Clinical trial NCT01381562: GSK2251052 in the Treatment of Complicated Intra-abdominal Infections
Official title: A Study to Assess the Safety, Tolerability and Preliminary Efficacy of GSK2251052 in the Treatment of Complicated Intra-abdominal Infection in Adults
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Infections, Intestinal
Keywords: intra-abdominal infection
belly
Gram-negative pathogen
abscess
peritonitis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-06-27
Enrollment: 15
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 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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Any Adverse Event
timeFrame: Up to Day 42
measure: Number of Participants With Clinically Significant Trends in Vital Signs Over the Period of Study Duration
timeFrame: Up to Day 42
measure: Number of Participants With Normal and Abnormal ECG Findings
timeFrame: Up to Day 42
measure: Laboratory Parameters of Interest- Mean Hemoglobin Over the Period of Study Duration
timeFrame: Up to Day 42
measure: Laboratory Parameters of Interest- Mean Reticulocytes Over the Period of Study Duration
timeFrame: Up to 42 days
measure: Mean Change From Baseline in Hemoglobin for Partcipants With Significant Hemoglobin Drop
timeFrame: Baseline (Day 1) and up to Day 42
measure: 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:
measure: 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
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
measure: 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)
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 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
measure: 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
measure: 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
measure: 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
measure: 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
measure: 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
Other outcomes:
Locations:
city: Mobile
country: United States
facility: GSK Investigational Site
state: Alabama
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Council Bluffs
country: United States
facility: GSK Investigational Site
state: Iowa
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Buffalo
country: United States
facility: GSK Investigational Site
state: New York
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Lima
country: United States
facility: GSK Investigational Site
state: Ohio
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Chicoutimi
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Trois-Rivières
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Saskatoon
country: Canada
facility: GSK Investigational Site
state: Saskatchewan
city: Praha 10
country: Czechia
facility: GSK Investigational Site
city: Praha 10
country: Czechia
facility: GSK Investigational Site
city: Limoges
country: France
facility: GSK Investigational Site
city: Nîmes cedex 9
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Verona
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Irkutsk
country: Russian Federation
facility: GSK Investigational Site
city: Perm
country: Russian Federation
facility: GSK Investigational Site
city: Perm
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburgh
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: Madrid
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: