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.
- Conditions
- Complicated Intra-abdominal InfectionHosptial Acquired PneumoniaVentilator Associated Pneumonia
- Interventions
- Drug: ATM-AVIDrug: MERDrug: MTZDrug: 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 422
All subjects:
- Male or female from 18 years of age
- Provision of informed consent
- Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
- 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:
-
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
-
Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
Additional for HAP/VAP:
- Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility
- New or worsening infiltrate on CXR or CT scan
- Clinical signs and symptoms and laboratory findings consistent with HAP/VAP
- Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation
Exclusion criteria:
All subjects:
- APACHE II score > 30
- Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
- Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
- 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
- Known Clostridium difficle associated diarrhoea
- Requirement for effective concomitant systemic antibacterials or antifungals
- Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
- Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
- 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
- Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
- 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
- Absolute neutrophil count <500/mm3
- Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
- Any other condition that may confound the results of the study or pose additional risks to the subject
- Unlikely to comply with protocol
- History of epilepsy or seizure disorders excluding febrile seizures of childhood
Additional for cIAI
- 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
- Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
- Prior liver, pancreas or small-bowel transplant
- Staged abdominal repair (STAR), open abdomen technique or marsupialisation
Additional for HAP/VAP
- APACHE II score < 10
- Known or high likelihood of Gram-positive monomicrobial infection
- Lung abscess, pleural empyema, post-obstructive pneumonia
- Lung or heart transplant
- Myasthenia gravis
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 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 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
- 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 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.
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.
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 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 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 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)
General Hospital of Athens "Laiko"
🇬🇷Athens, Greece
Koutlimbaneio and Triantafylleio General Hospital of Larissa
🇬🇷Larissa, Greece
Clinical Hospital Dubrava
🇭🇷Zagreb, Croatia
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
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
Lekarna Nemocnice Decin, Krajska zdravotni, a.s.- Nemocnice Decin, o.z.
🇨🇿Decin, Czechia
Klinicka bolnica Merkur
🇭🇷Zagreb, GRAD Zagreb, Croatia
Sanatorio Britanico
🇦🇷Rosario, Santa FE, Argentina
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
University Malaya Medical Centre
🇲🇾Kuala Lumpur, Malaysia
De La Salle Medical and Health Sciences Institute
🇵🇭City Of Dasmarinas, Cavite, Philippines
Baguio General Hospital and Medical Center
🇵🇭Baguio City, Philippines
Davao Doctors Hospital
🇵🇭Davao City, Philippines
Krajska zdravotni, a.s. - Nemocnice Decin, o.z.
🇨🇿Decin, Czechia
Public Hospital Kolin, a.s.
🇨🇿Kolin III, Czechia
University Multiprofile Hospital for Active Treatment ''Prof.Dr Stoyan Kirkovich''AD
🇧🇬Stara Zagora, Bulgaria
University General Hospital of Larissa
🇬🇷Larissa, Greece
Hospital Seberang Jaya
🇲🇾Seberang Jaya, Pulau Pinang, Malaysia
St. Paul's Hospital of Iloilo, Inc.
🇵🇭Iloilo City, Philippines
SC di Radiologia - Azienda Ospedaliera Universitaria di Modena
🇮🇹Modena, Italy
Memorial Medical Center
🇺🇸Springfield, Illinois, United States
T.C. Saglik Bakanligi Ankara Sehir Hastanesi
🇹🇷Ankara, Turkey
Farmacia Ospedaliera - Direzione Assistenza Farmaceutica
🇮🇹Modena, Italy
Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
🇮🇹Pisa, Italy
Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
🇲🇽Monterrey, Nuevo LEON, Mexico
West Visayas State University Medical Center
🇵🇭Iloilo City, Philippines
Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"
🇷🇴Timisoara, Romania
UO Radiognastostica 2 Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
🇮🇹Pisa, Italy
Hallym University Kangnam Sacred Heart Hospital
🇰🇷Seoul, Korea, Republic of
Gachon University Gil Medical Center - Infectious Disease
🇰🇷Incheon, Incheon Gwang'yeogsiv, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea, Eunpyeong St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
State autonomous institution of healthcare of the Perm Region" City clinical hospital #4"
🇷🇺Perm, Russian Federation
Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Presidio Ospedaliero Universitario Santa
🇮🇹Udine, Italy
Acibadem Atakent Hospital
🇹🇷Istanbul, Turkey
Faculty of Medicine Siriraj Hospital
🇹🇭Bangkoknoi, Bangkok, Thailand
Philippine General Hospital, Central Intensive Care Unit
🇵🇭Manila, Philippines
Spitalul Clinic de Boli Infectioase si tropicale "Dr. Victor Babes"
🇷🇴Bucuresti, Romania
Private Healthcare Institution "Clinical Hospital 'Russian Railroad Medicine, Chelyabinsk'"
🇷🇺Chelyabinsk, Russian Federation
Hospital Civil Fray Antonio Alcalde
🇲🇽Guadalajara, Jalisco, Mexico
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Makati Medical Center
🇵🇭Makati City, Philippines
Asian Hospital and Medical Center
🇵🇭Muntinlupa City, Philippines
St. Luke's Medical Center
🇵🇭Quezon City, Philippines
Songklanagarind Hospital, Prince of Songkla University
🇹🇭Hat Yai, Songkhla, Thailand
Hospital Sultanah Nur Zahirah
🇲🇾Kuala Terengganu, Terengganu, Malaysia
Kocaeli University Medical Faculty
🇹🇷Kocaeli, Turkey
Spitalul Clinic de Boli Infectioase Cluj-Napoca
🇷🇴Cluj-Napoca, Romania
Assuta Ashdod University Hospital
🇮🇱Ashdod, Israel
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
🇷🇴Bucuresti, Romania
Hospital Universitario Reina Sofia
🇪🇸Cordoba, Spain
Hospital Universitari i Politecnic la Fe
🇪🇸Valencia, Spain
Ivano-Frankivska tsentralna miska klin likarnia, viddilennia khirurhii,
🇺🇦Ivano-Frankivsk, Ukraine
GBUZ of Novosibirsk region "City Clinical Hospital # 2"
🇷🇺Novosibirsk, Russian Federation
Kyivska miska klinichna likarnia No. 3, khirurhichne viddilennia
🇺🇦Kyiv, Ukraine
Hacettepe Universitesi Tip Fakultesi
🇹🇷Ankara, Turkey
Ankara University Faculty of Medicine
🇹🇷Ankara, Turkey
Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi
🇹🇷Istanbul, Turkey
Karadeniz Technical University Medical Faculty Farabi Hospital
🇹🇷Trabzon, Turkey
Kaohsiung Veterans General Hospital
🇨🇳Kaohsiung, Taiwan
Bamrasnaradura Infectious Disease Institute (BIDI)
🇹🇭Muang, Nonthaburi, Thailand
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Odeska klinichna likarnia na zaliznychnomu transporti filii "Tsentr okhorony zdorovia" aktsionernoho
🇺🇦Odesa, Ukraine
Komunalne pidpryiemstvo "1-a miska klinichna likarnia Poltavskoi miskoi rady",
🇺🇦Poltava, Ukraine
Oblasna klinichna likarnia, viddilennia anesteziolohii ta intensyvnoi terapii
🇺🇦Ivano-Frankivsk, Ukraine
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Spain
Komunalnyi zaklad "Miska klinichna likarnia No.4" Dniprovskoi miskoi rady, viddilennia profpatolohii
🇺🇦Dnipro, Ukraine
DU "Instytut zahalnoi ta nevidkladnoi khirurhii imeni V.T. Zaitseva Natsionalnoi akademii medychnykh
🇺🇦Kharkiv, Ukraine
Hospital Universitario Mutua de Terrassa
🇪🇸Terrassa, Barcelona, Spain
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
Scientific Research Institute of Antimicrobial Chemotherapy
🇷🇺Smolensk, Russian Federation
Komunalne nekomertsiine pidpryiemstvo Lvivskoi oblasnoi rady Lvivska oblasna klinichna likarnia
🇺🇦Lviv, Ukraine
Kyivska miska klinichna likarnia #4, khirurhichne viddilennia #1
🇺🇦Kyiv, Ukraine
S.R. Kalla Memorial Gastro & General Hospital
🇮🇳Jaipur, Rajasthan, India
Apollo Hospitals
🇮🇳Chennai, Tamil NADU, India
Srinagarind Hospital, Division of Infectious Disease and Tropical Medicine
🇹🇭Muang, Khon Kaen, Thailand
Sahyadri Super Speciality Hospital
🇮🇳Pune, Maharashtra, India
JSS Hospital
🇮🇳Mysuru, Karnataka, India
M S Ramaiah Medical College and Hospitals
🇮🇳Bangalore, Karnataka, India
Sanatorio Servicios Medicos SM
🇦🇷Santo Tome, Santa FE, Argentina
Sahyadri Clinical Research & Development Center
🇮🇳Pune, India
King George Hospital
🇮🇳Visakhapatnam, Andhra Pradesh, India
Quirino Memorial Medical Center
🇵🇭Quezon City, Philippines
Sahyadri Specialty Hospital
🇮🇳Pune, India
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung City, Taiwan
Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi
🇷🇴Iasi, Romania
Taichung Veterans General Hospital
🇨🇳Taichung City, Taiwan
Zhangzhou Municipal Hospital of Fujian Province
🇨🇳Zhangzhou, Fujian, China
The First Affiliated Hospital of Shantou University Medical College
🇨🇳Shantou, Guangdong, China
The Second People's Hospital of Shenzhen
🇨🇳Shenzhen, Guangdong, China
Affiliated Hospital of Guilin Medical University
🇨🇳Guilin, Guangxi, China
ZhuJiang Hospital of Southern Medical University
🇨🇳Guangzhou, Guangdong, China
Peking University Third Hospital
🇨🇳Beijing, Beijing, China
Changsha Third Hospital
🇨🇳Changsha, Hunan, China
Jiangyin People's Hospital
🇨🇳Jiangyin, China
Affiliated Hospital of Jiangsu University
🇨🇳Zhenjiang, Jiangsu, China
The First people's Hospital of Kunming
🇨🇳Kunming, Yunnan, China
Taizhou Hospital of Zhejiang Province
🇨🇳Linhai, Zhejiang, China
Huashan Hospital, Fudan University
🇨🇳Shanghai, Shanghai, China
Shanghai Pulmonary Hospital
🇨🇳Shanghai, Shanghai, China
The First Affiliated Hospital of College of Medicine, Zhejiang University
🇨🇳Hangzhou, Zhejiang, China
Lishui People's Hospital
🇨🇳Lishui, Zhejiang, China
Quzhou People's Hospital
🇨🇳Quzhou, Zhejiang, China
Peking University People's Hospital
🇨🇳Beijing, China
Tianjin Union Medical Center
🇨🇳Tianjin, China
UO Farmaceutica Azienda Ospedaliero-Universitaria Pisana
🇮🇹Pisa, Italy
FGBOU VO "The First St. Petersburg state medical university n. a. I.P. Pavlova"
🇷🇺Saint-Petersburg, Russian Federation
The Chaim Sheba Medical Center
🇮🇱Tel-Hashomer, Israel
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
Nanning First People's Hospital
🇨🇳Nanning, Guangxi Zhuang Autonomous Region, China
Hunan Province People's Hospital
🇨🇳Changsha, Hunan, China
Baotou Central Hospital
🇨🇳Baotou, Inner Mongolia Autonomous Region, China
General Hospital "Dr. Josip Bencevic" Slavonski Brod
🇭🇷Slavonski Brod, Croatia
Klinicki bolnicki centar Rijeka
🇭🇷Rijeka, Primorsko-goranska Zupanija, Croatia
Nemocnice Kyjov, prispevkova organizace
🇨🇿Kyjov, Czechia
Fakultni nemocnice Kralovske Vinohrady
🇨🇿Praha 10, Czechia
General Hospital of Athens "Evangelismos"
🇬🇷Athens, Greece
General and Chest Diseases Hospital "Sotiria"
🇬🇷Athens, Greece
University General Hospital "ATTIKON"
🇬🇷Athens, Greece
University General Hospital of Heraklion
🇬🇷Heraklion, Crete, Greece
Kasturba Medical College and Hospital
🇮🇳Manipal, Karnataka, India
Victoria Hospital, Bangalore Medical College and Research Institute
🇮🇳Bangalore, Karnataka, India
Amrita Institute of Medical Sciences & Research Centre
🇮🇳Kochi, Kerala, India
Deenanath Mangeshkar Hospital And Research Centre
🇮🇳Pune, Maharashtra, India
King George's Medical University
🇮🇳Lucknow, Uttar Pradesh, India
Dayanand Medical College and Hospital
🇮🇳Ludhiana, India
Rambam Health Care Campus
🇮🇱Haifa, Israel
Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem
🇮🇱Jerusalem, Israel
Rabin Medical Center, Beilinson Hospital
🇮🇱Petah Tikva, Israel
Shamir Medical Center, Infectious Diseases Unit
🇮🇱Zerifin, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Milan, Italy
Azienda Ospedaliero-Universitaria Ospedali Riuniti
🇮🇹Foggia, Italy
Azienda Ospedaliero Universitaria di Modena
🇮🇹Modena, Italy
OGBUZ "Smolensk Regional Clinical Hospital"
🇷🇺Smolensk, Russian Federation
State Budgetary Healthcare Institution "Regional Clinical Hospital No. 2" of the Ministry of Health
🇷🇺Krasnodar, Russian Federation
FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF
🇷🇺Smolensk, Russian Federation
Parc de Salut Mar- Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Taipei Municipal Wanfang Hospital
🇨🇳Taipei, Taiwan
National Taiwan University Hospital
🇨🇳Taipei City, Taiwan
National Taiwan University Hospital Yun-Lin Branch
🇨🇳Douliou, Yunlin, Taiwan
Ege University Faculty of Medicine
🇹🇷Izmir, Turkey
OKU "Chernivetska oblasna klinichna likarnia", khirurhichne viddilennia
🇺🇦Chernivtsi, Ukraine
Sahyadri Super Specialty Hospital
🇮🇳Pune, Maharashtra, India
University Hospital Centre Osijek
🇭🇷Osijek, Croatia
KZ "Dnipropetrovska oblasna klinichna likarnia im. I.I. Mechnykova", viddilennia khirurhii №2
🇺🇦Dnipro, Ukraine
Vinnytska oblasna klinichna likarnia im. M.I. Pyrohova
🇺🇦Vinnytsia, Ukraine
Government Medical College, Kozhikode
🇮🇳Kozhikode, Kerala, India
Complejo Hospitalario Universitario de Vigo. Area Sanitaria de Vigo. Hospital Alvaro Cunqueiro
🇪🇸Vigo, Pontevedra, Spain