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.

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NCT03329092

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FOR MORE INFORMATION
Study Location
Banner University Medical Center - Tucson
Tucson, Arizona, 85719, United States
See other locations
Contact
1-800-718-1021
[email protected]
Related Links

FOR MORE INFORMATION

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Complicated Intra-abdominal Infection, Hosptial Acquired Pneumonia, Ventilator Associated Pneumonia
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


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

NEED INFO?

Questions about a trial? Call or email to reach a Pfizer Clinical Trial Contact Center Representative

Pfizer Clinical Trials Contact Center

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[email protected]

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Complicated Intra-abdominal Infection, Hosptial Acquired Pneumonia, Ventilator Associated PneumoniaA 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. NCT03329092
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ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE 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.
Official Title  ICMJE 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-?-LACTAMASE (MBL) - PRODUCING MULTIDRUG RESISTANT PATHOGENS, FOR WHICH THERE ARE LIMITED OR NO TREATMENT OPTIONS
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.
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 ? Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • Complicated Intra-abdominal Infection
  • Hosptial Acquired Pneumonia
  • Ventilator Associated Pneumonia
Intervention  ICMJE
  • 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
  • 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

Study Arms  ICMJE
  • Experimental: Aztreonam-Avibactam ± Metronidazole
    All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
    Interventions:
    • Drug: ATM-AVI
    • Drug: MTZ
  • 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
    Interventions:
    • Drug: MER
    • Drug: COL
Publications * Not Provided

*   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 Suspended
Estimated Enrollment  ICMJE
 (submitted: July 31, 2018)		375
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2017)		300
Estimated Study Completion Date  ICMJE November 30, 2021
Estimated Primary Completion Date November 14, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ?-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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (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,   Chile,   Croatia,   Czechia,   Hungary,   India,   Israel,   Italy,   Korea, Republic of,   Malaysia,   Mexico,   Peru,   Philippines,   Romania,   Russian Federation,   South Africa,   Spain,   Taiwan,   Thailand,   Turkey,   Ukraine,   United States,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03329092
Other Study ID Numbers  ICMJE C3601002
D4910C00004 ( Other Identifier: Alias Study Number )
2017-002742-68 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:Yes
Plan Description:Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/d….
URL:https://www.pfizer.com/science/clinical_trials/trial_data_and_results/d…
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE
  • Innovative Medicines Initiative (IMI) COMBACTE-CARE (EU)
  • Biomedical Advanced Research and Development Authority
Investigators  ICMJE
Study Director:Pfizer CT.gov Call CenterPfizer
PRS Account Pfizer
Verification Date May 2020

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