GSK2251052 in Complicated Urinary Tract Infection

NCT01381549 | Terminated Phase 2 Results DMC

• 1 other identifier: 114688
• Study Type: interventional
• Target: 20
• Locations: 6 countries
• Sites: 24

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.

Conditions

Infections, Urinary Tract

Keywords

Gram-negative; uropathogens; complicated lower urinary tract infection; pyelonephritis

Outcome Measures

Primary Outcomes (18)

• 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 Outcomes (12)

• Microbiological Response at the End of IV Therapy Visit, Test of Cure Visit and Late Follow-Up Visit

  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

  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

  End of IV therapy (0-24 hours post-therapy) and Late Follow-up (21-28 days post-therapy)

• Maximum Plasma Concentration (Cmax) of GSK2251052

  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

  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

Study Arms (3)

GSK2251052 750mg

EXPERIMENTAL

q12h administered via IV infusion, plus saline placebo

Drug: GSK2251052; Other: Placebo

GSK2251052 1500mg

EXPERIMENTAL

q12h administered via IV infusion, plus saline placebo

Drug: GSK2251052; Other: Placebo

imipenem-cilastatin

ACTIVE COMPARATOR

500 mg imipenem monohydrate and 500 mg cilastatin sodium; q6h administered via IV infusion, plus saline placebo

Drug: imipenem-cilastatin; Other: Placebo

Interventions

GSK2251052 DRUG

Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion

GSK2251052 1500mg; GSK2251052 750mg

imipenem-cilastatin DRUG

Prepare as per prescribing information instructions in 100 mL bag of 0.9% NaCl and administered via IV infusion

Also known as: Primaxin® (Manufacturer: Merck)

imipenem-cilastatin

Placebo OTHER

saline placebo

GSK2251052 1500mg; GSK2251052 750mg; imipenem-cilastatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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

You may not qualify if:

• 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);

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (24)

GSK Investigational Site

Los Angeles, California, 90033, United States

Location

GSK Investigational Site

Council Bluffs, Iowa, 51503, United States

Location

GSK Investigational Site

Topeka, Kansas, 66604, United States

Location

GSK Investigational Site

Corsicana, Texas, 75110, United States

Location

GSK Investigational Site

Chicoutimi, Quebec, G7H 5H6, Canada

Location

GSK Investigational Site

Sherbrooke, Quebec, J1H 5N4, Canada

Location

GSK Investigational Site

Suresnes, 92151, France

Location

GSK Investigational Site

Toulouse, 31059, France

Location

GSK Investigational Site

Athens, 11527, Greece

Location

GSK Investigational Site

Chaïdári, 12462, Greece

Location

GSK Investigational Site

Goudi, Athens, 11527, Greece

Location

GSK Investigational Site

Thessaloniki, 56429, Greece

Location

GSK Investigational Site

Irkutsk, 664079, Russia

Location

GSK Investigational Site

Moscow, 125367, Russia

Location

GSK Investigational Site

Rostov-on-Don, 344022, Russia

Location

GSK Investigational Site

Smolensk, 214018, Russia

Location

GSK Investigational Site

St'Petersburg, 194354, Russia

Location

GSK Investigational Site

Alicante, 03010, Spain

Location

GSK Investigational Site

Elche (Alicante), 03203, Spain

Location

GSK Investigational Site

Getafe/Madrid, 28905, Spain

Location

GSK Investigational Site

Granada, 18003, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Murcia, Spain

Location

GSK Investigational Site

Pama de Mallorca, 07010, Spain

Location

Related Publications (1)

• 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.

  PMID: 25348524 DERIVED

MeSH Terms

Conditions

Urinary Tract Infections; Pyelonephritis

Interventions

3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole; Cilastatin, Imipenem Drug Combination

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis, Interstitial; Nephritis; Kidney Diseases; Pyelitis

Intervention Hierarchy (Ancestors)

Imipenem; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 9, 2011
• First Posted: June 27, 2011
• Study Start: June 28, 2011
• Primary Completion: March 6, 2012
• Study Completion: March 6, 2012
• Last Updated: September 8, 2017
• Results First Posted: September 8, 2017

Record last verified: 2017-08

Locations

GR (4); RU (5); US (4); ES (7); FR (2); CA (2)