Clinical Trial Results:
A prospective, randomized, open-label, comparative study to assess the efficacy, safety and tolerability of aztreonam-avibactam (ATM-AVI) and best available therapy for the treatment of serious infections due to multi-drug resistant gram-negative bacteria producing metallo-β-lactamase (MBL)
Summary
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EudraCT number |
2017-004544-38 |
Trial protocol |
GR RO |
Global end of trial date |
23 Jan 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jan 2024
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First version publication date |
28 Jan 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
C3601009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03580044 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Assemble: Other study ID | ||
Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Jun 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jan 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy, of aztreonam- avibactam (ATM- AVI) and best available therapy (BAT) at the Test of Cure (TOC) visit in the microbiological Intent- To-Treat (micro-ITT) population for the treatment of selected serious infections that are due to MBL-producing Gram-negative bacteria.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Dec 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
China: 2
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Country: Number of subjects enrolled |
Greece: 3
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Country: Number of subjects enrolled |
India: 1
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Country: Number of subjects enrolled |
Malaysia: 2
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Country: Number of subjects enrolled |
Mexico: 1
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Country: Number of subjects enrolled |
Philippines: 1
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Country: Number of subjects enrolled |
Romania: 2
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Country: Number of subjects enrolled |
Russian Federation: 2
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Country: Number of subjects enrolled |
Thailand: 1
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Worldwide total number of subjects |
15
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EEA total number of subjects |
5
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
10
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects hospitalized with a diagnosis of complicated intra-abdominal infection (cIAI), nosocomial pneumonia (NP) including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI) due to producing Gram-negative bacteria were enrolled. | |||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 15 subjects signed the informed consent form and were randomized in the study. This study was conducted across 9 countries from 25 Dec-2020 to 23-Jan-2023. The study was terminated as recruitment of subjects with serious infections caused by gram-negative bacteria producing MBL was challenging. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Aztreonam- Avibactam (ATM- AVI) | |||||||||||||||||||||
Arm description |
Subjects were administered a loading dose of aztreonam- avibactam (ATM-AVI) by intravenous (IV) infusion over 30 minutes immediately followed by an extended loading dose of ATM-AVI by infusion over 3 hours, and then started a maintenance dose of ATM-AVI by IV infusion over 3 hours on Day 1. Subjects with creatinine clearance >50 milliliters per minute (mL/min) and >30 to 50 mL per minute were administered maintenance dose once every 6 hours for maximum of 14 days. Subjects with creatinine clearance >15 to 30 mL/min were administered maintenance dose once every 8 hours for maximum of 14 days. Subjects with cIAI also received metronidazole (MTZ) 500 milligram (mg) every 8 hours by IV infusion over 60 minutes. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Aztreonam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Aztreonam 2 gram powder concentrate for infusion.
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Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Metronidazole 500 mg/100 millilitre (mL) solution for infusion.
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Investigational medicinal product name |
Avibactam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Avibactam 600 milligrams (mg) powder concentrate for infusion.
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Arm title
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Best Available Therapy (BAT) | |||||||||||||||||||||
Arm description |
Subjects who were hospitalized with a diagnosis of cIAI, NP, HAP, VAP, cUTI or BSI received Best Available Therapy (BAT) based upon site practice and local epidemiology for a maximum of 14 days. Subjects with cIAI in the BAT arm received metronidazole if BAT did not provide adequate anaerobic coverage. | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
BAT
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Based on investigative site practice and local epidemiology.
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Baseline characteristics reporting groups
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Reporting group title |
Aztreonam- Avibactam (ATM- AVI)
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Reporting group description |
Subjects were administered a loading dose of aztreonam- avibactam (ATM-AVI) by intravenous (IV) infusion over 30 minutes immediately followed by an extended loading dose of ATM-AVI by infusion over 3 hours, and then started a maintenance dose of ATM-AVI by IV infusion over 3 hours on Day 1. Subjects with creatinine clearance >50 milliliters per minute (mL/min) and >30 to 50 mL per minute were administered maintenance dose once every 6 hours for maximum of 14 days. Subjects with creatinine clearance >15 to 30 mL/min were administered maintenance dose once every 8 hours for maximum of 14 days. Subjects with cIAI also received metronidazole (MTZ) 500 milligram (mg) every 8 hours by IV infusion over 60 minutes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Best Available Therapy (BAT)
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Reporting group description |
Subjects who were hospitalized with a diagnosis of cIAI, NP, HAP, VAP, cUTI or BSI received Best Available Therapy (BAT) based upon site practice and local epidemiology for a maximum of 14 days. Subjects with cIAI in the BAT arm received metronidazole if BAT did not provide adequate anaerobic coverage. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Aztreonam- Avibactam (ATM- AVI)
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Reporting group description |
Subjects were administered a loading dose of aztreonam- avibactam (ATM-AVI) by intravenous (IV) infusion over 30 minutes immediately followed by an extended loading dose of ATM-AVI by infusion over 3 hours, and then started a maintenance dose of ATM-AVI by IV infusion over 3 hours on Day 1. Subjects with creatinine clearance >50 milliliters per minute (mL/min) and >30 to 50 mL per minute were administered maintenance dose once every 6 hours for maximum of 14 days. Subjects with creatinine clearance >15 to 30 mL/min were administered maintenance dose once every 8 hours for maximum of 14 days. Subjects with cIAI also received metronidazole (MTZ) 500 milligram (mg) every 8 hours by IV infusion over 60 minutes. | ||
Reporting group title |
Best Available Therapy (BAT)
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Reporting group description |
Subjects who were hospitalized with a diagnosis of cIAI, NP, HAP, VAP, cUTI or BSI received Best Available Therapy (BAT) based upon site practice and local epidemiology for a maximum of 14 days. Subjects with cIAI in the BAT arm received metronidazole if BAT did not provide adequate anaerobic coverage. |
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End point title |
Percentage of Subjects With Clinical Cure at the Test of Cure (TOC) Visit -Microbiological Intent to Treat (Micro-ITT) Analysis Set [1] | ||||||||||||
End point description |
Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI subjects, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% confidence interval (CI) was calculated using Jeffrey’s method. Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. 99999 indicates data could not be calculated due to insufficient number of subjects.
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End point type |
Primary
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End point timeframe |
Day 28
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinical Cure at the TOC Visit-Microbiologically Evaluable (ME) Analysis Set | ||||||||||||
End point description |
Clinical cure = improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI subjects, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI calculated using Jeffrey’s method. ME analysis set: Subjects from micro-ITT who received at least 48 hours of study therapy or <48 hours before discontinuation due to an adverse event, no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding subjects with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed) and no indeterminate clinical outcomes at TOC. 99999= data could not be calculated due to insufficient number of subjects.
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End point type |
Secondary
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End point timeframe |
Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinical Cure at the End of Treatment (EOT) Visit- Micro-ITT Analysis Set | ||||||||||||
End point description |
Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI subjects, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey’s method. Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. 99999 indicates data could not be calculated due to insufficient number of subjects.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Clinical Cure at the EOT Visit- ME Analysis Set | ||||||||||||
End point description |
Clinical cure: improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for index infection (i.e. cIAI,cUTI,HAP/VAP or BSI)after study treatment.For cIAI subjects,no unplanned drainage or surgical intervention was necessary since the initial procedure.The clinical response assessment was determined by a blinded independent adjudication committee.95% CI was calculated using Jeffrey’s method.ME analysis set:Subjects from micro-ITT who received at least 48 hours of study therapy or <48 hours before discontinuation due to an adverse event, no concomitant antibiotics against baseline MBL positive pathogens between first dose of study therapy and TOC(excluding subjects with failed study therapy requiring additional antibiotics)had baseline organisms confirmed by central microbiological testing (except when locally confirmed) and no indeterminate clinical outcomes at TOC.99999=data could not be calculated due to insufficient number of subjects.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With a Favorable Per Subject Microbiological Response at EOT Visit-Micro-ITT Analysis Set | ||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 colony forming units per milliliter [CFU/mL] for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. Subjects with a per subject response of Indeterminate were excluded from this analysis. Here ‘Number of Subjects Analyzed’ signifies subjects evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With a Favorable Per Subject Microbiological Response at EOT Visit-ME Analysis Set | ||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). ME analysis set: Subjects from micro-ITT who received at least 48 hours of study therapy or <48 hours before discontinuation due to an adverse event; no concomitant antibiotics against baseline MBL positive pathogens between first dose of study therapy and TOC (excluding subjects with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed) and no indeterminate clinical outcomes at TOC.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With a Favorable Per Subject Microbiological Response at TOC Visit-Micro-ITT Analysis Set | ||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 colony forming units per milliliter [CFU/mL] for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. Subjects with a per subject response of Indeterminate were excluded from this analysis. Here ‘Number of Subjects Analyzed’ signifies participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With a Favorable Per Subject Microbiological Response at TOC Visit-ME Analysis Set | ||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). ME analysis set: Subjects from micro-ITT who received at least 48 hours of study therapy or <48 hours before discontinuation due to an adverse event, no concomitant antibiotics against baseline MBL positive pathogens between first dose of study therapy and TOC (excluding subjects with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed) and no indeterminate clinical outcomes at TOC.
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End point type |
Secondary
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End point timeframe |
Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-Micro-ITT Analysis Set | ||||||||||||||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication: absence (or urine quantification <10^3 CFU/mL for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. Here, n= pathogens evaluable for specified rows. 99999 indicates data could not be calculated due to insufficient pathogen.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-Micro-ITT Analysis Set | ||||||||||||||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication: absence (or urine quantification <10^3 CFU/mL for cUTI subjects) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a subject who had a clinical response of cure (specific to cIAI and HAP/VAP subject).Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment. n= pathogens evaluable for specified rows. 99999 indicates data could not be calculated due to insufficient pathogen.
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End point type |
Secondary
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End point timeframe |
Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-ME Analysis Set | |||||||||||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication:absence (or urine quantification <10^3 CFU/mL for cUTI subjects)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 subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). ME analysis set: Subjects from micro-ITT who received at least 48 hours or <48 hours of study therapy before discontinuation due to AE,no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics),had baseline organisms confirmed by central microbiological testing (except when locally confirmed);no indeterminate clinical outcomes at TOC. n= pathogens evaluable for specified rows. 99999= data could not be calculated due to insufficient number of subjects.
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End point type |
Secondary
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End point timeframe |
Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-ME Analysis Set | |||||||||||||||||||||
End point description |
Favorable microbiological response was defined as eradication or presumed eradication. Eradication: absence (or urine quantification <10^3 CFU/mL for cUTI subjects)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 subject who had a clinical response of cure (specific to cIAI and HAP/VAP subjects). ME analysis set: Subjects from micro-ITT who received at least 48 hours or <48 hours of study therapy before discontinuation due to AE,no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics),had baseline organisms confirmed by central microbiological testing (except when locally confirmed);no indeterminate clinical outcomes at TOC. n= pathogens evaluable for specified rows. 99999= data could not be calculated due to insufficient pathogens.
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End point type |
Secondary
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End point timeframe |
Up to 24 hours after the last infusion on Day 14
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects who Died Within 28 Days From Randomisation- Micro ITT Analysis Set | ||||||||||||
End point description |
Percentage of subjects who died due to any cause on or before 28 days after randomisation were reported in this this endpoint. Micro-ITT analysis set was a subset of the ITT analysis set and included all subjects who had at least 1 MBL-positive Gram-negative baseline pathogen from an adequate specimen at the start of study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to Day 28
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects who Died Within 28 Days From Randomisation-ITT Analysis Set | ||||||||||||
End point description |
Percentage of subjects who died due to any cause on or before 28 days after randomisation were reported in this endpoint. ITT analysis set included all randomized subjects regardless of receipt of study drug.
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End point type |
Secondary
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End point timeframe |
From randomisation up to Day 28
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment Emergent Adverse Events and Serious Adverse Events | |||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a study subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; considered an important medical event. Treatment-emergent adverse event (TEAE) was any AE that started after the study medication start date and time. Safety analysis set included all subjects who received any amount of study treatment. Subjects were analysed according to the treatment they received.
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment (Day 1) until late follow-up visit (Up to Day 45)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Vital Sign Abnormalities | ||||||||||||||||||||||||
End point description |
Vital signs included blood pressure and heart rate and were measured in a supine position after at least 10 minutes of rest for the subjects. Criteria for vital sign abnormalities included: systolic blood pressure (SBP): value >150 millimeters of mercury (mmHg) and increase from baseline >=30 mmHg and value <90 and decrease from baseline >=30. Diastolic BP (DBP) (mm Hg) Value >100 and increase from baseline >= 20 and Value <50 and decrease from baseline >=20. Heart Rate (beats per minute [BPM]) Value <40 or >120. Safety analysis set included all subjects who received any amount of study treatment. Subjects were analyzed according to the treatment they received. Here ‘Number of Subjects Analysed’ signifies subjects evaluable for this endpoint.
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End point type |
Secondary
|
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End point timeframe |
From first dose of study treatment (Day 1) until TOC (Up to Day 28)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Abnormal Physical Examination Findings | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Physical examination included assessment of the following: abdomen, cardiovascular, ears, eyes, general appearance, head, lungs, lymph nodes, musculoskeletal, neurological, nose, skin and throat. Number of subjects with abnormal physical examination findings for each body system is reported in this outcome measure. Safety analysis set included all subjects who received any amount of study treatment. Subjects were analyzed according to the treatment they received. Here, 'Number Analyzed’= subjects evaluable for specified rows.
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End point type |
Secondary
|
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End point timeframe |
Baseline (last non-missing value observed before start of treatment on Day 1), EOT (Up to 24 hours after the last infusion on Day 14), TOC (Day 28)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Hematology Assessments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Potential clinically significant criteria included: Hematocrit, hemoglobin and erythrocytes <0.7*lower limit of normal (LLN) and >30% Decrease from Baseline (DFB) or >1.3*upper limit of normal (ULN) and >30% Increase from Baseline (IFB); Leukocytes:<0.65*LLN and >60% DFB or >1.5*ULN and >100% DFB; Basophils/Leukocytes, Eosinophils/Leukocytes and Monocytes/Leukocytes:>4.0*ULN and >300% Increase from Baseline; Lymphocytes/Leukocytes <0.25*LLN and >75% DFB and >1.5* ULN and >100% IFB; Neutrophils/Leukocytes: <0.65*LLN and >75% DFB or >1.6*ULN and >100% IFB; Platelets<0.65*LLN and >50% DFB or >1.5*ULN and >100% IFB. Safety analysis set- all subjects who received any amount of study treatment. Subjects were analyzed according to the treatment received. All subjects reported under ‘N’ contributed data to the table but may not have evaluable data for every row. ‘n’= subjects evaluable for specified rows.
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of study treatment (Day 1) until TOC (Up to Day 28)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Clinical Chemistry Assessments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Potential clinically significant criteria included: Aspartate Aminotransferase(AST) and Alanine Aminotransferase (ALT): >3.0*ULN and >100% IFB; Bilirubin: >1.5*ULN and >100% IFB;Direct Bilirubin: >2.0*ULN and >150% IFB; Alkaline Phosphatase (ALP): 80% decrease from baseline (DFB) and >3.0*ULN and >100% IFB; Urea Nitrogen:100% DFB and >3.0*ULN and >200% IFB; Creatinine >2.0*ULN and >100% IFB; Sodium :10% DFB or >1.1*ULN and >10% IFB; Potassium: 20% DFB or >1.2*ULN and >20% IFB; Chloride: 20% DFB or >1.2*ULN and >20% IFB; Bicarbonate: 40% DFB or >1.3*ULN and >40% IFB; Calcium: 30% DFB or >1.3*ULN and >30% IFB; Albumin: 50% DFB or >1.5* ULN and >50% IFB; Glucose: 40% DFB or >3.0*ULN and >200% IFB. Safety analysis set- all subjects who received any amount of study treatment. Subject were analysed according to the treatment received. All subjects reported under ‘N’ contributed data to the table but may not have evaluable data for every row. Here,‘n’= subjects evaluable for specified rows.
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of study treatment (Day 1) until TOC (Up to Day 28)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Clinically Significant Abnormalities in Electrocardiogram (ECG) | |||||||||
End point description |
A standard 12-lead ECG was recorded with the subject in a supine position after at least 10 minutes of rest. The following ECG parameters were recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval, RR interval. Clinical significance of ECG abnormalities were judged by Investigator. Safety analysis set included all subjects who received any amount of study treatment. Subjects were analyzed according to the treatment they received.
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End point type |
Secondary
|
|||||||||
End point timeframe |
From first dose of study treatment (Day 1) until TOC (Up to Day 28)
|
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|
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of study drug up to the Last follow up visit (up to maximum of 45 days)
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Adverse event reporting additional description |
Same event may appear as non-SAE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have
experienced both serious and non-serious event during study. Analysis was performed on safety population.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Best Available Therapy (BAT)
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Reporting group description |
Subjects who were hospitalized with a diagnosis of cIAI, NP, HAP, VAP, cUTI or BSI received Best Available Therapy (BAT) based upon site practice and local epidemiology for a maximum of 14 days. Subjects with cIAI in the BAT arm received metronidazole if BAT did not provide adequate anaerobic coverage. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Aztreonam- Avibactam (ATM- AVI)
|
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Reporting group description |
Subjects were administered a loading dose of aztreonam- avibactam (ATM-AVI) by intravenous (IV) infusion over 30 minutes immediately followed by an extended loading dose of ATM-AVI by infusion over 3 hours, and then started a maintenance dose of ATM-AVI by IV infusion over 3 hours on Day 1. Subjects with creatinine clearance >50 milliliters per minute (mL/min) and >30 to 50 mL per minute were administered maintenance dose once every 6 hours for maximum of 14 days. Subjects with creatinine clearance >15 to 30 mL/min were administered maintenance dose once every 8 hours for maximum of 14 days. Subjects with cIAI also received metronidazole (MTZ) 500 milligram (mg) every 8 hours by IV infusion over 60 minutes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
23 May 2022 |
Amendment 2.0: Updated section 4: Study eligibility criteria to better reflect the target patient population in clinical practice. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Total number of deaths is reported for safety set under Adverse Events section. Actual number of deaths were 2 for Aztreonam-Avibactam and 1 for Best Available Therapy for ITT population as well. |