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Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01499290
Recruitment Status : Completed
First Posted : December 26, 2011
Results First Posted : March 1, 2016
Last Update Posted : September 6, 2017
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE December 19, 2011
First Posted Date  ICMJE December 26, 2011
Results First Submitted Date  ICMJE November 6, 2015
Results First Posted Date  ICMJE March 1, 2016
Last Update Posted Date September 6, 2017
Study Start Date  ICMJE March 2012
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2016)
  • Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention is necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, death where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure. Results from two identical protocols D4280C00001 and D4280C00005 combined into a single database with agreement from FDA and EMA.
  • Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.
  • Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2011)
Clinical Cure as Measured by proportion of patients meeting cure criteria in the microbiological modified Intent-To-Treat analysis set. [ Time Frame: 28 to 35 days after start of study drug ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2016)
  • Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
  • Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
  • Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT) [ Time Frame: EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU: 42 to 49 days after start of study drug ]
    Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.
  • Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set [ Time Frame: EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU 42 to 49 days after start of study drug ]
    Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to a surgical review panel (SRP) assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
  • Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set. [ Time Frame: TOC: 28 to 35 days after start of study drug. ]
    The number of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
  • Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set [ Time Frame: Test of Cure: 28 to 35 days after start of study drug ]
    Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
  • Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
    The number of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
  • Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set [ Time Frame: Test of Cure: 28 to 35 days after start of study drug ]
    Microbiological responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
  • Number of Patients Afebrile at Last Observation in the Clinically Evaluable Analysis Set for Patients Who Have Fever at Study Entry [ Time Frame: Test of Cure: 1 to 14 days after start of study drug ]
    Time to first defervescence was calculated for patients with a fever (>38ºC) at baseline. Defervescence (≤37.8ºC) was defined as the absence of fever based on the highest temperature recorded on each study day.
  • Plasma Concentrations for Ceftazidime and Avibactam [ Time Frame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug ]
    Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2011)
  • The proportion of patients with clinical cure in the microbiologically evaluable analysis set. [ Time Frame: 28 to 35 days after start of study drug ]
  • The proportion of patients with clinical cure in the microbiological modified intent-to-treat and microbiologically evaluable analysis sets. [ Time Frame: within 24 hours after last dose of study drug and 42 to 49 days after start of study drug ]
  • The proportion of patients with clinical cure in the clinically evaluable analysis set. [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
  • The proportion of patients with a favorable per-patient microbiological response in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
  • The proportion of favorable per-pathogen microbiological response in the microbiological modified intent to treat and microbiologically evaluable analysis sets. [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
  • The favorable per-pathogen microbiologic response by minimum inhibitory concentration (MIC) categories in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
  • The favorable per-patient clinical response and favorable per-patient microbiological response for patients infected with ceftazidime-resistant pathogens in the microbiological modified intent to treat and microbiologically evaluable analysis sets. [ Time Frame: 28 to 35 days after start of study drug ]
  • The proportion of patients with a favorable per-pathogen microbiological response for patients infected with ceftazidime-resistant pathogens in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: 28 to 35 days after start of study drug ]
  • The time to first defervescence in the clinically evaluable and microbiologically evaluable analysis sets for patients who have fever at study entry. [ Time Frame: 1 to 14 days after start of study drug ]
  • The safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams. [ Time Frame: study duration (from screening visit (Day -1) through last follow up visit (up to 50 days) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections
Official Title  ICMJE A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections In Hospitalized Adults
Brief Summary The purpose of this study is to evaluate the effects of Ceftazidime Avibactam plus Metronidazole compared to Meropenem for treating hospitalized patients with complicated intra-abdominal infections.
Detailed Description A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections In Hospitalized Adults
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Complicated Intra-Abdominal Infection
Intervention  ICMJE
  • Drug: CAZ-AVI
    Ceftazidime 2000 mg and 500 mg of avibactam
  • Drug: Metronidazole
    500 mg of Metronidazole
  • Drug: Meropenem
    1 gram of Meropenem
Study Arms  ICMJE
  • Experimental: CAZ-AVI + Metronidazole
    IV treatment
    Interventions:
    • Drug: CAZ-AVI
    • Drug: Metronidazole
  • Active Comparator: Meropenem
    IV treatment
    Intervention: Drug: Meropenem
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 3, 2014)
493
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2011)
1106
Actual Study Completion Date  ICMJE April 2014
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 to 90 years of age inclusive
  • Female patient is authorized to participate if at least one of the following criteria are met:

    1. Surgical sterilization
    2. Age ≥50 years and postmenopausal as defined by amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments
    3. Age <50 years and postmenopausal as defined by documented LH and FSH levels in the postmenopausal range PLUS amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments
    4. Patient has a negative serum pregnancy test (serum ß-human chorionic gonadotropin [ß-hCG]) within 1 day prior to study entry, and agrees to use highly effective contraception methods during treatment and for at least 7 days after last dose of IV study therapy
  • Intraoperative/postoperative enrollment with confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis
  • Confirmation of infection by surgical intervention within 24 hours of entry: evidence of systemic inflammatory response; physical findings consistent with intra-abdominal infection; supportive radiologic imaging findings of intra-abdominal infections

Exclusion Criteria:

  • Patient is diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-abdominal processes in which primary etiology is not likely to be infectious
  • Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation
  • Patient has suspected intra-abdominal infections due to fungus, parasites, virus or tuberculosis
  • Patient is considered unlikely to survive the 6 to 8 week study period or has a rapidly progressive or terminal illness, including septic shock that is associated with a high risk of mortality
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Bulgaria,   Croatia,   Czechia,   Hungary,   India,   Israel,   Latvia,   Malaysia,   Mexico,   Netherlands,   Peru,   Romania,   Russian Federation,   South Africa,   Spain,   Taiwan,   Thailand,   Ukraine,   United States
Removed Location Countries Australia,   Belgium,   Brazil,   Canada,   Chile,   Czech Republic,   France,   Germany,   Greece,   Italy,   Lithuania,   Poland,   Portugal,   Serbia,   Slovakia,   Turkey,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT01499290
Other Study ID Numbers  ICMJE D4280C00001
2011-003893-97
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Forest Laboratories
Investigators  ICMJE
Study Director: Paul Newell, MBBS, MRCP AstraZeneca
PRS Account Pfizer
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP