Clinical Trials List
Protocol NumberC3601009
NCT Number(ClinicalTrials.gov Identfier)NCT03580044
Completed
2018-08-01 - 2023-01-31
Phase III
Not yet recruiting3
ICD-10A49.9
Bacterial infection, unspecified
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)
-
Sponsor
Pfizer
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- 施正蓮 Division of General Internal Medicine
- 翁雅為 Division of General Internal Medicine
- Susan Shin-Jung Lee Division of General Internal Medicine
- 周稚偵 Division of General Internal Medicine
- 曾鈺婷 Division of General Internal Medicine
- 郭書宏 Division of General Internal Medicine
- 吳冠陞 Division of General Internal Medicine
- 洪宛廷 Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Co-Principal Investigator
- 莊祐中 Division of General Internal Medicine
- 黃昱璁 無
- - - Division of General Internal Medicine
- Jann-Tay Wang Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Audit
None
Co-Principal Investigator
- 張雅婷 Division of Infectious Disease
- Chau-Chyun Sheu Division of Infectious Disease
- Shang-Yi Lin Division of Infectious Disease
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Condition/Disease
SERIOUS INFECTIONS DUE TO MULTI-DRUG RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING METALLO -Β-LACTAMASE (MBL)
Objectives
Primary Objective:
To evaluate the efficacy of aztreonam-avibactam (ATM-AVI) compared to 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.
Secondary Objectives:
-To evaluate the efficacy of ATM-AVI compared to BAT at the TOC in the microbiologically evaluable (ME) population, and at the End of Treatment (EOT) visit in the micro-ITT and ME populations.
-To assess the microbiological response to ATM-AVI at the EOT and TOC visits in the micro-ITT and microbiologically evaluable (ME) populations.
-To assess 28-day all cause mortality
-To evaluate the safety and tolerability profile of ATM-AVI compared to BAT.
Test Drug
PF-06947387 (Aztreonam –Avibactam)
Active Ingredient
Avibactam
Aztreonam
Aztreonam
Dosage Form
lyophilisate for concentrate for solution for infusion
lyophilised powder for solution for injection or infusion
lyophilised powder for solution for injection or infusion
Dosage
600 mg
2 g
2 g
Endpoints
Primary Outcome Measures :
Proportion of subjects with clinical cure in the microbiological Intent-To-Treat (micro-ITT) analysis set [ Time Frame: Up to 31 days ]
Proportion of subjects with clinical cure at the TOC visit in the micro-ITT analysis set
Secondary Outcome Measures :
Proportion of subjects with clinical cure in the Microbiologically Evaluable (ME) analysis set [ Time Frame: up to 31 days ]
Proportion of subjects with clinical cure at the TOC visit in the ME analysis set
Proportion of subjects with clinical cure in the micro-ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment ]
Proportion of subjects with clinical cure at the EOT visit in the micro-ITT and ME analysis sets
Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]
Proportion of subjects with a favorable (defined as eradication or presumed eradication) per subject microbiological response at the EOT and TOC visits in the micro-ITT and ME analysis sets
Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]
Proportion of subjects with a favorable per pathogen microbiological response at the EOT and TOC visits in the micro- ITT and ME analysis sets
Proportion of subjects who died on or before 28 days in the Intent-To-Treat (ITT) and micro-ITT analysis sets [ Time Frame: from randomization up to 31 days ]
Proportion of subjects who died on or before 28 days from randomization in ITT and micro-ITT analysis sets
Incidence and severity of adverse events [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by adverse events
Incidence of abnormalities in physical examination [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by physical examination
Incidence of vital sign abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by vital sign assessments
Incidence of ECG abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by ECGs assessments
Incidence of clinical laboratory abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by clinical laboratory assessments
Proportion of subjects with clinical cure in the microbiological Intent-To-Treat (micro-ITT) analysis set [ Time Frame: Up to 31 days ]
Proportion of subjects with clinical cure at the TOC visit in the micro-ITT analysis set
Secondary Outcome Measures :
Proportion of subjects with clinical cure in the Microbiologically Evaluable (ME) analysis set [ Time Frame: up to 31 days ]
Proportion of subjects with clinical cure at the TOC visit in the ME analysis set
Proportion of subjects with clinical cure in the micro-ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment ]
Proportion of subjects with clinical cure at the EOT visit in the micro-ITT and ME analysis sets
Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]
Proportion of subjects with a favorable (defined as eradication or presumed eradication) per subject microbiological response at the EOT and TOC visits in the micro-ITT and ME analysis sets
Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]
Proportion of subjects with a favorable per pathogen microbiological response at the EOT and TOC visits in the micro- ITT and ME analysis sets
Proportion of subjects who died on or before 28 days in the Intent-To-Treat (ITT) and micro-ITT analysis sets [ Time Frame: from randomization up to 31 days ]
Proportion of subjects who died on or before 28 days from randomization in ITT and micro-ITT analysis sets
Incidence and severity of adverse events [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by adverse events
Incidence of abnormalities in physical examination [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by physical examination
Incidence of vital sign abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by vital sign assessments
Incidence of ECG abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by ECGs assessments
Incidence of clinical laboratory abnormalities [ Time Frame: from first dose up to 48 days ]
Safety and tolerability as assessed by clinical laboratory assessments
Inclution Criteria
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1.1.1. All Subjects
1. Subject must be ≥18 years of age.
2. Evidence of a personally signed and dated informed consent document indicating that
the subject or a legally acceptable representative has been informed of all pertinent
aspects of the study. If a subject is unable to consent for themselves at Screening, the
subject’s legally acceptable representative may provide written consent, in
accordance with the country-specific regulations. Those subjects who are
unconscious or considered by the investigator clinically unable to consent at
Screening and who are entered into the study by the consent of a legally acceptable
representative should provide their own written informed consent for continuing to
participate in the study as soon as possible on recovery, as applicable in accordance
with local regulations.
3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically
cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy
(see additional Inclusion Criteria on HAP/VAP, cIAI, cUTI, or BSI for minimum
disease criteria).
4. Subjects must have an MBL- positive Gram-negative bacteria (an Enterobacteriaceae
and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is
≥ 4 µg/mL), that was isolated from an appropriate culture obtained within 5 days
prior to study entry (the study qualifying culture, which was determined to be the
causative agent of entry infection and there is an isolate available to be sent to the
central laboratory). Prior to study entry, genotypic confirmation of an MBL-positive
pathogen at the local laboratory is required. If this is not possible then selected
phenotypic tests may be acceptable with prior approval of the sponsor. In the case of
mixed infection, the subject is allowed to participate in the study if the species are
deemed susceptible to ATM-AVI or the investigator considers that the additional
species are colonizers which do not warrant specific treatment.
5. Female subjects of nonchildbearing potential must meet at least 1 of the following
criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or
physiological cause; and status may be confirmed with a serum
follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure.
Note: All other female subjects (including female subjects with tubal ligations) are
considered to be of childbearing potential.
6. Female subject of childbearing potential must have a negative serum or urine
pregnancy test, with sensitivity of at least 25 mIU/mL.
7. Subjects who have received appropriate priorsystemic antibiotic[s] for a
carbapenem-non-susceptible pathogen must meet the following criteria (Note:
antibiotic[s] is considered appropriate if microbiological susceptibility test results
show that all carbapenem- non-susceptible pathogens are susceptible to the systemic
antibiotic[s] received):
a. Worsening or lack of improvement of objective symptoms or signs of infection
after at least 48 hours of antibacterial therapy
Note: Symptomatic subjects (see inclusion criteria 3 and 4) with an isolated causative
pathogen that was not susceptible to the prior systemic therapy received or who
received no prior systemic therapy are eligible for this trial.
8. Subject must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1.1.1. All Subjects
1. Subject must be ≥18 years of age.
2. Evidence of a personally signed and dated informed consent document indicating that
the subject or a legally acceptable representative has been informed of all pertinent
aspects of the study. If a subject is unable to consent for themselves at Screening, the
subject’s legally acceptable representative may provide written consent, in
accordance with the country-specific regulations. Those subjects who are
unconscious or considered by the investigator clinically unable to consent at
Screening and who are entered into the study by the consent of a legally acceptable
representative should provide their own written informed consent for continuing to
participate in the study as soon as possible on recovery, as applicable in accordance
with local regulations.
3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically
cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy
(see additional Inclusion Criteria on HAP/VAP, cIAI, cUTI, or BSI for minimum
disease criteria).
4. Subjects must have an MBL- positive Gram-negative bacteria (an Enterobacteriaceae
and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is
≥ 4 µg/mL), that was isolated from an appropriate culture obtained within 5 days
prior to study entry (the study qualifying culture, which was determined to be the
causative agent of entry infection and there is an isolate available to be sent to the
central laboratory). Prior to study entry, genotypic confirmation of an MBL-positive
pathogen at the local laboratory is required. If this is not possible then selected
phenotypic tests may be acceptable with prior approval of the sponsor. In the case of
mixed infection, the subject is allowed to participate in the study if the species are
deemed susceptible to ATM-AVI or the investigator considers that the additional
species are colonizers which do not warrant specific treatment.
5. Female subjects of nonchildbearing potential must meet at least 1 of the following
criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or
physiological cause; and status may be confirmed with a serum
follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure.
Note: All other female subjects (including female subjects with tubal ligations) are
considered to be of childbearing potential.
6. Female subject of childbearing potential must have a negative serum or urine
pregnancy test, with sensitivity of at least 25 mIU/mL.
7. Subjects who have received appropriate priorsystemic antibiotic[s] for a
carbapenem-non-susceptible pathogen must meet the following criteria (Note:
antibiotic[s] is considered appropriate if microbiological susceptibility test results
show that all carbapenem- non-susceptible pathogens are susceptible to the systemic
antibiotic[s] received):
a. Worsening or lack of improvement of objective symptoms or signs of infection
after at least 48 hours of antibacterial therapy
Note: Symptomatic subjects (see inclusion criteria 3 and 4) with an isolated causative
pathogen that was not susceptible to the prior systemic therapy received or who
received no prior systemic therapy are eligible for this trial.
8. Subject must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
Exclusion Criteria
Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the
study:
1.2.1. All Subjects
1. Subject has an Acute Physiology and Chronic Health Evaluation (APACHE) II score
>30.
2. Clinical judgment by the investigator that the subject has a high likelihood of dying
within the specified study treatment period despite delivery of adequate antibiotics for
treatment of the index infection.
3. Subject has a history of serious allergy such as anaphylaxis, angioedema and
bronchospasm, hypersensitivity or any serious reactions to any systemic antibacterial
which is allowed per protocol including ATM, carbapenem, monobactam or other
β-lactam antibiotics, AVI, colistimethate or polymixin B, nitroimidazoles or MTZ,
vancomycin, linezolid, daptomycin, aminoglycosides (eg, amikacin, gentamicin,
tobramycin), or any of the excipients of the respective (investigational) medicinal
products to be administered during the study.
4. Subject is unlikely to respond to up to 14 days of study treatment.
5. Subject has a concurrent infection that may interfere with the evaluation of response
to the study antibiotics.
6. Subject has a need for effective concomitant systemic antibacterials in addition to
those allowed per protocol for the diagnoses under study.
7. Subject has known Clostridium difficile associated diarrhoea.
8. Subjects receiving hemodialysis or peritoneal dialysis.
9. Subject has an estimated CrCL ≤ 15 mL/min by Cockcroft-Gault formula (Cockcroft
and Gault 1976), receiving or requirement for peritoneal dialysis, haemodialysis or
hemofiltration.
10. Presence of hepatic disease as indicated by alanine transaminase (ALT) or aspartate
aminotransferase (AST) >3 × upper limit of normal (ULN) at Screening. However,
subjects with AST and/or ALT up to 5 × ULN are eligible if these elevations are
acute and are documented as being directly related to the infectious process being
treated.
11. Subject has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly
related to the acute infection or due to known Gilbert's disease.
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure
(any Child-Pugh class).
13. Alkaline phosphatase >3.0 × ULN. However, subjects with values >3.0 × ULN and
<5.0 x ULN are eligible if this value is acute and directly related to the infectious
process being treated. This must be documented.
14. Subject has an absolute neutrophil count <500/mm3
.
15. Subject has a perinephric infection.
16. Subject has previously been treated with ATM-AVI.
17. Subject has been previously enrolled in this study.
18. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and
female subjects of childbearing potential who are unwilling or unable to use a highly
effective method of contraception as outlined in this protocol for the duration of the
study and for at least 7 days after the last infusion of investigational product.
19. Subject is participating in or has participated in other studies involving investigational
drug(s) within the last 30 days (or five times the half-life of the previously
administered investigational compound, whichever is longer) prior to study entry
and/or during study participation.
20. Subject has other acute or chronic medical or psychiatric condition including recent
(within the past year) or active suicidal ideation or behavior or laboratory abnormality
that may increase the risk associated with study participation or investigational
product administration or may interfere with the interpretation of study results and, in
the judgment of the investigator, would make the subject inappropriate for entry into
this study (eg, in HAP/VAP subjects with pulmonary disease such as lung cancer,
active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary disease
or recent pulmonary embolism).
21. Subject has past or current history of epilepsy or seizure disorders excluding febrile
seizures of childhood.
22. Colonisation with a metallo-ß-lactamase producing Enterobacteriaceae without signs
or symptoms.
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and
unlikelihood of completing the study.
24. Investigator site staff members directly involved in the conduct of the study and their
family members, site staff members otherwise supervised by the investigator, or
subjects who are Pfizer employees, including their family members, directly involved
in the conduct of the study.
Subjects with any of the following characteristics/conditions will not be included in the
study:
1.2.1. All Subjects
1. Subject has an Acute Physiology and Chronic Health Evaluation (APACHE) II score
>30.
2. Clinical judgment by the investigator that the subject has a high likelihood of dying
within the specified study treatment period despite delivery of adequate antibiotics for
treatment of the index infection.
3. Subject has a history of serious allergy such as anaphylaxis, angioedema and
bronchospasm, hypersensitivity or any serious reactions to any systemic antibacterial
which is allowed per protocol including ATM, carbapenem, monobactam or other
β-lactam antibiotics, AVI, colistimethate or polymixin B, nitroimidazoles or MTZ,
vancomycin, linezolid, daptomycin, aminoglycosides (eg, amikacin, gentamicin,
tobramycin), or any of the excipients of the respective (investigational) medicinal
products to be administered during the study.
4. Subject is unlikely to respond to up to 14 days of study treatment.
5. Subject has a concurrent infection that may interfere with the evaluation of response
to the study antibiotics.
6. Subject has a need for effective concomitant systemic antibacterials in addition to
those allowed per protocol for the diagnoses under study.
7. Subject has known Clostridium difficile associated diarrhoea.
8. Subjects receiving hemodialysis or peritoneal dialysis.
9. Subject has an estimated CrCL ≤ 15 mL/min by Cockcroft-Gault formula (Cockcroft
and Gault 1976), receiving or requirement for peritoneal dialysis, haemodialysis or
hemofiltration.
10. Presence of hepatic disease as indicated by alanine transaminase (ALT) or aspartate
aminotransferase (AST) >3 × upper limit of normal (ULN) at Screening. However,
subjects with AST and/or ALT up to 5 × ULN are eligible if these elevations are
acute and are documented as being directly related to the infectious process being
treated.
11. Subject has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly
related to the acute infection or due to known Gilbert's disease.
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure
(any Child-Pugh class).
13. Alkaline phosphatase >3.0 × ULN. However, subjects with values >3.0 × ULN and
<5.0 x ULN are eligible if this value is acute and directly related to the infectious
process being treated. This must be documented.
14. Subject has an absolute neutrophil count <500/mm3
.
15. Subject has a perinephric infection.
16. Subject has previously been treated with ATM-AVI.
17. Subject has been previously enrolled in this study.
18. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and
female subjects of childbearing potential who are unwilling or unable to use a highly
effective method of contraception as outlined in this protocol for the duration of the
study and for at least 7 days after the last infusion of investigational product.
19. Subject is participating in or has participated in other studies involving investigational
drug(s) within the last 30 days (or five times the half-life of the previously
administered investigational compound, whichever is longer) prior to study entry
and/or during study participation.
20. Subject has other acute or chronic medical or psychiatric condition including recent
(within the past year) or active suicidal ideation or behavior or laboratory abnormality
that may increase the risk associated with study participation or investigational
product administration or may interfere with the interpretation of study results and, in
the judgment of the investigator, would make the subject inappropriate for entry into
this study (eg, in HAP/VAP subjects with pulmonary disease such as lung cancer,
active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary disease
or recent pulmonary embolism).
21. Subject has past or current history of epilepsy or seizure disorders excluding febrile
seizures of childhood.
22. Colonisation with a metallo-ß-lactamase producing Enterobacteriaceae without signs
or symptoms.
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and
unlikelihood of completing the study.
24. Investigator site staff members directly involved in the conduct of the study and their
family members, site staff members otherwise supervised by the investigator, or
subjects who are Pfizer employees, including their family members, directly involved
in the conduct of the study.
The Estimated Number of Participants
-
Taiwan
0 participants
-
Global
0 participants
