GSK2251052 in the Treatment of Complicated Intra-abdominal Infections

This study has been terminated.
(Microbiological findings of resistance on therapy in patients with complicated urinary tract infection)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01381562
First received: June 9, 2011
Last updated: July 24, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Infections, Intestinal
Drug: Drug: GSK2251052
Drug: Meropenem
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Double-blind, Multi-center, Dose-ranging Study of the Safety, Tolerability and Efficacy of GSK2251052 in the Treatment of Complicated Intra-abdominal Infections in Adults

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety outcome - On Therapy [ Time Frame: On therapy (days 1-14) ] [ Designated as safety issue: Yes ]
    Evaluation of ata 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

  • Safety outcome - End of Therapy [ Time Frame: End of therapy (0-24 hours post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of ata 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

  • Safety outcome - Test of Cure [ Time Frame: Test of cure (5-9 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of ata 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

  • Safety outcome - Early Follow-up [ Time Frame: Early Follow-up (14-17 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of ata 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

  • Safety outcome - Follow-up [ Time Frame: Follow-up (21-28 days post-therapy) ] [ Designated as safety issue: Yes ]
    Evaluation of ata 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

  • Efficacy outcome - clinical response [ Time Frame: Test of cure visit 5-9 days post-therapy ] [ Designated as safety issue: No ]
    Clinical success or failure in subjects who have a qualifying Gram-negative pathogen at Baseline and who have a minimum of 5 days of IV therapy

  • Safety outcome at Hematology Safety Visit [ Time Frame: Hematology Safety (2-4 days post-therapy ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Microbiological response [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Microbiological success or failure in subjects who have a qualifying Gram-negative pathogen at Baseline and who have a minimum of 5 days of IV therapy

  • Clinical response [ Time Frame: End of IV therapy (0-24 hours post-therapy) and Late Follow-up (21-28 days post-therapy) ] [ Designated as safety issue: No ]
    Clinical success or failure in subjects who have a qualifying Gram-negative pathogen at Baseline and who have a minimum of 5 days of IV therapy

  • Therapeutic response [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Combined clinical and microbiological response

  • Maximum plasma concentration (Cmax) of GSK2251052 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Pharmcokinetics (PK) in all subjects

  • Area under the concentration time curve (AUC) of GSK2251052 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Pharmcokinetics (PK) in all subjects

  • Time to Cmax (Tmax) of GSK2251052 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Pharmcokinetics (PK) in all subjects

  • Cmax of GSK2251052 using Non-intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • AUC of GSK2251052 using Non-intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • Tmax of GSK2251052 using Non-intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Non-intensive PK sampling for all patients who are not participating in Intensive PK Sampling

  • Cmax of GSK2251052 using intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients

  • AUC of GSK2251052 using intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients

  • Tmax of GSK2251052 using intensive PK sampling [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Sub-set of approximately 15 patients


Enrollment: 15
Study Start Date: October 2011
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2251052 750mg
q12h administered via IV infusion, plus saline placebo
Drug: Drug: GSK2251052
Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion
Other: Placebo
saline placebo
Experimental: GSK2251052 1500mg
q12h administered via IV infusion, plus saline placebo
Drug: Drug: GSK2251052
Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion
Other: Placebo
saline placebo
Active Comparator: Meropenem 1G
q8h administered via IV infusion, plus saline placebo
Drug: Meropenem
Reconstituted, added to 100mL 0.9% NaCl solution and administered via IV infusion
Other Names:
  • Merrem ®
  • Meronem
Other: Placebo
saline placebo

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01381562

  Show 31 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01381562     History of Changes
Other Study ID Numbers: 114689
Study First Received: June 9, 2011
Last Updated: July 24, 2014
Health Authority: Netherlands: Centrale Commissie Mensgesbonden Onderzoek (Central Committee on Research Involving Human Subjects) Den Haag (The Hague), The Netherlands
Italy: AIFA - Italian Ministry of Health
India: Ministry of Health
Netherlands: Centrale Commissie Mensgebonden Onderzoek
Poland: Ministerstwo Zdrowia
Hungary: National Institute of Pharmacy
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
United States: Food and Drug Administration
Spain: Ministry of Health
South Africa: Department of Health
Israel: Ministry of Health
Russian Federation: Ministry of Health and social development of Russian Federation, Federal
Canada: Health Canada
Romania: National Medicine and Medical Devices Agency (NMMDA)
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Czech Republic: State Institute for Drug Control

Keywords provided by GlaxoSmithKline:
intra-abdominal infection
belly
Gram-negative pathogen
abscess
peritonitis

Additional relevant MeSH terms:
Intraabdominal Infections
Infection
Meropenem
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014