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

ID: NCT01147640
Status: Completed
Phase: Phase 2
Start Date: June 01, 2010
First Submitted: June 17, 2010
Last Updated: January 06, 2016
Results: Available
Success Rate: 95%
Sponsors & Collaborators: Cubist Pharmaceuticals LLC
Location: Argentina, Georgia, Russian Federation, Serbia, United States
Conditions: Complicated Intra-abdominal Infection
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

Study Description

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.

Detailed Description

Condition or disease Intervention/treatment Phase

Complicated Intra-abdominal Infection

Drug: CXA-101/ tazobactam and metronidazole
Other Names
Drug: meropenem plus saline placebo
Other Names
Phase 2

Tracking Information

First Submitted DateJune 17, 2010
Last Update Posted DateJanuary 06, 2016
Start DateJune 01, 2010
Actual Completion DateMarch 01, 2011
Primary Completion DateFebruary 01, 2011
Results First Submitted DateJanuary 09, 2015
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population [Time Frame: Test-of-Cure Visit (7-14 days after End of Therapy [EOT])]

    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.

Original Primary Outcome Measures

  • 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.

Current Secondary Outcome Measures

  • Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population [Time Frame: Test-of-Cure Visit (7-14 days after EOT)]

    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)

Original Secondary Outcome Measures

  • 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)

Study Design

Brief TitleSafety and Efficacy Study to Compare IV CXA 101/Tazobactam and Metronidazole With Meropenem in Complicated Intraabdominal Infections
Official TitleA 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
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.

Detailed Description

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
122
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
Quadruple
Primary Purpose
Treatment
Conditions
Complicated Intra-abdominal Infection
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: CXA-101/ tazobactam and metronidazole

CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion

Other Names
Drug: meropenem plus saline placebo

meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Other Names
Study Groups/Cohorts
CXA 101/tazobactam and metronidazole

meropenem with matching saline placebo

Study Arms
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

Arm Intervention/Treatment
Experimental CXA 101/tazobactam and metronidazole
Drug : CXA-101/ tazobactam and metronidazole
Active Comparator meropenem with matching saline placebo
Drug : meropenem plus saline placebo

Recruitment Information

Recruitment Status:Completed
Enrollment122
Completion DateMarch 01, 2011
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.
GenderAll
Age18 Years to 90 Years
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
Argentina
Georgia
Russian Federation
Serbia
United States

Administrative Information

NCT Number:NCT01147640
Other Study ID Numbers
7625A-012
CXA-IAI-10-01
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Cubist Pharmaceuticals LLC
Collaborators
Not Available
Investigators
Study Director
Ian Friedland, MD
Cubist Pharmaceuticals LLC

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Not Available

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Not Available

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Participant Flow: Overall

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline Placebo
Started8339
Completed7838
Not Completed51
Adverse Event20
Didn't meet eligibility criteria10
Lost to Follow-up01
Physician Decision10
Withdrawal by Subject10

Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Microbiological Intent-to-Treat

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion
Total
Total of all reporting groups

Baseline Measures

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline PlaceboTotal
Overall Participants Analyzed
Units: Participants
Participants Analyzed
8239121
8239121
Age
Units: years - Mean (Standard Deviation)
Participants Analyzed
8239121
48.5 (18.79)46.4 (18.48)47.8 (18.64)
Gender
Units: participants - Number
Participants Analyzed
8239121
Female371552
Male452469

Outcome Measures

1. Primary: Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population

Measure Type
Primary
Measure Title
Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population
Measure Description
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.
Time Frame
Test-of-Cure Visit (7-14 days after End of Therapy [EOT])

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mMITT: Treated subjects, with baseline pathogen

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Outcome Measures

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline Placebo
Participants Analyzed
Units: Participants
6125
Clinical Response of CXA 101/Tazobactam and Metronidazole at Test of Cure (TOC) Visit in the Microbiological Modified Intent to Treat (mMITT) Analysis Population
Units: percentage of subjects - Number (95% Confidence Interval)
83.696.0

Statistical Analysis

Groups
All Groups
Statistical Test Type
Superiority or Other
Statistical Method
Not Available
P Value
Not Available
Risk Difference (RD)
-12.40000
to
  1. Additional details about the analysis, such as null hypothesis and power calculation
    Not Available
  2. Details of power calculation, definition of non-inferiority margin, and other key parameters
    Not Available
  3. Other relevant method information, such as adjustments or degrees of freedom
    Not Available
  4. Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance
    Not Available
  5. Other relevant estimation information
    Not Available

2. Secondary: Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population

Measure Type
Secondary
Measure Title
Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population
Measure Description
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)
Time Frame
Test-of-Cure Visit (7-14 days after EOT)

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Microbiologically Evaluable: treated subjects, with baseline pathogen susceptible to study drug, complied with protocol

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Outcome Measures

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline Placebo
Participants Analyzed
Units: Participants
5324
Microbiological Response of CXA 101/Tazobactam and Metronidazole at the TOC Visit in the Microbiologically Evaluable (ME) Population
Units: percentage of subjects - Number (95% Confidence Interval)
90.695.8

Statistical Analysis

Groups
All Groups
Statistical Test Type
Superiority or Other
Statistical Method
Not Available
P Value
Not Available
Risk Difference (RD)
-5.20000
95% Confidence Interval
to
  1. Additional details about the analysis, such as null hypothesis and power calculation
    Not Available
  2. Details of power calculation, definition of non-inferiority margin, and other key parameters
    Not Available
  3. Other relevant method information, such as adjustments or degrees of freedom
    Not Available
  4. Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance
    Not Available
  5. Other relevant estimation information
    Not Available

Serious Adverse Events

Time Frame
Not Available
Additional Description
Not Available
Frequency Threshold0% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Serious Adverse Events

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline Placebo
Total, serious adverse events
No. of participants affected / at risk14/82 (0.00%)2/39 (0.00%)
Atrial fibrillation
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Atrial flutter
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Cardio-respiratory arrest
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Colitis ischaemic
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Duodenal ulcer haemorrhage
No. of participants affected / at risk0/82 (0.00%)1/39 (0.00%)
Gastritis erosive
No. of participants affected / at risk0/82 (0.00%)1/39 (0.00%)
Intestinal obstruction
No. of participants affected / at risk0/82 (0.00%)1/39 (0.00%)
Intestinal perforation
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Pancreatitis acute
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Cholelithiasis
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Peridiverticular abscess
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Pneumonia
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Postoperative wound infection
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Urosepsis
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Seroma
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Wound dehiscence
No. of participants affected / at risk0/82 (0.00%)1/39 (0.00%)
Hyponatraemia
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Renal failure
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Female genital tract fistula
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Pulmonary embolism
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Haematoma
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)
Shock
No. of participants affected / at risk1/82 (0.00%)0/39 (0.00%)

Other Adverse Events

Time Frame
Not Available
Additional Description
Not Available
Frequency Threshold3% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
CXA 101/Tazobactam and Metronidazole
CXA-101/ tazobactam and metronidazole: CXA-101/tazobactam (1000/500 mg q8h) plus metronidazole (500 mg q8h) administered via IV infusion
Meropenem With Matching Saline Placebo
meropenem plus saline placebo: meropenem IV infusion (1000 mg q8h) plus a matching saline placebo (q8h) administered via IV infusion

Other Adverse Events

CXA 101/Tazobactam and MetronidazoleMeropenem With Matching Saline Placebo
Total, other adverse events
No. of participants affected / at risk30/82 (0.00%)12/39 (0.00%)
Anaemia
No. of participants affected / at risk5/82 (0.00%)1/39 (0.00%)
Nausea
No. of participants affected / at risk5/82 (0.00%)4/39 (0.00%)
Vomiting
No. of participants affected / at risk4/82 (0.00%)3/39 (0.00%)
Diarrhoea
No. of participants affected / at risk4/82 (0.00%)3/39 (0.00%)
Ileus
No. of participants affected / at risk3/82 (0.00%)0/39 (0.00%)
Pyrexia
No. of participants affected / at risk12/82 (0.00%)4/39 (0.00%)
Anaemia postoperative
No. of participants affected / at risk3/82 (0.00%)1/39 (0.00%)
Gamma-glutamyltransferase increased
No. of participants affected / at risk1/82 (0.00%)2/39 (0.00%)
Alanine aminotransferase increased
No. of participants affected / at risk0/82 (0.00%)3/39 (0.00%)
Aspartate aminotransferase increased
No. of participants affected / at risk0/82 (0.00%)2/39 (0.00%)
Hypokalaemia
No. of participants affected / at risk3/82 (0.00%)1/39 (0.00%)
Hypomagnesaemia
No. of participants affected / at risk2/82 (0.00%)2/39 (0.00%)
Atelectasis
No. of participants affected / at risk3/82 (0.00%)0/39 (0.00%)
Hypertension
No. of participants affected / at risk4/82 (0.00%)2/39 (0.00%)
Phlebitis
No. of participants affected / at risk2/82 (0.00%)2/39 (0.00%)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.
The data generated in this clinical study are the exclusive property of the Sponsor and are confidential. Authorship on any primary publication of the results from this study will be based on contributions to study design, enrollment, data analysis, and interpretation of results. All investigators who enroll at least one subject will be acknowledged in any journal publication.

Results Point of Contact

Name/TitleOrganizationPhoneEmail
Dr. Obi Umeh, Vice President Global Medical Sciences
Cubist Pharmaceuticals, Inc.
781-860-8415