Safety and Efficacy Study to Compare IV CXA 101/Tazobactam and Metronidazole With Meropenem in Complicated Intraabdominal Infections

Condition(s) targeted: Complicated Intra-abdominal Infection

Intervention: CXA-101/ tazobactam and metronidazole (Drug); meropenem plus saline placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Cubist Pharmaceuticals

Official(s) and/or principal investigator(s):
Ian Friedland, MD, Study Director, Affiliation: Cubist Pharmaceuticals

Overall contact:
Denise Sharp, Phone: 781-860-8660, Email: denise.sharp@cubist.com

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.

Official title: A Multicenter, Double-Blind, Randomized, Phase 2 Study to Compare the Safety and Efficacy of Intravenous CXA 101/ Tazobactam and Metronidazole With That of Meropenem in Complicated Intraabdominal Infections

Study design: Allocation: Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: clinical response of CXA 101/tazobactam and metronidazole

Secondary outcome:

microbiological response of CXA 101/tazobactam and metronidazole

assess safety of CXA 101/ tazobactam and metronidazole

Evaluate the PK of CXA 101/ tazobactam

Minimum age: 18 Years. Maximum age: 90 Years. Gender(s): Both.

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.

Denise Sharp, Phone: 781-860-8660, Email: denise.sharp@cubist.com

Ltd Vakhtang Bochorishvili Antiseptic Center, Tbilisi 0160, Georgia; Recruiting

JSC K.Eristavi National Center of Experimental and Clinical Surgery, Tbilisi 0159, Georgia; Recruiting

Ltd Ivane Javakhishvili Tbilisi State University Center, Tbilisi 0102, Georgia; Recruiting

Tbilisi State Hospital #4, Tbilisi 0160, Georgia; Recruiting

Federal State Institution, Moscow 105203, Russian Federation; Recruiting

State Healthcare Institution, Moscow 111020, Russian Federation; Recruiting

State Moscow Healthcare, Moscow 109240, Russian Federation; Recruiting

Municipal Healthcare Institution "City Clinical Hospital #2", Novosibirsk 630051, Russian Federation; Recruiting

State Educational Institution of Higher Professional Education, Saint-Petersburg 195067, Russian Federation; Recruiting

State Healthcare Institution, Saint-Petersburg 194291, Russian Federation; Recruiting

Saint Petersburg State Healthcare Institution "City Hospital # 26", Saint-Petersburg 196247, Russian Federation; Recruiting

Clinical Hospital Centre Zvezdara, Belgrade 11000, Serbia; Recruiting

Emergency Centre, Clinical Centre of Serbia, Belgrade 11000, Serbia; Recruiting

Clincal Centre Nis, Nis 18000, Serbia; Recruiting

Clinical Centre of Vojvodina, Novi Sad 21000, Serbia; Recruiting

Pulmonary Consultants and Primary Care Physicians Medical Group, Inc., Orange, California 92868, United States; Recruiting

Los Angeles Biomedical Research Institue at Harbor UCLA Medical Center, Torrance, California 90509, United States; Recruiting

University of Colorado Hospital, Aurora, Colorado 88045, United States; Not yet recruiting

South Jersey Infectious Disease, Somers Point, New Jersey 08244, United States; Recruiting

Metro Health Medical Center, Cleveland, Ohio 44109, United States; Recruiting

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States; Recruiting

University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States; Recruiting

Starting date: June 2010
Last updated: September 20, 2010