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Trial record 1 of 3 for:    aztreonam-avibactam
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A Study to Determine the Efficacy, Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem (MER) ± Colistin (COL) for the Treatment of Serious Infections Due to Gram Negative Bacteria. (REVISIT)

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ClinicalTrials.gov Identifier: NCT03329092
Recruitment Status : Recruiting
First Posted : November 1, 2017
Last Update Posted : June 4, 2018
Sponsor:
Collaborators:
Innovative Medicines Initiative (IMI) COMBACTE-CARE (EU)
Biomedical Advanced Research and Development Authority (BARDA) (RoW)
Information provided by (Responsible Party):
Pfizer

Brief Summary:
A Phase 3 comparative study to determine the efficacy, safety and tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) versus Meropenem (MER) ± Colistin (COL) for the treatment of serious infections due to Gram negative bacteria.

Condition or disease Intervention/treatment Phase
Complicated Intra-abdominal Infection Hosptial Acquired Pneumonia Ventilator Associated Pneumonia Drug: ATM-AVI Drug: MTZ Drug: MER Drug: COL Phase 3

Detailed Description:
A Phase 3 Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem±Colistin (MER±COL) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo Β Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study
Masking: Single (Outcomes Assessor)
Masking Description:

An independent adjudication committee (central blinded assessor) will be convened at regular intervals during the study. The adjudication committee will be blinded to study treatment and will review the clinical response assessments at each visit. In case of a discrepancy with the Investigator's assignment of clinical response, the adjudication committee's assessment will prevail.

In addition, for cIAI subjects classified as a clinical failure, and all cIAI subjects classified as a cure who undergo another procedure (eg, another surgical procedure) subsequent to randomization, the expert panel will review the adequacy of the surgical source control.

Primary Purpose: Treatment
Official Title: A Phase 3 Prospective, Randomized, Multicenter, Open-label, Central Assessor-blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-avibactam (Atm-avi) ±Metronidazole (Mtz) Versus Meropenem±Colistin (Mer±Col) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo-β-lactamase (Mbl) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options
Actual Study Start Date : April 5, 2018
Estimated Primary Completion Date : June 13, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Aztreonam-Avibactam ± Metronidazole
All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
Drug: ATM-AVI

(Creatinine clearance > 50 mL/min) 6500 mg ATM/2167 mg (loading dose, extended loading dose and maintenance dose) by iv infusion on Day 1 followed by a total daily dose of 6000 mg ATM/2000 mg AVI

(Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1417 mg AVI on Day 1 (loading dose, extended loading dose, maintenance dose) followed by total daily dose 3000 mg ATM/1000 mg AVI

(Creatinine clearance 16 - 30 mL/min) 2700 mg ATM/900 mg AVI on Day 1 (loading dose, extended loading dose maintenance dose), followed by total daily dose 2025 mg ATM/675 mg AVI


Drug: MTZ
For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h

Active Comparator: Meropenem ± Colistin
All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice
Drug: MER

Where pathogen initially not suspected of being MER-resistant:

(Creatinine clearance > 50 mL/min) 1000 mg meropenem by 30 min iv infusion q8h

(Creatinine clearance 26 - 50 mL/min) 1000mg meropenem by 30 min iv infusion q12h

(Creatinine clearance 16 - 25 mL/min) 500 mg meropenem by 30 min iv infusion q12h

Where pathogen initially suspected of being MER-resistant (Creatinine clearance > 50 mL/min) 2000 mg meropenem by 180 min iv infusion q8h

(Creatinine clearance 26 - 50 mL/min) 2000 mg meropenem by 180 min iv infusion q12h

(Creatinine clearance 16 - 25 mL/min) 1000 mg meropenem by 180 min iv infusion q12h


Drug: COL

Loading dose 9 million IU by 30 -60 min iv infusion (6 million IU where weight < 60 kg) followed by one of the following maintenance doses:

(Creatinine clearance > 50 mL/min) after a 12h interval, commence maintenance dosing 9 million IU daily in 2 or 3 divided doses by 30 -60 min iv infusions.

(Creatinine clearance 31 - 50 mL/min) After a 24 hr interval, commence maintenance dosing of 6 million IU daily in 2 divided doses by 30 -60 min iv infusion

(Creatinine clearance 21 - 30 mL/min) After a 24 hr interval, commence maintenance dosing 5 million IU daily in 2 divided doses by 30 -60 min iv infusion

(Creatinine clearance 16 - 20 mL/min) after a 24 hr interval, commence maintenance dosing 4 million IU daily in 2 divided doses by 30 -60 min iv infusion





Primary Outcome Measures :
  1. Proportion of subjects with clinical cure in the ITT and CE analysis sets [ Time Frame: Test of Cure (TOC) visit, Day 28 +/- 3 days ]
    Proportion of subjects meeting the criteria for clinical cure


Secondary Outcome Measures :
  1. Proportion of subjects with clinical cure in the m-ITT and ME analysis sets [ Time Frame: Test of Cure (TOC) visit, Day 28 (+/- 3 days) ]
    Proportion of subjects meeting the criteria for clinical cure

  2. Proportion of subjects with clinical cure by infection type in the ITT and CE analysis sets. [ Time Frame: Test of Cure (TOC) visit, Day 28 (+/- 3 days) ]
    Proportion of subjects meeting the criteria for clinical cure

  3. Proportion of subjects with clinical cure for subjects with MBL positive pathogens in the micro ITT and ME analysis sets. [ Time Frame: Test of Cure (TOC) visit, Day 28 (+/- 3 days) ]
    Proportion of subjects meeting the criteria for clinical cure

  4. Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets. [ Time Frame: Test of Cure (TOC) visit, Day 28 (+/- 3 days) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication + presumed eradication)

  5. Proportion of subjects who died [ Time Frame: Day 28 ]
    Daily mortality assessment

  6. PK of ATM [ Time Frame: Days 1 and 4 ]
    Plasma concentration of ATM

  7. PK/PD relationship between exposure and clinical response for ATM AVI±MTZ in the popPK analysis set [ Time Frame: Test of Cure (TOC) visit, Day 28 (+/- 3 days) ]
    Correlation between plasma concentration of ATM and clinical cure

  8. PK of AVI [ Time Frame: Days 1 and 4 ]
    Plasma concentration of AVI

  9. PK/PD relationship between exposure and clinical response for ATM/AVI +/- MTZ in the popPK analysis set [ Time Frame: Test of Cure (TOC) days 28 (+/- 3 days) ]
    Correlation between concentration of AVI and clinical cure

  10. PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set [ Time Frame: Test of Cure (TOC) visit, Days 28 (+/- 3 days) ]
    Correlation between plasma concentration of ATM and microbiological response

  11. PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set [ Time Frame: Test of Cure (TOC) visit, day 28 (+/- 3 days) ]
    Correlation between plasma concentration of AVI and microbiological response

  12. Description of safety in terms of adverse events [ Time Frame: Throughout study to Late Follow Up visit (Day 45 +/- 3 days) ]
    Descriptive summary of adverse events


Other Outcome Measures:
  1. Proportion of subjects with clinical cure in the ITT, micro ITT, CE and ME analysis sets [ Time Frame: End of Treatment (EOT) visit (variable, between Days 1 and 15) ]
    Proportion of subjects meeting the criteria for clinical cure

  2. Proportion of subjects with clinical cure by infection type in the ITT and CE analysis sets [ Time Frame: End of Treatment (EOT) visit (variable, between Days 1 and 15) ]
    Proportion of subjects meeting the criteria for clinical cure

  3. Proportion of subjects with a favorable per subject microbiological response in the the micro ITT and ME analysis sets [ Time Frame: End of Treatment (EOT) visit (variable, between Days 1 and 15) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  4. Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets [ Time Frame: End of Treatment (EOT), (variable between Days 1 and 15) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  5. Proportion of subjects with a favorable per subject microbiological response by pathogen resistance type (eg, ATM resistant, ESBL positive, carbapenamase positive, MBL positive) in the micro ITT and ME analysis sets [ Time Frame: End of Treatment (EOT), (variable, between Days 1 and 15) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  6. Proportion of subjects with a favorable per pathogen microbiological response by pathogen resistance type in the micro ITT and ME analysis sets [ Time Frame: End of Treatment (EOT) visits, (variable between Days 1 and 15) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  7. Proportion of subjects with clinical cure using objective clinical measures [ Time Frame: Test of Cure (TOC) visit, Day 28 +/- 3 days) ]
    Proportion of subjects with clinical cure

  8. Proportion of subjects who died [ Time Frame: Day 14 ]
    Daily mortality assessment

  9. Health resource utilization in terms of length of hospital stay [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Length of hospital stay (days), including any readmissions

  10. Relationship between (as yet undetermined) biomarkers and liver transaminase elevations in response to exposure to ATM-AVI [ Time Frame: Day 1 and 4 ]
    Correlation between (yet to be determined) plasma biomarkers and elevated liver transaminases

  11. Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets [ Time Frame: Test of Cure (TOC) visit (Day 28 +/- 3 days) ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  12. Proportion of subjects with a favorable per subject microbiological response by pathogen resistance type (eg, ATM resistant, ESBL positive, carbapenamase positive, MBL positive) in the micro ITT and ME analysis sets [ Time Frame: Test of Cure (TOC) visits, Day 28 +/- 3 days ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  13. Proportion of subjects with a favorable per pathogen microbiological response by pathogen resistance type in the micro ITT and ME analysis sets [ Time Frame: Test of Cure (TOC) visits, Day 28 +/- 3 days ]
    Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)

  14. Health resource utilization in terms of treatment duration [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Length of study treatment (days)

  15. Health resource utilization in terms of length of ICU stay [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Length of intensive care unit (ICU) stay (days)

  16. Health resource utilization in terms of transfer to ICU [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Transfer to the ICU (Yes/No)

  17. Health resource utilization in terms of use of mechanical ventilation [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Mechanical ventilation (Yes/No) for HAP/VAP subjects

  18. Health resource utilization in terms of duration of mechanical ventilation [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Length of mechanical ventilation (days) for HAP/VAP subjects

  19. Health resource utilization in terms of subsequent unplanned surgical intervention [ Time Frame: Test of Cure (TOC), Day 28 +/- 3 days ]
    Subsequent unplanned surgical intervention (YES/NO) for cIAI subjects



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All subjects:

  1. Male or female from 18 years of age
  2. Provision of informed consent
  3. Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
  4. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test

Additional for cIAI:

  1. Diagnosis of cIAI, EITHER:

    Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

  2. Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Additional for HAP/VAP:

  1. Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility
  2. New or worsening infiltrate on CXR or CT scan
  3. Clinical signs and symptoms and laboratory findings consistent with HAP/VAP
  4. Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation

Exclusion criteria:

All subjects:

  1. APACHE II score > 30
  2. Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
  3. Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
  4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs
  5. Known Clostridium difficle associated diarrhoea
  6. Requirement for effective concomitant systemic antibacterials or antifungals
  7. Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
  8. Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
  9. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process
  10. Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
  11. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and directly related to the infectious process being treated
  12. Absolute neutrophil count <500/mm3
  13. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
  14. Any other condition that may confound the results of the study or pose additional risks to the subject
  15. Unlikely to comply with protocol
  16. History of epilepsy or seizure disorders excluding febrile seizures of childhood

Additional for cIAI

  1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery < 24 hours of diagnosis primary etiology is not likely to be infectious
  2. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
  3. Prior liver, pancreas or small-bowel transplant
  4. Staged abdominal repair (STAR), open abdomen technique or marsupialisation

Additional for HAP/VAP

  1. APACHE II score < 10
  2. Known or high likelihood of Gram-positive monomicrobial infection
  3. Lung abscess, pleural empyema, post-obstructive pneumonia
  4. Lung or heart transplant
  5. Myasthenia gravis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03329092


Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
United States, California
LA BioMed at Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90502
LA BioMed, Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90502
Harbor UCLA Medical Center Recruiting
Torrance, California, United States, 90509
Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90509
United States, Missouri
Barnes Jewish Hospital Pharmacy Not yet recruiting
Saint Louis, Missouri, United States, 63110
Barnes-Jewish Hospital Laboratories Not yet recruiting
Saint Louis, Missouri, United States, 63110
Barnes-Jewish Hospital Not yet recruiting
Saint Louis, Missouri, United States, 63110
Washington University in St. Louis, School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
United States, Oklahoma
OU Medical Center Hospital Not yet recruiting
Oklahoma City, Oklahoma, United States, 73104
OU Physicians Building (Clinic) Not yet recruiting
Oklahoma City, Oklahoma, United States, 73104
Presbyterian Professional Building (Clinic) Not yet recruiting
Oklahoma City, Oklahoma, United States, 73104
University of Oklahoma Health Sciences Center Not yet recruiting
Oklahoma City, Oklahoma, United States, 73104
Turkey
Hacettepe Universitesi Tip Fakultesi Not yet recruiting
Ankara, Turkey, 06100
Ankara Numune Training and Research Hospital Not yet recruiting
Ankara, Turkey, 06230
Sponsors and Collaborators
Pfizer
Innovative Medicines Initiative (IMI) COMBACTE-CARE (EU)
Biomedical Advanced Research and Development Authority (BARDA) (RoW)
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03329092     History of Changes
Other Study ID Numbers: C3601002
D4910C00004 ( Other Identifier: Alias Study Number )
2017-002742-68 ( EudraCT Number )
First Posted: November 1, 2017    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Information relating to our policy on data sharing and the process for requesting data can be found at the following link: http://www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests
URL: http://

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:
Complicated intra-abdominal infection
Hosptial acquired pneumonia
Ventilator associated pneumonia
Gram negative infections
Metallo-beta lactamase
Multi drug resistant pathogens

Additional relevant MeSH terms:
Infection
Communicable Diseases
Pneumonia
Pneumonia, Ventilator-Associated
Intraabdominal Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cross Infection
Ventilator-Induced Lung Injury
Lung Injury
Meropenem
Avibactam
Metronidazole
Thienamycins
Colistin
Aztreonam
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Bacterial Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action