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

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

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.

Study Overview

• Status: Completed
• Conditions: Complicated Intra-abdominal Infection
• Intervention / Treatment: Drug: CXA-101/ tazobactam and metronidazole; Drug: meropenem plus saline placebo

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • C.a.b.a., Argentina, C1180AAX
    • Sanatorio Güemes
  • Cordoba, Argentina, X5000JRD
    • Hospital Nuestra Señora de la Misericordia
  • Cordoba, Argentina, X5000
    • Hospital San Roque
  • Mendoza, Argentina, M5500CHQ
    • Hospital Central de Mendoza
  • Santa Fe, Argentina, S3000EOZ
    • Hospital Dr. Jose Maria Cullen
  • Entre Ríos
    • Paraná, Entre Ríos, Argentina, E3100BBJ
      • Hospital San Martin
• Georgia
  • Tbilisi, Georgia, 0102
    • Ltd Ivane Javakhishvili Tbilisi State University Center
  • Tbilisi, Georgia, 0159
    • JSC K.Eristavi National Center of Experimental and Clinical Surgery
  • Tbilisi, Georgia, 0160
    • Ltd Vakhtang Bochorishvili Antiseptic Center
  • Tbilisi, Georgia, 0160
    • Tbilisi State Hospital #4
• Russian Federation
  • Moscow, Russian Federation, 105203
    • Federal State Institution
  • Moscow, Russian Federation, 109240
    • State Moscow Healthcare
  • Moscow, Russian Federation, 111020
    • State Healthcare Institution
  • Novosibirsk, Russian Federation, 630051
    • Municipal Healthcare Institution "City Clinical Hospital #2"
  • Novosibirsk, Russian Federation, 630087
    • Regional State Healthcare
  • Saint-Petersburg, Russian Federation, 194291
    • State Healthcare Institution
  • Saint-Petersburg, Russian Federation, 195067
    • State Educational Institution of Higher Professional Education
  • Saint-Petersburg, Russian Federation, 196247
    • Saint Petersburg State Healthcare Institution "City Hospital # 26"
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Hospital Centre Zvezdara
  • Belgrade, Serbia, 11000
    • Emergency Centre, Clinical Centre of Serbia
  • Nis, Serbia, 18000
    • Clincal Centre Nis
  • Novi Sad, Serbia, 21000
    • Clinical Centre of Vojvodina
• United States
  • California
    • Orange, California, United States, 92868
      • Pulmonary Consultants and Primary Care Physicians Medical Group, Inc.
    • Torrance, California, United States, 90509
      • Los Angeles Biomedical Research Institue at Harbor UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 88045
      • University of Colorado Hospital
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System
  • Florida
    • Pensacola, Florida, United States, 32504
      • Pensacola Research Consultants, Inc.
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New Jersey
    • Somers Point, New Jersey, United States, 08244
      • South Jersey Infectious Disease
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • Metro Health Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CXA 101/tazobactam and metronidazole	Drug: CXA-101/ tazobactam and metronidazole; CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Active Comparator: meropenem with matching saline placebo	Drug: meropenem plus saline placebo; meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population	Clinical response is complete resolution or significant improvement of all signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection.	Test-of-Cure Visit (7-14 days after End of Therapy [EOT])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population	Microbiological response is eradication (absence of the baseline pathogen from a suitable intra-abdominal specimen) or presumed eradication (absence of a suitable intra-abdominal specimen to culture at the TOC visit in a subject who is assessed as a clinical cure at TOC)	Test-of-Cure Visit (7-14 days after EOT)

Collaborators and Investigators

• Sponsor: Cubist Pharmaceuticals LLC
• Investigators: Study Director: Ian Friedland, MD, Cubist Pharmaceuticals LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2010
• Primary Completion (Actual): February 20, 2011
• Study Completion (Actual): March 25, 2011

Study Registration Dates

• First Submitted: June 17, 2010
• First Submitted That Met QC Criteria: June 17, 2010
• First Posted (Estimate): June 22, 2010

Study Record Updates

• Last Update Posted (Actual): October 25, 2018
• Last Update Submitted That Met QC Criteria: September 27, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Intraabdominal Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; beta-Lactamase Inhibitors; Metronidazole; Meropenem; Tazobactam; Ceftolozane
• Other Study ID Numbers: 7625A-012; CXA-IAI-10-01 (Other Identifier: Cubist Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf