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.

Phase 3

Completed

• Conditions: Complicated Intra-abdominal Infection; Hosptial Acquired Pneumonia; Ventilator Associated Pneumonia
• Interventions: Drug: MER; Drug: ATM-AVI; Drug: MTZ; Drug: COL

• Registration Number: NCT03329092
• Lead Sponsor: 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.

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 Timeline

• Study First Submitted: 2017-10-06
• Study First Submitted QC: 2017-10-27
• Study First Posted: 2017-11-01
• Study Start: 2018-04-05
• Primary Completion: 2023-02-23
• Study Completion: 2023-02-23
• Results First Submitted: 2024-02-21
• Results First Submitted QC: 2024-04-16
• Results First Posted: 2024-05-07
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-19
• Last Update Posted: 2024-12-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 422

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aztreonam-Avibactam ± Metronidazole	MTZ	All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
Meropenem ± Colistin	MER	All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice
Meropenem ± Colistin	COL	All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice
Aztreonam-Avibactam ± Metronidazole	ATM-AVI	All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: Intent-To-Treat (ITT) Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% confidence interval (CI) was based on Jeffrey's method.
Percentage of Participants With Clinical Cure at TOC Visit: Clinically Evaluable (CE) Analysis Set	At TOC visit (Day 28)	Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set:all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or \<48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinical Cure at TOC Visit: Microbiological Intent-To-Treat (Micro-ITT) Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Evaluable (ME) Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: ITT Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method.
Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: CE Analysis Set	At TOC visit (Day 28)	Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set:all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or \<48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
Percentage of Participants With Clinical Cure in Participants With Metallo-beta-lactamase (MBL) Positive Pathogen at TOC Visit: Micro-ITT Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee.
Percentage of Participants With Clinical Cure in Participants With MBL Positive Pathogen at TOC Visit: ME Analysis Set	At TOC visit (Day 28)	Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee.
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: Micro- ITT Analysis Set	At TOC visit day (28)	Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: ME Analysis Set	At TOC Visit (Day 28)	Participants were determined to have a favorable microbiological response if all baseline pathogens for that participant had a favorable outcome (eradicated or presumed eradicated). Eradication: Absence of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure.
Percentage of Participants Who Died on or Before 28 Days After Randomization: ITT Analysis Set	From randomization up to 28 days	Percentage of participants who died on or before 28 days after randomization is reported in this outcome measure.
Percentage of Participants Who Died on or Before 28 Days After Randomization: Micro-ITT Analysis Set	From randomization up to 28 days	Percentage of participants who died on or before 28 days after randomization is reported in this outcome measure.
Plasma Concentration of Aztreonam	Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4	Plasma concentration for aztreonam according to renal function (augmented, normal and mild, moderate and severe is presented in this outcome measure. Augmented = Creatinine clearance (CrCL) \> 150 milliliters per minute (mL/min); Normal \& Mild = CrCL \> 50 to \<=150 mL/min; Moderate = CrCL \> 30 to ≤ 50 mL/min; Severe = CrCL \> 15 to ≤ 30 mL/min.
Plasma Concentration of Avibactam	Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4	Plasma concentration for avibactam according to renal function (augmented, normal and mild, moderate and severe is presented in this outcome measure. Augmented = CrCL \> 150 mL/min; Normal \& Mild = CrCL \> 50 to \<=150 mL/min; Moderate = CrCL \> 30 to ≤ 50 mL/min; Severe = CrCL \> 15 to ≤ 30 mL/min.
Maximum Plasma Concentration for a Dosing Interval at Steady-State (Cmax, ss) According to Clinical Response by Infection Type at TOC: Aztreonam	At TOC (Day 28)	Population PK predicted maximum plasma concentration for a dosing interval at steady-state (Cmax,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Clinical Response by Infection Type at TOC: Aztreonam	At TOC (Day 28)	Population PK predicted (%fT\>MIC ATM of 8 mg/L) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss ) According to Clinical Response by Infection Type at TOC: Aztreonam	0 to 24 hours at TOC (Day 28)	Population PK predicted (AUC24,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam	At TOC (Day 28)	Population PK predicted (Cmax,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving \< 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam	0 to 24 hours at TOC (Day 28)	Population PK predicted (AUC24,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving \< 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Microbiological Response by Infection Type at TOC: Aztreonam	At TOC (Day 28)	Population PK predicted (%fT\>MIC ATM of 8 mg/L) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving \< 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval (%fT>CT of 2.5mg/L) According to Clinical Response by Infection Type at TOC: Avibactam	At TOC (Day 28)	Population PK predicted (%fT\>CT of 2.5mg/L) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Clinical Response by Infection Type at TOC: Avibactam	0 to 24 hours at TOC (Day 28)	Population PK predicted (AUC24,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss ) According to Clinical Response by Infection Type at TOC: Avibactam	At TOC (Day 28)	Population PK predicted (Cmax,ss) for participants who received aztreonam-avibactam in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Clinical response categories included, clinical cure=improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. For cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Failure was defined as participants who met any of the following criteria like death (after receiving at least 48 hours of study treatment) and participants who received treatment with further antibiotics for the index infection. Indeterminate was defined as death (after receiving less than 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Avibactam	0 to 24 hours At TOC (Day 28)	Population PK predicted (AUC24,ss) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving\<48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss (mg/L)) According to Microbiological Response by Infection Type at TOC: Avibactam	At TOC (Day 28)	Population PK predicted (Cmax,ss (mg/L)) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving\<48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval; (%fT>CT of 2.5 mg/L) According to Microbiological Response by Infection Type at TOC: Avibactam	At TOC (Day 28)	Population PK predicted (%fT\>CT of 2.5 mg/L) for participants who received ATM-AVI in studies C3601002 (NCT03329092) and C3601009 (NCT03580044). Microbiological response included Favorable =baseline pathogens for participant had a favorable outcome. Eradication: Absence of causative pathogen from an appropriately obtained specimen at site of infection. Presumed eradication: repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure. Unfavorable=persistence, persistence with increasing MIC, or presumed persistence. Persistence= Causative organism still present from appropriately obtained specimen at site of infection. Presumed persistence= Participant assessed as a clinical failure and repeat culture of specimens were not performed/clinically indicated. Indeterminate = death (after receiving \< 48 hours of study treatment) and for cIAI participants inadequate infection source control at time of initial surgical procedure.
Number of Participants With Adverse Events (AEs) and Serious AEs	From start of study treatment until end of late follow-up (Up to Day 45)	An adverse event (AE) was any untoward medical occurrence in a study participant administered medicinal product,; the event need not necessarily have a causal relationship with product treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital abnormal/birth defect or considered an important medical event.
Number of Participants With Potentially Clinically Significant Hematology Abnormalities	From start of study treatment until TOC visit (Up to Day 28)	Criteria for potential clinically significant hematology results were as follows: hemoglobin, hematocrit and erythrocyte \<0.7\*lower limit of normal \[LLN\] and \>30% decrease from Baseline (DFB); \>1.3\*upper limit of normal (ULN) and \>30% increase from Baseline (IFB). Platelet count \<0.65\*LLN and \> 50% decrease from baseline; \> 1.5 \* ULN and \> 100% increase from baseline. leukocyte: \< 0.65\* LLN and \> 60% decrease from baseline; \> 1.5\* ULN and 100% increase from baseline. Neutrophils/leukocytes \< 0.65 \* LLN and \>75% decrease from baseline; \> 1.6\*ULN and \> 100% increase from baseline. Lymphocytes/leukocytes \< 0.25\* LLN and \> 75% decrease from baseline;\> 1.5\* ULN and \> 100% increase from baseline, Eosinophils/leukocytes, Monocytes/leukocytes, Basophils/leukocytes \> 4.0\* ULN and \> 300% increase from baseline.
Number of Participants With Abnormalities in Vital Signs	From start of study treatment until TOC visit (Up to Day 28)	Vitals signs, included blood pressure and, heart rate. Blood pressure (BP) and heart rate were measured using a semiautomatic BP recording device with the participant in a supine position after at least 10 minutes of rest. Criteria for abnormalities included: Systolic BP (millimeters of mercury \[mmHg\]): value more than (\>) 150 and increase from baseline more than equal (\>= 30) or value less than (\<) 90 and decrease from baseline \>= 30; DBP: value \> 100 and increase from baseline \>=20 or Value \< 50 and decrease from baseline \>= 20; Heart Rate (beats per minute \[BPM\]): value \< 40 or \> 120.
Number of Participants With Potentially Clinically Significant Clinical Chemistry Abnormalities	From start of study treatment until At TOC visit (Up to Day 28)	Albumin \< 0.5\* LLN and\> 50% decrease from baseline (DFB);\> 1.5 \* ULN and\> 50% increase from baseline (IFB). Alkaline phosphatase \< 0.5 \* LLN and\> 80% DFB;\> 3.0 \* ULN and\> 100%. Alanine and Aspartate aminotransferase \> 3.0 \* ULN and\> 100% IFB. Bicarbonate \< 0.7 \* LLN and \> 40% DFB;\> 1.3 \* ULN and\> 40% IFB. Blood urea nitrogen \< 0.2 \* LLN and \> 100% DFB; \> 3.0 \* ULN and \> 200% IFB. Calcium \< 0.7 \* LLN and \> 30% DFB;\> 1.3 \* ULN and\> 30% IFB. Chloride \< 0.8 \* LLN \>and 20% DFB; \> 1.2 \* ULN and \> 20% IFB. Creatinine \> 2.0 \* ULN and\> 100% IFB; Glucose \< 0.6 \* LLN and\> 40% DFB; \> 3.0 \* ULN and\> 200% IFB. Potassium \< 0.8 \* LLN and \> 20% DFB; \> 1.2 \* ULN and\> 20% IFB. Sodium \< 0.85 \* LLN and\> 10% DFB;\> 1.1 \* ULN and \>10% IFB. Bilirubin \> 1.5 \* ULN and \> 100% IFB.; Direct bilirubin \> 2.0 \* ULN and \> 150% IFB.
Number of Participants With Abnormal Physical Examination Finding	Screening, End of treatment (up to 24 hours post infusion on Day 14) and Test of Cure (Day 28)	A complete physical examination was performed and included an assessment of the following: general appearance including site of infection, skin, head and throat (head, eyes, ears, nose, and throat), lymph nodes, lungs, cardiovascular (CV), abdomen, musculoskeletal, and neurological systems.
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings	Baseline (latest non-missing value before start of treatment) and Day 3	Standard 12-lead ECGs were recorded with the participants in the supine position after the participant had rested in this position for 10 minutes. Clinically significant findings were based on investigators assessment.

Trial Locations

Locations (156)

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; 🇺🇸 Torrance, California, United States

Harbor-UCLA Medical Center; 🇺🇸 Torrance, California, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Memorial Medical Center; 🇺🇸 Springfield, Illinois, United States

Sanatorio Britanico; 🇦🇷 Rosario, Santa FE, Argentina

Sanatorio Servicios Medicos SM; 🇦🇷 Santo Tome, Santa FE, Argentina

Hospital San Roque; 🇦🇷 Córdoba, Argentina

University Hospital Alexandrovska, Clinic of Anesthesiology and Intensive Care; 🇧🇬 Sofia, Bulgaria

University Hospital Queen Joanna ISUL, Clinic of Surgery; 🇧🇬 Sofia, Bulgaria

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