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

This study has been completed.
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01499290
First received: December 19, 2011
Last updated: July 1, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
Complicated Intra-Abdominal Infection
Drug: CAZ-AVI
Drug: Metronidazole
Drug: Meropenem
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations


Enrollment: 493
Study Start Date: March 2012
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CAZ-AVI + Metronidazole
IV treatment
Drug: CAZ-AVI
Ceftazidime 2000 mg and 500 mg of avibactam
Drug: Metronidazole
500 mg of Metronidazole
Active Comparator: Meropenem
IV treatment
Drug: Meropenem
1 gram of Meropenem

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
  Eligibility

Ages Eligible for Study:   18 Years to 90 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01499290

  Show 57 Study Locations
Sponsors and Collaborators
AstraZeneca
Forest Laboratories
Investigators
Study Director: Paul Newell, MBBS, MRCP AstraZeneca
  More Information

Publications:
Study Data/Documents: Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: D4280C00001 Revised CSP
RECLAIM 1 (D4280C00001) Revised Clinical Study Protocol

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01499290     History of Changes
Obsolete Identifiers: NCT01500239
Other Study ID Numbers: D4280C00001  2011-003893-97 
Study First Received: December 19, 2011
Results First Received: November 6, 2015
Last Updated: July 1, 2016
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: National Health Surveillance Agency
Bulgaria: Bulgarian Drug Agency
Czech Republic: State Institute for Drug Control
Hungary: National Institute of Pharmacy
India: Drugs Controller General of India
Israel: Ministry of Health
Mexico: Federal Commission for Sanitary Risks Protection
Peru: Ministry of Health
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Ministry of Health of the Russian Federation
South Africa: Department of Health
Spain: Spanish Agency of Medicines
Taiwan : Food and Drug Administration
Thailand: Food and Drug Administration
Ukraine: State Pharmacological Center - Ministry of Health
United States: Food and Drug Administration

Keywords provided by AstraZeneca:
Ceftazidime
Meropenem
Metronidazole
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
cIAI, Complicated Intra-Abdominal Infection

Additional relevant MeSH terms:
Infection
Communicable Diseases
Intraabdominal Infections
Avibactam, ceftazidime drug combination
Avibactam
Meropenem
Metronidazole
Ceftazidime
Thienamycins
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on December 07, 2016