included CCE. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in CCE are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Clinical Laboratory Parameters- Creatinine, Direct Bilirubin and Total Bilirubin | Clinical laboratory parameters included creatinine, direct bilirubin and total bilirubin. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in creatinine, direct bilirubin and total bilirubin are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Clinical Laboratory Parameters- Calcium, Carbon-dioxide (C02) Content/Bicarbonate, Chloride, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN) | Clinical laboratory parameters included C02 content/bicarbonate, chloride, glucose, potassium, sodium and urea/BUN. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in C02 content/bicarbonate, chloride, glucose, potassium, sodium and urea/BUN are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| 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) | Clinical laboratory parameters included ALT, ALP, AST, Creatine kinase and GGT. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in ALT, ALP, AST, Creatine kinase and GGT are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. | Up to 28 days post-therapy | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Twelve lead ECGs were obtained during the study using an ECG machine that automatically measured PR, QRS, QT, and QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) intervals. Twelve lead ECGs were performed with the participant in a semi-supine position having rested in this position for at least 10 minutes beforehand. Measurements that deviated substantially from previous readings were repeated immediately. Three measurements were taken at pre-dose on Day 1 at least 5 min apart. One additional ECG measurement was taken after completion of the first infusion of study medication. Two ECG measurements (pre and post-1st infusion of the day) were taken on Day 4 while the participant was on IV therapy. When there was an abnormal finding, two more were taken and the mean PR interval, QRS duration, QT interval and QTcB were calculated from automated ECG readings. One ECG measurement was taken at the early safety follow-up visit. | Up to Late Follow-up Visit (21 to 28 days post-IV therapy) | 
| Summary of Vital Signs: Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Vital sign measurements included SBP and DBP (supine or semi-supine). Measurements that deviated substantially from previous readings were repeated immediately. Mean SBP and DBP are presented. | Up to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Summary of Vital Signs- Mean Heart Rate | Vital sign measurements included heart rate. Measurements that deviated substantially from previous readings were repeated immediately. Mean heart rate is presented. | Up to Late Follow-up Visit (21 to 28 days post-IV therapy) | 
| Summary of Vital Signs- Mean Respiration Rate | Vital sign measurements included respiratory rate. Measurements that deviated substantially from previous readings were repeated immediately. Mean respiration rate are presented. | Up to Late Follow-up Visit (21 to 28 days post-IV therapy) | 
| Summary of Vital Signs- Mean Temperature | Vital sign measurements included temperature (oral, tympanic or rectal). Measurements that deviated substantially from previous readings were repeated immediately. Temperature was assessed as normal hospital practice dictated and the maximum daily temperature was recorded in the electronic case report form (eCRF). | Up to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Therapeutic Response at the Test of Cure Visit | The therapeutic response was the combination of a participant's clinical and microbiological response. It was assessed at the Test of Cure visit in participants who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy. Therapeutic response was a measure of the overall efficacy response, and a therapeutic success referred to participants who have been deemed both a 'clinical success' and a 'microbiological success'. All other combinations (other than 'clinical success' + 'microbiological success') were deemed failures for therapeutic response. | Test of Cure Visit (5 to 9 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Hematocrit | Hematology parameters included hematocrit. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in hematocrit are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Mean Corpuscle Hemoglobin (MCH) | Hematology parameters included MCH. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in MCH are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Mean Corpuscle Volume (MCV) | Hematology parameters included MCV. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in MCV are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Red Blood Cell (RBC) Count and Reticulocytes | Hematology parameters included RBC count and reticulocytes. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in RBC count and reticulocytes are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) | Hematology parameters included hemoglobin and MCHC. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in hemoglobin and MCHC are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 
| Change From Baseline in Hematology Parameters- Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Total Neutrophils and White Blood Cell Count (WBC) | Hematology parameters included basophils, eosinophils, lymphocytes, monocytes, platelet count, total neutrophils and WBC. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Late follow-up visit in basophils, eosinophils, lymphocytes, monocytes, platelet count, total neutrophils and WBC are presented. | Baseline (Day 1) to Late Follow up Visit (21 to 28 days post-IV therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiological Response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit | Microbiological response involved both microbiological success and microbiological failure. A reduction in the uropathogens in the urine culture and no growth on blood culture was termed as microbiological success. Increase in the uropathogens in the urine culture and pathogens identified in the blood culture or use of antibacterials other than study treatments were classified as microbiological failures. | 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) | 
| Clinical Response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit | Clinical response was a combination of clinical success and clinical failure. In clinical success, participants showed no signs and symptoms of pyelonephritis and lower complicated urinary tract infection and antibiotics are not used for the same. In clinical failure, there is reappearance of signs and symptoms of and lower complicated urinary tract infection and participant required antibiotics for the same. | 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) | 
| Therapeutic Response (Combined Clinical and Microbiological Response) at the End of IV Visit and Late Follow-Up Visit | The therapeutic response was the combination of a participant's clinical and microbiological response. It was assessed at the Test of Cure visit in participants who have a qualifying Gram-negative uropathogen at Baseline and have had a minimum of 5 days of IV therapy. Therapeutic response was a measure of the overall efficacy response, and a therapeutic success referred to participants who have been deemed both a 'clinical success' and a 'microbiological success'. All other combinations (other than 'clinical success' + 'microbiological success') were deemed failures for therapeutic response. | End of IV therapy (0-24 hours post-therapy) and Late Follow-up (21-28 days post-therapy) | 
| Maximum Plasma Concentration (Cmax) of GSK2251052 | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Area Under the Concentration Time Curve (AUC) of GSK2251052 | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Time to Cmax (Tmax) of GSK2251052 | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Cmax of GSK2251052 Using Non-intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| AUC of GSK2251052 Using Non-intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Tmax of GSK2251052 Using Non-intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Cmax of GSK2251052 Using Intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| AUC of GSK2251052 Using Intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 
| Tmax of GSK2251052 Using Intensive PK Sampling | The planned pharmacokinetic (PK) and PK/pharmacodynamic analyses were not performed, because the PK data was not collected. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gram-negative, uropathogens, complicated lower urinary tract infection, pyelonephritis