Clinical trial NCT01147640: Safety and Efficacy Study to Compare IV CXA 101/Tazobactam and Metronidazole With Meropenem in Complicated Intraabdominal Infections
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Complicated Intra-abdominal Infection
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2010-06-22
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population
timeFrame: Test-of-Cure Visit (7-14 days after End of Therapy [EOT])
Secondary outcomes:
measure: Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population
timeFrame: Test-of-Cure Visit (7-14 days after EOT)
Other outcomes:
Locations:
city: Orange
country: United States
facility: Pulmonary Consultants and Primary Care Physicians Medical Group, Inc.
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institue at Harbor UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Newark
country: United States
facility: Christiana Care Health System
state: Delaware
city: Pensacola
country: United States
facility: Pensacola Research Consultants, Inc.
state: Florida
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Somers Point
country: United States
facility: South Jersey Infectious Disease
state: New Jersey
city: Cleveland
country: United States
facility: Metro Health Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Paraná
country: Argentina
facility: Hospital San Martín
state: Entre Ríos
city: C.a.b.a.
country: Argentina
facility: Sanatorio Guemes
city: Cordoba
country: Argentina
facility: Hospital Nuestra Señora de la Misericordia
city: Cordoba
country: Argentina
facility: Hospital San Roque
city: Mendoza
country: Argentina
facility: Hospital Central de Mendoza
city: Santa Fe
country: Argentina
facility: Hospital Dr. José María Cullen
city: Tbilisi
country: Georgia
facility: Ltd Ivane Javakhishvili Tbilisi State University Center
city: Tbilisi
country: Georgia
facility: JSC K.Eristavi National Center of Experimental and Clinical Surgery
city: Tbilisi
country: Georgia
facility: Ltd Vakhtang Bochorishvili Antiseptic Center
city: Tbilisi
country: Georgia
facility: Tbilisi State Hospital #4
city: Moscow
country: Russian Federation
facility: Federal State Institution
city: Moscow
country: Russian Federation
facility: State Moscow Healthcare
city: Moscow
country: Russian Federation
facility: State Healthcare Institution
city: Novosibirsk
country: Russian Federation
facility: Municipal Healthcare Institution "City Clinical Hospital #2"
city: Novosibirsk
country: Russian Federation
facility: Regional State Healthcare
city: Saint-Petersburg
country: Russian Federation
facility: State Healthcare Institution
city: Saint-Petersburg
country: Russian Federation
facility: State Educational Institution of Higher Professional Education
city: Saint-Petersburg
country: Russian Federation
facility: Saint Petersburg State Healthcare Institution "City Hospital # 26"
city: Belgrade
country: Serbia
facility: Clinical Hospital Centre Zvezdara
city: Belgrade
country: Serbia
facility: Emergency Centre, Clinical Centre of Serbia
city: Nis
country: Serbia
facility: Clincal Centre Nis
city: Novi Sad
country: Serbia
facility: Clinical Centre of Vojvodina
Study officials:
affiliation: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
name: Ian Friedland, MD
role: STUDY_DIRECTOR
References:
citation: Lucasti C, Hershberger E, Miller B, Yankelev S, Steenbergen J, Friedland I, Solomkin J. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014 Sep;58(9):5350-7. doi: 10.1128/AAC.00049-14. Epub 2014 Jun 30.