Safety and Efficacy Study to Compare IV CXA 101/Tazobactam and Metronidazole With Meropenem in Complicated Intraabdominal Infections
Condition: Complicated Intra-abdominal Infection
MeSH terms: Infections; Communicable Diseases; Intraabdominal Infections
Intervention: CXA-101/ tazobactam and metronidazole; meropenem plus saline placebo
Intervention description: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion; meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion
Intervention MeSH terms: Metronidazole; Meropenem; Tazobactam; Ceftolozane
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 122.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No

Summary:

      A Phase 2, multicenter, prospective, randomized, double-blind study of CXA-101/ tazobactam
      (1000/500 mg q8h) and metronidazole (500 mg q8h) IV infusion vs. meropenem IV infusion (1000
      mg q8h) and a matching saline placebo (q8h) in the treatment of cIAI in adult subjects. Dose
      adjustments for subjects with mild renal impairment are not necessary and subjects with more
      severe degrees of renal failure are excluded.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female, from 18 to 90 years of age, inclusive

          -  One of the following diagnoses (in which there is evidence of intraperitoneal
             infection) including:(a) Cholecystitis (including gangrenous cholecystitis) with
             rupture, perforation, or progression of the infection beyond the gallbladder
             wall;(b)Diverticular disease with perforation or abscess; (c) Appendiceal perforation
             or periappendiceal abscess; (d) Acute gastric or duodenal perforation, only if
             operated on >24 hours after perforation occurs; (e) Traumatic perforation of the
             intestine, only if operated on > 12 hours after perforation occurs; (f) Peritonitis
             due to perforated viscus, postoperative or spread from other focus of infection (but
             not spontaneous [primary] bacterial peritonitis or peritonitis associated with
             cirrhosis and chronic ascites).Subjects with inflammatory bowel disease or ischemic
             bowel disease are eligible provided there is bowel perforation; or (g) Intraabdominal
             abscess (including liver and spleen).

          -  Subject requires surgical intervention (e.g. laparotomy, laparoscopic surgery, or
             percutaneous draining of an abscess) within 24 hours of (before or after) the first
             dose of study drug

          -  If subject is to be enrolled preoperatively, the subject must have radiographic
             evidence of bowel perforation or intraabdominal abscess

          -  Subjects who failed prior antibacterial treatment for the current cIAI can be enrolled
             but must: (a) have a positive culture (from an intraabdominal site) and (b) require
             surgical intervention. Such subjects can be enrolled before the results of the culture
             are known; however, if the culture is negative, study drug administration must be
             discontinued.

          -  Willing and able to comply with all study procedures and restrictions

          -  Willing and able to provide written informed consent

        Exclusion Criteria:

          -  Women who are pregnant, nursing, or - if of child bearing potential - not using a
             medically accepted, effective method of birth control (e.g. condom, oral
             contraceptive, indwelling intrauterine device, or sexual abstinence)

          -  Diagnosis of 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 (these are considered
             situations of peritoneal soiling before infection has become established); another
             intraabdominal process in which the primary etiology is not likely to be infectious.

          -  Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis,
             acute suppurative cholangitis, infected, necrotizing pancreatitis, or pancreatic
             abscess

          -  cIAI managed by staged abdominal repair (STAR), open abdomen technique or any
             situation where infection source control is not likely to be achieved

          -  Known prior to randomization to have an IAI or postoperative infection caused by
             pathogen(s) resistant to meropenem

          -  Considered unlikely to survive the 4- to 5-week study period

          -  Any rapidly-progressing disease or immediately life-threatening illness (including
             acute hepatic failure, respiratory failure and septic shock)

          -  The need for concomitant systemic antibacterial agents (other than vancomycin or
             linezolid) in addition to study drug(s)

          -  Moderate or severe impairment of renal function (estimated CrCl < 50 mL/min), or
             requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20
             mL/h urine output over 24 hours)

          -  The presence of hepatic disease defined as: (a) ALT or AST > 4 x ULN; (b)Total
             bilirubin >2 x ULN, unrelated to cholecystitis (c) Alkaline phosphatase >4 x ULN.
             Subjects with a value >4 x ULN and <5 x ULN are eligible if this value is historically
             stable.

          -  Subjects with acute hepatic failure or acute decompensation of chronic hepatic failure

          -  Hematocrit < 25% or hemoglobin < 8 gm/dL

          -  Neutropenia with absolute neutrophil count < 1000/mm3

          -  Platelet count < 75,000 /mm3. Subjects with a platelet count as low as 50,000 /mm3 are
             permitted if the reduction is historically stable.

          -  Immunocompromising illness, including known human immunodeficiency virus (HIV)
             positivity or AIDS, organ (including bone marrow) transplant recipients, and
             hematological malignancy. Immunosuppressive therapy, including use of high-dose
             corticosteroid therapy (e.g. >40 mg prednisone or equivalent per day for greater than
             2 weeks).

          -  History of hypersensitivity reactions to cephalosporins, carbapenems, penicillins,
             ß-lactamase inhibitors, metronidazole, or nitroimidazole derivatives. Subjects with a
             history of mild skin rash, not documented to be caused by previous ß-lactam use, may
             be enrolled.

          -  Any condition or circumstance that, in the opinion of the Investigator, would
             compromise the safety of the subject or the quality of study data

          -  Clinically significant abnormality in baseline electrocardiogram (ECG)

          -  Participation in any investigational drug or device study within 30 days prior to
             study entry

          -  Use of systemic antibiotic therapy for IAI for 24 or more hours in the 48-hour period
             prior to the first dose of study drug, unless there is a documented treatment failure
             with such therapy

          -  More than one dose of an active non-study antibacterial regimen was given
             postoperatively. For subjects enrolled preoperatively, no postoperative non-study
             antibacterial therapy is allowed

          -  who previously participated in a study with CXA-101

          -  Subjects who previously received imipenem, meropenem, doripenem or cefepime for the
             current intraabdominal infection

          -  Subjects who have received disulfiram in the past 14 days or who are currently
             receiving probenecid.