Last updated: 11/07/2018 08:10:33
GSK2251052 in the treatment of complicated intra-abdominal Infections
EudraCT ID
EU CT Number
Not applicable
Trial status
Other
Other
Trial overview
Official title: A Study to Assess the Safety, Tolerability and Preliminary Efficacy of GSK2251052 in the treatment of complicated intra-abdominal infection in adults
Trial description: This study is being conducted to evaluate the safety, efficacy and pharmacokinetics/pharmacodynamics of GSK2251052 in subjects with complicated intra abdominal infections. GSK2251052 will be compared to meropenem, an IV therapy that is approved for use in the treatment of subjects with cIAI. GSK2251052 has a spectrum of microbiological activity that includes pathogens responsible for cIAI.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Allocation:
Randomized
Primary outcomes:
Number of participants with any adverse event
Timeframe: Up to Day 42
Number of participants with clinically significant trends in vital signs over the period of study duration
Timeframe: Up to Day 42
Number of participants with normal and abnormal ECG findings
Timeframe: Up to Day 42
Laboratory parameters of interest- Mean hemoglobin over the period of study duration
Timeframe: Up to Day 42
Laboratory parameters of interest- Mean reticulocytes over the period of study duration
Timeframe: Up to 42 days
Mean change from Baseline in hemoglobin for partcipants with significant hemoglobin drop
Timeframe: Baseline (Day 1) and up to Day 42
Number of participants with clinical response at test of cure visit (5-9 days post-therapy) in Microbiological Intent to Treat (MITT) Population
Timeframe: Day 5 to 9 post IV therapy
Secondary outcomes:
Number of participants with clinical response at test of cure visit (5-9 days post-therapy) in Microbiological Evaluable population.
Timeframe: Day 5 to 9 post IV therapy
Number of participants with microbiological response in MITT population
Timeframe: 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)
Number of participants with microbiological response in microbiological evaluable population
Timeframe: 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)
Number of participants with clinical response in microbiological evaluable population
Timeframe: 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)
Number of participants with clinical response in MITT population
Timeframe: End of IV therapy (0-24 hours post-therapy) and Late Follow-up (21-28 days post-therapy)
Number of participants with therapeutic response in microbiological evaluable population
Timeframe: 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)
Number of participants with therapeutic response in MITT population
Timeframe: 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)
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
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
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
Cmax of GSK2251052 using Non-intensive PK sampling
Timeframe: Day 5: 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
Timeframe: Day 5: 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
Timeframe: Day 5: 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
Timeframe: Day 5: 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
Timeframe: Day 5: 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
Timeframe: Day 5: 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
Interventions:
Enrollment:
15
Primary completion date:
2012-05-03
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
O’Dwyer K, Spivak A, Ingraham K, Min S, Holmes D, Jakielaszek C, Rittenhouse S, Kwan A, George L, Sathe G, Thomas E, Van Horn S, Miller L, Twynholm M, Tomayko J, Dalessandro M, Caltabiano M, Scangarella-Oman N, Brown JR.Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.Antimicrob Agents Chemother.2015;59(1):289-98doi: 10.1128/AAC.03774-14
Medical condition
Infections, Intestinal
Product
epetraborole
Collaborators
Not applicable
Study date(s)
October 2011 to March 2012
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- Adult subjects least 18 years of age.
- N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraindicated to enrol females of childbearing potential; however, 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:
- Subject has a known or suspected diagnosis of the following:
- Abdominal wall abscess
Inclusion and exclusion criteria
Inclusion criteria:
- Adult subjects least 18 years of age. N.B. Females of non-childbearing or childbearing potential may be enrolled. It is not contraindicated to enrol females of childbearing potential; however, 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 has evidence of a systemic inflammatory response believed to be related to an intra-abdominal infectious process with no evidence of another infectious source (e.g., catheter related, lung, urinary tract)
- Subject has an abnormal white blood cell count (>12,000/µL or <4,000/µL or >10% bands) PLUS one or more of the following
- Fever, defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24 hours
- Heart rate of more than 90 beats per minute
- Respiratory rate of more than 20 breaths per minute or a PaCO2 level of less than 32 mm Hg
- Altered mental status thought due to an infectious process
- Subject is post-op and required surgery within the last 24 hours prior to first dose of study medication OR subject requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) within 24 hours of first dose of study medication with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis.
- Subject has a known Gram-negative pathogen(s) isolated prior to study entry or a suspected Gram-negative post-operative infection or has failed a prior Gram negative treatment regimen A subject enrolled as a failure of a previous antibacterial treatment regimen must: Show lack of improvement or worsening in signs and symptoms of infection, including continued or worsening peritoneal findings Require additional surgical intervention which must be performed within 24 hours of first dose of study medication with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis AND/OR Be post-op and have required surgery within 24 hours prior to first dose of study medication with no more than one pre-surgical dose of an antibiotic given for pre-operative prophylaxis. Have a culture positive for a Gram-negative pathogen (from an intra-abdominal site) N.B. Such subjects may be enrolled before the results of the culture are known but if the culture is negative, the subject must be removed from study drug therapy.
- Subject requires antibacterial therapy for an anticipated duration of 7 days or more, in addition to surgical intervention, for one of the following eligible diagnoses:
- Cholecystitis (including gangrenous cholecystitis) with rupture, perforation or progression of the infection beyond the gallbladder wall
- Diverticular disease with perforation or abscess
- Appendiceal perforation with duration of symptoms >=48 hours AND imaging that is strongly suggestive of free fluid or abscess
- Acute gastric and duodenal perforations, only if operated more than 24 hours after perforation occurred
- Traumatic perforation of the intestine only if operated more than 12 hours after perforation occurred
- Peritonitis due to perforated viscus, post-operative, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
- Inflammatory bowel disease or ischemic bowel disease with bowel perforation
- If pre-operative, subject must have peritoneal findings highly suspicious for cIAI, defined as one or more of the following:
- Abdominal pain and/or tenderness
- Localized or diffuse abdominal wall rigidity
- An imaging procedure, ie. ultrasound or CT scan showing evidence of IAI
- Mass
- Ileus
- QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block
Exclusion criteria:
- Subject has a known or suspected diagnosis of the following:
- Abdominal wall abscess
- Small bowel obstruction or ischemic bowel disease without perforation
- Traumatic bowel perforation with surgery within 12 hours
- Perforation of gastroduodenal ulcer with surgery within 24 hours
- Any other intra-abdominal processes in which the primary etiology is not likely to be infectious.
- Simple cholecystitis
- Gangrenous or suppurative cholecystitis without rupture or extension beyond the gallbladder wall
- Simple appendicitis
- Acute suppurative cholangitis
- Infected, necrotizing pancreatitis, or pancreatic abscess
- Subject must not be managed by staged abdominal repair or open abdominal technique
- Subject is known at study entry, prior to randomization to study medication, to have a cIAI caused by a Gram-positive pathogen or a pathogen resistant to the study antimicrobial agent.
- Subject has an APACHE II score >20.
- 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 requires treatment with concomitant systemic antibacterial agents other than vancomycin.
- Subject has moderate to severe impairment of renal function including a calculated creatinine clearance (CrCl) of less than 50 mL/min; requirement for peritoneal dialysis, hemodialysis, or hemofiltration; or oliguria (less than 20 mL urine output per hour over 24 hours).
- Subject has a prior history of seizures or CNS abnormality and/or is using concomitant medications with seizure potential
- Subject requires probenecid or valproic acid medications
- Subject has evidence of known or pre-existing severe hepatic disease(Child-Pugh score of B or C)
- Subject has a known baseline hemoglobin less than 10 g/dL ,hematocrit less than 30% and/or a known reticulocyte count of >5% (ie, reticulocytes >5% of total RBC mass)
- Subject has known neutropenia or is anticipated to develop neutropenia during the course of the study (ie, new chemotherapy patient), 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) transplant recipients, and hematological malignancy, and immunosuppressive therapy , including high-dose corticosteroids (e.g., greater than 40mg 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 had more than 24 hours of systemic antibacterial therapy for cIAI within the 48 hour period prior to first dose of IV study drug therapy, unless there is a documented lack of clinical response to such therapy
- Subject has a history of moderate or severe hypersensitivity to Meropenem or to beta-lactam antibiotics
- Subject has previously received treatment with GSK2251052
- Subject is pregnant or nursing.
- Subject, in the opinion of the investigator, may be significantly compromised by a potential drop in haemoglobin greater than 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.
Trial location(s)
Location
GSK Investigational Site
Praha 10, Czech Republic, 100 34
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Council Bluffs, Iowa, United States, 51503
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Sherbrooke, Québec, Canada, J1H 5N4
Status
Terminated/Withdrawn
Location
GSK Investigational Site
Chicoutimi, Québec, Canada, G7H 5H6
Status
Terminated/Withdrawn
Showing 1 - 6 of 30 Results
Study documents
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Other
Actual primary completion date
2012-05-03
Actual study completion date
2012-05-03
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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