GSK2251052 in the Treatment of Complicated Intra-abdominal Infections
Condition: Infections, Intestinal
MeSH terms: Infections; Communicable Diseases; Intraabdominal Infections
Intervention: Drug: GSK2251052; Meropenem; Placebo
Intervention description: Reconstituted, added to 250mL 0.9% NaCl solution and administered via IV infusion; Reconstituted, added to 100mL 0.9% NaCl solution and administered via IV infusion; saline placebo
Intervention MeSH terms: Meropenem
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: intra-abdominal infection; belly; Gram-negative pathogen; abscess; peritonitis

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.