Clinical Trials List
Protocol NumberC3601002
NCT Number(ClinicalTrials.gov Identfier)NCT03329092
Completed
2018-05-01 - 2023-05-17
Phase III
Not yet recruiting6
Terminated1
ICD-10A49.9
Bacterial infection, unspecified
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
-
Sponsor
Pfizer
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Co-Principal Investigator
- Fu-Lun Chen Division of Infectious Disease
- Yu-Tien Tzeng Division of Infectious Disease
- Wen-Sen Lee Division of Infectious Disease
- Han-Lin Hsu Division of Infectious Disease
- Tsong-Yih Ou 未分科
- Chih-Hsin Lee Division of Infectious Disease
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Audit
None
Co-Principal Investigator
- 陳瑞光 Division of General Internal Medicine
- 周稚偵 Division of General Internal Medicine
- 張博閔 Division of General Internal Medicine
- 陳垚生 Division of General Internal Medicine
- 曾鈺婷 Division of General Internal Medicine
- 王國強 Division of General Internal Medicine
- 吳冠陞 Division of General Internal Medicine
- 陳以書 Division of General Internal Medicine
- 蔡忠育 Division of General Internal Medicine
- 施正蓮 Division of General Internal Medicine
- 梁宗榮 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
- Jann-Tay Wang Division of General Internal Medicine
- - - Division of General Internal Medicine
- Chung-Yu Chen 未分科
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
- Chung-Hao Huang Division of Infectious Disease
- Shang-Yi Lin Division of Infectious Disease
The Actual Total Number of Participants Enrolled
0 Not yet recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
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
Objectives
Primary Objective:
To evaluate the efficacy of ATM-AVI MTZ and MER COL at the Test of Cure (TOC) visit for the treatment of serious infections due to Gram-negative bacteria, including those due to MBL-producing MDR pathogens.
Test Drug
PF-06947387 (Aztreonam –Avibactam)
Active Ingredient
Avibactam
Aztreonam
Aztreonam
Dosage Form
lyophilised powder for solution for injection or infusion
lyophilisate for concentrate for solution for infusion
lyophilisate for concentrate for solution for infusion
Dosage
2g
600mg
600mg
Endpoints
Primary Endpoint:
Proportion of subjects with clinical cure at Test of Cure visit in the Intent-To-Treat and Clinically Evaluable analysis sets (Note: For
non-United States countries, the Intent-To-Treat and Clinically Evaluable are considered co-primary analysis sets. For the
US, the Intent-To-Treat is considered the primary analysis set, while Clinically Evaluable is secondary).
Secondary Endpoint(s):
-Proportion of subjects with clinical cure at the Test of Cure visit in the microbiological Intent-To-Treat and Microbiologically
Evaluable analysis sets.
-Proportion of subjects with clinical cure at the Test of Cure visit by infection type in the Intent-To-Treat and Clinically
Evaluable analysis sets.
-poportion of subjects with clinical cure at the Test of Cure visit for subjects with metallo-β-lactamase-positive pathogens in
the microbiological Intent-To-Treat and Microbiologically Evaluable analysis sets.
-Proportion of subjects with a favorable per-subject microbiological response at the Test of Cure visit in the microbiological
Intent-To-Treat and Microbiologically Evaluable analysis sets.
-Proportion of subjects who died on or before 28 days from randomization in the Intent-To-Treat and microbiological
Intent-To-Treat analysis sets.
-Pharmacokinetics of aztreonam and avibactam in subjects in the population pharmacokinetic analysis set.
-Pharmacokinetic/pharmacodynamic relationship between exposure and clinical and microbiological response for
aztreonam-avibactam ±metronidazole in the population pharmacokinetic analysis set.
Proportion of subjects with clinical cure at Test of Cure visit in the Intent-To-Treat and Clinically Evaluable analysis sets (Note: For
non-United States countries, the Intent-To-Treat and Clinically Evaluable are considered co-primary analysis sets. For the
US, the Intent-To-Treat is considered the primary analysis set, while Clinically Evaluable is secondary).
Secondary Endpoint(s):
-Proportion of subjects with clinical cure at the Test of Cure visit in the microbiological Intent-To-Treat and Microbiologically
Evaluable analysis sets.
-Proportion of subjects with clinical cure at the Test of Cure visit by infection type in the Intent-To-Treat and Clinically
Evaluable analysis sets.
-poportion of subjects with clinical cure at the Test of Cure visit for subjects with metallo-β-lactamase-positive pathogens in
the microbiological Intent-To-Treat and Microbiologically Evaluable analysis sets.
-Proportion of subjects with a favorable per-subject microbiological response at the Test of Cure visit in the microbiological
Intent-To-Treat and Microbiologically Evaluable analysis sets.
-Proportion of subjects who died on or before 28 days from randomization in the Intent-To-Treat and microbiological
Intent-To-Treat analysis sets.
-Pharmacokinetics of aztreonam and avibactam in subjects in the population pharmacokinetic analysis set.
-Pharmacokinetic/pharmacodynamic relationship between exposure and clinical and microbiological response for
aztreonam-avibactam ±metronidazole in the population pharmacokinetic analysis set.
Inclution Criteria
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
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 HAP/VAP, or presumed diagnosis of cIAI
requiring administration of IV antibacterial treatment (see additional Inclusion Criteria on
cIAI and HAP/VAP for minimum disease criteria).
4. 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; 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.
5. Female subject of childbearing potential must have a negative serum or urine pregnancy
test, with sensitivity of at least 25 mIU/mL.
6. Subject must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
Additional Inclusion Criteria - cIAI Subjects
1. Diagnosis of cIAI as:
EITHER:
Intra-operative/postoperative enrolment with visual confirmation (presence of pus
within the abdominal cavity) of an intra-abdominal infection associated with
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of
an abscess, or laparoscopic surgery. Specimens from the surgical intervention must
be sent for culture. Subjects who undergo a surgical procedure with complete fascial
closure are appropriate for the study. The skin incision may be left open for purposes
of wound management as long as complete fascial closure is accomplished. The
subject has at least 1 of the following diagnosed during the surgical intervention:
a. Cholecystitis with gangrenous rupture or perforation or progression of the
infection beyond the gallbladder wall;
b. Diverticular disease with perforation or abscess;
c. Appendiceal perforation or peri-appendiceal abscess;
d. Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis;
e. Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis;
f. Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis
associated with cirrhosis or chronic ascites);
g. Intra-abdominal abscess (including of the liver and spleen provided that there is
extension beyond the organ with evidence of intra-peritoneal involvement).
OR
Pre-operative enrollment where the following clinical criteria are met with
confirmation of infection by surgical intervention within 24 hours (before or after) of
randomization:
h. Requirement for surgical intervention, defined per protocol as open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery;
i. Evidence of systemic inflammatory response, with at least one of the following:
Documented fever (defined as body temperature ≥ 38°C) or hypothermia (with
a rectal core body temperature ≤ 35°C);
Elevated white blood cells (WBC) (>12000 cells/μL);
Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP)
<70 mmHg, or a SBP decrease of >40 mmHg;
Increased heart rate ( >90 beats per minute [bpm]) and respiratory rate
(>20 breaths/min);
Hypoxemia (defined as oxygen [O2] saturation <95% by pulse oximetry);
Altered mental status.
j. Physical findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness, with or without rebound;
Localized or diffuse abdominal wall rigidity;
Abdominal mass.
k. Supportive radiologic imaging findings of intra-abdominal infection such as
perforated intraperitoneal abscess detected on computed tomography scan,
magnetic resonance image, or ultrasound.
l. Specimens from the surgical intervention will be sent for culture for isolation of
both aerobic and anaerobic bacteria.
2. Subject must have had or will have a surgical intervention within 24 hours (before or
after) of randomization. A specimen from an abdominal source must be obtained for
culture during surgical intervention. Surgical intervention includes open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery. Isolates taken from
surgical wound exudates must not be used.
Additional Inclusion Criteria – HAP/VAP Subjects
1. Onset of symptoms >48 hours after admission or <7 days after discharge from an
inpatient care facility (for which the duration of admission was >3 days).
2. New or worsening infiltrate on chest X-ray (or computerized tomography [CT] scan)
obtained within 48 hours prior to randomization.
3. At least 1 of the following:
Documented fever (temperature 38°C) or hypothermia (rectal/core temperature
35°C);
WBC 10,000 cells/mm3
, leukopenia with total WBC 4500 cells/mm3
, or
>15% immature neutrophils (bands) noted on peripheral blood smear.
4. At least 2 of the following:
A new cough (or worsening of cough at baseline);
Production of purulent sputum or purulent endotracheal secretions;
Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales,
rhonchi, bronchial breath sounds, dullness on percussion, egophony);
Dyspnea, tachypnea, or hypoxemia (O2 saturation <90% or partial pressure of
O2 [pO2]<60 mmHg while breathing room air);
Need for acute changes in the ventilator support status/system to enhance
oxygenation, as determined by worsening oxygenation (arterial blood gas [ABG] or
pO2 in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed changes in the
amount of positive end-expiratory pressure.
5. Subjects must have a respiratory specimen obtained for Gram- stain and culture after the
onset of signs and symptoms for HAP/VAP and 48h prior to randomization. This
includes culture of either expectorated sputum or a specimen of respiratory secretions
obtained by endotracheal aspiration in intubated subjects, or by bronchoscopy with
bronchoalveolar lavage (BAL), mini-BAL or protected-specimen brush (PSB) sampling.
See Appendix 6 for details on appropriate specimen collection for ventilated and
non-ventilated subjects.
Additional Criteria for Optional Biomarker Analysis
In addition to the above criteria, for inclusion in the optional exploratory biomarker analysis,
subjects must fulfil the following criterion:
1. Subjects must provide a signed written informed consent for possible future biomarker
analysis. However, if a subject is unable, 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 possible
future biomarker analysis as soon as possible on recovery, as applicable in accordance
with local regulations. If a subject declines to consent for their blood samples to be used
for possible future biomarker analysis, there will be no penalty or loss of benefit to the
subject. The subject will not be excluded from other aspects of the study described in
this CSP, so long as he or she provides a signed written informed consent to participate in
the main study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
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 HAP/VAP, or presumed diagnosis of cIAI
requiring administration of IV antibacterial treatment (see additional Inclusion Criteria on
cIAI and HAP/VAP for minimum disease criteria).
4. 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; 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.
5. Female subject of childbearing potential must have a negative serum or urine pregnancy
test, with sensitivity of at least 25 mIU/mL.
6. Subject must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
Additional Inclusion Criteria - cIAI Subjects
1. Diagnosis of cIAI as:
EITHER:
Intra-operative/postoperative enrolment with visual confirmation (presence of pus
within the abdominal cavity) of an intra-abdominal infection associated with
peritonitis. Surgical intervention includes open laparotomy, percutaneous drainage of
an abscess, or laparoscopic surgery. Specimens from the surgical intervention must
be sent for culture. Subjects who undergo a surgical procedure with complete fascial
closure are appropriate for the study. The skin incision may be left open for purposes
of wound management as long as complete fascial closure is accomplished. The
subject has at least 1 of the following diagnosed during the surgical intervention:
a. Cholecystitis with gangrenous rupture or perforation or progression of the
infection beyond the gallbladder wall;
b. Diverticular disease with perforation or abscess;
c. Appendiceal perforation or peri-appendiceal abscess;
d. Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis;
e. Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis;
f. Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis
associated with cirrhosis or chronic ascites);
g. Intra-abdominal abscess (including of the liver and spleen provided that there is
extension beyond the organ with evidence of intra-peritoneal involvement).
OR
Pre-operative enrollment where the following clinical criteria are met with
confirmation of infection by surgical intervention within 24 hours (before or after) of
randomization:
h. Requirement for surgical intervention, defined per protocol as open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery;
i. Evidence of systemic inflammatory response, with at least one of the following:
Documented fever (defined as body temperature ≥ 38°C) or hypothermia (with
a rectal core body temperature ≤ 35°C);
Elevated white blood cells (WBC) (>12000 cells/μL);
Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP)
<70 mmHg, or a SBP decrease of >40 mmHg;
Increased heart rate ( >90 beats per minute [bpm]) and respiratory rate
(>20 breaths/min);
Hypoxemia (defined as oxygen [O2] saturation <95% by pulse oximetry);
Altered mental status.
j. Physical findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness, with or without rebound;
Localized or diffuse abdominal wall rigidity;
Abdominal mass.
k. Supportive radiologic imaging findings of intra-abdominal infection such as
perforated intraperitoneal abscess detected on computed tomography scan,
magnetic resonance image, or ultrasound.
l. Specimens from the surgical intervention will be sent for culture for isolation of
both aerobic and anaerobic bacteria.
2. Subject must have had or will have a surgical intervention within 24 hours (before or
after) of randomization. A specimen from an abdominal source must be obtained for
culture during surgical intervention. Surgical intervention includes open laparotomy,
percutaneous drainage of an abscess, or laparoscopic surgery. Isolates taken from
surgical wound exudates must not be used.
Additional Inclusion Criteria – HAP/VAP Subjects
1. Onset of symptoms >48 hours after admission or <7 days after discharge from an
inpatient care facility (for which the duration of admission was >3 days).
2. New or worsening infiltrate on chest X-ray (or computerized tomography [CT] scan)
obtained within 48 hours prior to randomization.
3. At least 1 of the following:
Documented fever (temperature 38°C) or hypothermia (rectal/core temperature
35°C);
WBC 10,000 cells/mm3
, leukopenia with total WBC 4500 cells/mm3
, or
>15% immature neutrophils (bands) noted on peripheral blood smear.
4. At least 2 of the following:
A new cough (or worsening of cough at baseline);
Production of purulent sputum or purulent endotracheal secretions;
Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales,
rhonchi, bronchial breath sounds, dullness on percussion, egophony);
Dyspnea, tachypnea, or hypoxemia (O2 saturation <90% or partial pressure of
O2 [pO2]<60 mmHg while breathing room air);
Need for acute changes in the ventilator support status/system to enhance
oxygenation, as determined by worsening oxygenation (arterial blood gas [ABG] or
pO2 in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed changes in the
amount of positive end-expiratory pressure.
5. Subjects must have a respiratory specimen obtained for Gram- stain and culture after the
onset of signs and symptoms for HAP/VAP and 48h prior to randomization. This
includes culture of either expectorated sputum or a specimen of respiratory secretions
obtained by endotracheal aspiration in intubated subjects, or by bronchoscopy with
bronchoalveolar lavage (BAL), mini-BAL or protected-specimen brush (PSB) sampling.
See Appendix 6 for details on appropriate specimen collection for ventilated and
non-ventilated subjects.
Additional Criteria for Optional Biomarker Analysis
In addition to the above criteria, for inclusion in the optional exploratory biomarker analysis,
subjects must fulfil the following criterion:
1. Subjects must provide a signed written informed consent for possible future biomarker
analysis. However, if a subject is unable, 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 possible
future biomarker analysis as soon as possible on recovery, as applicable in accordance
with local regulations. If a subject declines to consent for their blood samples to be used
for possible future biomarker analysis, there will be no penalty or loss of benefit to the
subject. The subject will not be excluded from other aspects of the study described in
this CSP, so long as he or she provides a signed written informed consent to participate in
the main study.
Exclusion Criteria
Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the
study:
All Subjects
1. Subject has an APACHE II score >30.
2. At Screening the subject is found to have/or strongly suspected to have an infection
caused by a Gram-negative species not expected to respond to either ATM-AVI and/or
MER (eg, Acinetobacter baumannii), or an infection caused by only Gram-positive
species. The subject is allowed to participate in the study if the Investigator considers
that the species is a colonizer which does not warrant specific treatment.
3. Subject has received more than one day (>24 hours) of any systemic antibiotic within
48 hours prior to randomization. This is inclusive of all doses of any systemic antibiotic
initiated in this time period (but not counting overlapping periods of antibiotics), eg, a
subject who receives 4 doses of an 8 hourly regimen with the last dose given just before
randomization is calculated as 32 hours of prior antibiotic.
The exception to this is a subject who is a failure of prior systemic antibiotic treatment as
evident by either documented worsening of objective signs and symptoms of infection or
lack of improvement in at least one objective sign or symptom of infection despite a
minimum of 48 hours antibiotic treatment.
For cIAI subjects, who received less than one day (<24 hours) of any systemic antibiotic
within 48 hours prior to randomization, one dose of antibiotic may be received
postoperatively within 6 hours of the surgical procedure (defined as 6 hours from the time
of skin closure or, if skin closure is not performed, 6 hours from the time the wound
dressing is applied).
4. 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
-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.
5. Subject is unlikely to respond to up to 14 days of study treatment.
6. 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.
7. Subject has a concurrent infection that may interfere with the evaluation of response to
the study antibiotics.
8. Subject has known Clostridium difficile associated diarrhea.
9. Subject has a need for effective concomitant systemic antibacterials in addition to those
allowed per protocol, and/or systemic antifungals, and/or any prohibited medication
(eg, probenecid) (see Section 5.10).
10. Subjects receiving hemodialysis or peritoneal dialysis.
11. Subject has an estimated CrCL 15 mL/min by Cockcroft-Gault formula (Cockcroft and
Gault 1976) or expected to require peritoneal dialysis, hemodialysis or hemofiltration
during the study.
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure
(any Child-Pugh class).
13. Presence of hepatic disease as indicated by ALT or AST >3 x upper limit of normal
(ULN) at Screening. However, subjects with AST and/or ALT up to 5 x ULN are
eligible if these elevations are acute and are documented as being directly related to the
infectious process being treated.
14. Subject has a total bilirubin (TBili) >2 x ULN, unless isolated hyperbilirubinemia is
directly related to the acute infection or due to known Gilbert’s disease. This must be
documented.
15. Alkaline phosphatase (ALP) >3 x ULN. However, subjects with values >3 x ULN and
<5 x ULN are eligible if this value is acute and directly related to the infectious process
being treated. This must be documented.
16. Subject has a perinephric infection.
17. Subject has an absolute neutrophil count <500/mm3.
18. Subject has previously been treated with the ATM-AVI.
19. Subject has been previously enrolled in this study.
20. 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
treatment and for at least 7 days after the last infusion of investigational product (see
Section 4.6.1).
21. Subject is participating in or has participated in other investigational interventional
studies (drug) within the last 30 days (or 5 times the half-life of the previously
administered investigational compound, whichever is longer) prior to screening and/or
during study participation.
22. 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).
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and unlikelihood
of completing the study.
24. Subject has past or current history of epilepsy or seizure disorders excluding febrile
seizures of childhood.
25. 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.
Additional Exclusion Criteria – cIAI Subjects
1. Subject was diagnosed with traumatic bowel perforation undergoing surgery within
12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours.
Other intra-abdominal processes in which the primary etiology is not likely to be
infectious.
2. Subject has infections limited to the hollow viscous, such as simple cholecystitis,
gangrenous cholecystitis without rupture, and simple appendicitis, or has acute
suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess.
3. Subject has abdominal wall abscess or small-bowel obstruction without perforation or
ischemic bowel without perforation.
4. Subject has a prior liver, pancreas, or small-bowel transplant.
5. Subject whose surgery will include staged abdominal repair, or “open abdomen”
technique, or marsupialization. This criterion is intended to exclude subjects in whom
the abdomen is left open, particularly those for whom re-operation is planned.
Additional Exclusion Criteria – HAP/VAP Subjects
1. APACHE II score <10.
2. HAP/VAP subject has a known or high likelihood (based on any available
microbiological results at the time of enrollment) of monomicrobial infection with a
Gram-positive organism.
3. Subjects with lung abscess, pleural empyema, or post-obstructive pneumonia.
4. Subject is a recipient of a lung or heart transplant.
5. Subjects with myasthenia gravis
Subjects with any of the following characteristics/conditions will not be included in the
study:
All Subjects
1. Subject has an APACHE II score >30.
2. At Screening the subject is found to have/or strongly suspected to have an infection
caused by a Gram-negative species not expected to respond to either ATM-AVI and/or
MER (eg, Acinetobacter baumannii), or an infection caused by only Gram-positive
species. The subject is allowed to participate in the study if the Investigator considers
that the species is a colonizer which does not warrant specific treatment.
3. Subject has received more than one day (>24 hours) of any systemic antibiotic within
48 hours prior to randomization. This is inclusive of all doses of any systemic antibiotic
initiated in this time period (but not counting overlapping periods of antibiotics), eg, a
subject who receives 4 doses of an 8 hourly regimen with the last dose given just before
randomization is calculated as 32 hours of prior antibiotic.
The exception to this is a subject who is a failure of prior systemic antibiotic treatment as
evident by either documented worsening of objective signs and symptoms of infection or
lack of improvement in at least one objective sign or symptom of infection despite a
minimum of 48 hours antibiotic treatment.
For cIAI subjects, who received less than one day (<24 hours) of any systemic antibiotic
within 48 hours prior to randomization, one dose of antibiotic may be received
postoperatively within 6 hours of the surgical procedure (defined as 6 hours from the time
of skin closure or, if skin closure is not performed, 6 hours from the time the wound
dressing is applied).
4. 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
-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.
5. Subject is unlikely to respond to up to 14 days of study treatment.
6. 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.
7. Subject has a concurrent infection that may interfere with the evaluation of response to
the study antibiotics.
8. Subject has known Clostridium difficile associated diarrhea.
9. Subject has a need for effective concomitant systemic antibacterials in addition to those
allowed per protocol, and/or systemic antifungals, and/or any prohibited medication
(eg, probenecid) (see Section 5.10).
10. Subjects receiving hemodialysis or peritoneal dialysis.
11. Subject has an estimated CrCL 15 mL/min by Cockcroft-Gault formula (Cockcroft and
Gault 1976) or expected to require peritoneal dialysis, hemodialysis or hemofiltration
during the study.
12. Subject has acute hepatitis or acute hepatic failure, cirrhosis or chronic hepatic failure
(any Child-Pugh class).
13. Presence of hepatic disease as indicated by ALT or AST >3 x upper limit of normal
(ULN) at Screening. However, subjects with AST and/or ALT up to 5 x ULN are
eligible if these elevations are acute and are documented as being directly related to the
infectious process being treated.
14. Subject has a total bilirubin (TBili) >2 x ULN, unless isolated hyperbilirubinemia is
directly related to the acute infection or due to known Gilbert’s disease. This must be
documented.
15. Alkaline phosphatase (ALP) >3 x ULN. However, subjects with values >3 x ULN and
<5 x ULN are eligible if this value is acute and directly related to the infectious process
being treated. This must be documented.
16. Subject has a perinephric infection.
17. Subject has an absolute neutrophil count <500/mm3.
18. Subject has previously been treated with the ATM-AVI.
19. Subject has been previously enrolled in this study.
20. 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
treatment and for at least 7 days after the last infusion of investigational product (see
Section 4.6.1).
21. Subject is participating in or has participated in other investigational interventional
studies (drug) within the last 30 days (or 5 times the half-life of the previously
administered investigational compound, whichever is longer) prior to screening and/or
during study participation.
22. 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).
23. Subject is unlikely to comply with protocol, eg, uncooperative attitude and unlikelihood
of completing the study.
24. Subject has past or current history of epilepsy or seizure disorders excluding febrile
seizures of childhood.
25. 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.
Additional Exclusion Criteria – cIAI Subjects
1. Subject was diagnosed with traumatic bowel perforation undergoing surgery within
12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours.
Other intra-abdominal processes in which the primary etiology is not likely to be
infectious.
2. Subject has infections limited to the hollow viscous, such as simple cholecystitis,
gangrenous cholecystitis without rupture, and simple appendicitis, or has acute
suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess.
3. Subject has abdominal wall abscess or small-bowel obstruction without perforation or
ischemic bowel without perforation.
4. Subject has a prior liver, pancreas, or small-bowel transplant.
5. Subject whose surgery will include staged abdominal repair, or “open abdomen”
technique, or marsupialization. This criterion is intended to exclude subjects in whom
the abdomen is left open, particularly those for whom re-operation is planned.
Additional Exclusion Criteria – HAP/VAP Subjects
1. APACHE II score <10.
2. HAP/VAP subject has a known or high likelihood (based on any available
microbiological results at the time of enrollment) of monomicrobial infection with a
Gram-positive organism.
3. Subjects with lung abscess, pleural empyema, or post-obstructive pneumonia.
4. Subject is a recipient of a lung or heart transplant.
5. Subjects with myasthenia gravis
The Estimated Number of Participants
-
Taiwan
16 participants
-
Global
426 participants
