Clinical trial NCT04973826
Conditions: Healthy
Keywords: no clinically relevant abnormalities
Sponsor: Pfizer
Start date: 2021-08-20; Completion date: 2021-09-27
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase 1, single center, single arm, open-label study to assess the PK, safety and tolerability of Aztreonam-Avibactam after single and repeated IV infusion of doses in healthy Chinese participants.

Detailed description:

Arms: arm 1: Chinese healthy volunteers
Interventions: intervention 1: Aztreonam-Avibactam
Intervention descriptions: intervention 1: 500/167 mg ATM/AVI loading infusion, followed by 1500/500 mg ATM/AVI extended loading infusion, then 1500/500 mg ATM/AVI maintenance dose infusion every 6 hours

Protocol documents:
Prot_000.pdf: 
Protocol C3601007 (PF-06947387) Statistical Analysis Plan
Page 1 of 14
         
 
PFIZER CONFIDENTIAL
Protocol C3601007
A PHASE I, SINGLE CENTER, OPEN LABEL STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
AZTREONAM-AVIBACTAM ADMINISTERED AS SINGLE AND
REPEATED INTRAVENOUS DOSES IN HEALTHY CHINESE 
SUBJECTS
Statistical Analysis Plan
(SAP)
Version:
1.0
SAP Author: 
(
China)
Date:
20Sept2018 
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PFIZER CONFIDENTIAL
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
Sept 20, 2018
Initial Statistical Analysis Plan based on final
Protocol of Aug 30, 2018
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS SETS .................................................................................................................6
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................6
5.1.1. Concentration Analysis Set...........................................................................6
5.1.2. Parameter Analysis Set.................................................................................6
5.2. Pharmacodynamic Analysis Set................................................................................7
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................7
5.6.1. Deviations Assessed Prior to Treatment Assignment...................................7
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoint(s) .................................................................................................8
6.2. Safety Endpoints .......................................................................................................8
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints................................................................................................9
6.4. Covariates..................................................................................................................9
7. HANDLING OF MISSING VALUES ..................................................................................9
7.1. Concentrations Below the Limit of Quantification.................................................10
7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
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7.3. Pharmacokinetic Parameters ...................................................................................10
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................10
8.1. Statistical Methods ..................................................................................................10
8.2. Statistical Analyses .................................................................................................11
8.3. Safety Analysis........................................................................................................12
8.3.1. Treatment and Disposition of Subjects.......................................................12
8.3.2. Demographic and Clinical Examination Data............................................12
8.3.3. Discontinuation(s).......................................................................................12
8.3.4. Adverse Events...........................................................................................12
8.3.5. Laboratory Data..........................................................................................12
8.3.6. Vital Signs Data..........................................................................................13
8.3.7. ECG Data....................................................................................................13
8.3.8. Other Safety Data .......................................................................................13
8.3.9. Concomitant Treatments.............................................................................13
8.3.10. Screening and Other Special Purpose Data ..............................................13
9. REFERENCES ....................................................................................................................14
LIST OF TABLES
Table 1.
Noncompartmental PK Parameters.........................................................................9
Table 2.
PK Parameters to be Summarized Descriptively by Treatment ...........................11
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PFIZER CONFIDENTIAL
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None. This is the initial Statistical Analysis Plan, version 1.0.
2. INTRODUCTION
In order to facilitate development of ATM-AVI in China, this study will investigate the safety, 
tolerability and the PK after single and repeated IV infused doses of ATM with AVI to 
healthy male and female  Chinese subjects.  This study will be the first time to investigate PK 
profile of ATM when dosed in combination with AVI, evaluate the PK exposure of ATM when 
combined with AVI, and determine safety and tolerability of this combination in Chinese 
subjects.
2.1. Study Design
This is a Phase 1, single center, open label study to assess the PK, safety and tolerability of 
AVI in combination with ATM (ATM-AVI) administered as single and repeated IV infusion of 
doses in healthy Chinese subjects. 
Twelve (12) healthy male and female Chinese subjects, aged 18 to 55 years, inclusive, will be 
recruited in this study in order to have at least 9 subjects complete the study procedures and 
have sufficient post-dose PK samples to calculate PK parameters.
The study will consist of a screening phase, a treatment phase and a follow-up phase.  All 
screening evaluations will occur within up to 28 days prior to administration of the
investigational product.  All subjects will provide informed consent and undergo screening
evaluations to determine their eligibility.  Eligible subjects will check into the Clinical
Research Unit (CRU) on Day -1.  Subjects will receive a 3 hour IV infusion of 1500 mg ATM 
plus 500 mg AVI as a single dose on Day 1.  Afterwards, subjects will receive a 
loading/extended loading dose followed by multiple doses of ATM-AVI IV infusion. The 
loading dose in this study is 500 mg ATM plus 167 mg AVI infused over a 30 minute period, 
immediately followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI over a 
3 hour period. Three (3) hours after the extended loading dose is completed, a maintenance 
dose of 1500 mg ATM and 500 mg AVI will be infused over 3 hours and administered q6h.
Serial blood samples and urine samples at specified intervals will be collected pre-dose and 
post-dose. 
Detailed study activities are described in the SOA of the study protocol.
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2.2. Study Objectives
Primary Objective(s):
•
To investigate the PK of AVI administered in combination with ATM (ATM-AVI);
•
To investigate the PK of ATM administered in combination with AVI.
Secondary Objective(s):
•
To investigate the safety and tolerability of ATM-AVI as single and repeated 
intravenous (IV) infusions in healthy Chinese subjects.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned for this study.  However, as this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or supporting clinical development. 
Final analysis will follow the official database release.  As this will be an open-label study, 
there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all subjects treated with study drug who have
at least 1 ATM and AVI concentration measurement.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all subjects treated with study drug who
have at least 1 of the PK parameters of interest.
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5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
Safety analysis will be conducted in safety analysis set, ie, all subjects who received at least 
one dose of investigational product (ATM-AVI).
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are not treated.
If a subject takes a treatment that is not consistent with the treatment they are assigned to, for 
example takes a treatment out of sequence or takes the same treatment twice, then they will 
be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Treatment Assignment
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
Deviations Assessed Post-Treatment Assignment
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events;
•
laboratory data;
•
vital signs data;
•
ECG results.
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6.3. Other Endpoints
6.3.1. PK Endpoints
Blood and urine samples for PK analysis of aztreonam and avibactam will be taken according 
to the Schedule of Activities in the protocol.
The following PK parameters will be calculated for aztreonam and avibactam (if possible) 
from the concentration-time data using standard noncompartmental methods (see the protocol
Section 9.3 for detailed definition and method of determination):
Table 1.
Noncompartmental PK Parameters
Matrix
PK Parameter
Analysis 
Scale
Aztreonam and Avibactam
Plasma
AUC(0-6), AUC(0-24), 
AUC0-24,ss
ln
D
AUClast, AUC0-τ, 
AUCinf 
ln
D
Cmax, Cmin
ln
D
Tmax
R
D
t1/2
*
R
D
CL*
ln
D
Vss, VZ
*
ln
D
RCmax, RAUC
R
D
Urine
CLr
ln
D
Ae0-τ
R
D
Ae0-τ (%)
R
D
Key: D=displayed with descriptive statistics, ln=natural-log transformed, R=raw 
(untransformed), *=if data permits, ss=steady state. 
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
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7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented with ≥3 evaluable measurements.  
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
No formal statistical inference or statistical modeling will be performed. All PK parameters
will be summarized descriptively. 
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8.2. Statistical Analyses
The following PK parameters will be summarized descriptively:
Table 2.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
AUC(0-6), AUC(0-24), 
AUC0-24,ss,
AUClast, AUC0-τ, 
AUCinf,
Cmax, Cmin,
CL, CLr,
Vss, VZ
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
RCmax, RAUC,
t1/2, Ae0-τ, Ae0-τ%
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.
Box and whisker plots for individual subject aztreonam and avibactam parameters (AUC(0-6),
AUC(0-24), AUC0-24,ss, AUC0-τ, AUClast, AUCinf, Cmax, and Cmin) will be presented overlaid with 
geometric means.
Supporting data from the estimation of t½ and AUCinf will be listed by analyte:  terminal 
phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); the 
percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of time 
points used in the estimation of kel.  This data may be included in the appendix of clinical 
study report.
Concentrations will be listed and summarized descriptively by PK sampling time for Day 1 
and Day 4.  Summary profiles (means and medians) of the concentration-time data will be 
plotted for Day 1 and Day 4.  
Presentations for aztreonam and avibactam concentrations will include:
•
a listing of all concentrations sorted by subject ID, Day 1 and Day 4, and nominal 
time postdose.  The concentration listing will also include the actual times.  
Deviations from the nominal time will be given in a separate listing.
•
a summary of concentrations by Day 1 and Day 4, nominal time postdose, where the 
set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the 
lower limit of quantification.
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•
median concentrations time plots (on both linear and semi-log scales) by Day 1 and 
Day 4 against nominal time postdose.
•
mean concentrations time plots (on both linear and semi-log scales) by Day 1 and 
Day 4  against nominal time postdose.
•
individual concentration time plots (on both linear and semi-log scales) by Day 1 and 
Day 4 against actual time postdose (there will be separate spaghetti plots per scale).
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables will be produced to evaluate any potential risk associated with the 
safety and toleration of administering aztreonam and avibactam.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
8.3.5. Laboratory Data
Laboratory data will be listed and summarized in accordance with the sponsor reporting 
standards.
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8.3.6. Vital Signs Data
The baseline measurement is the predose measurement at hour 0 taken on Day 1.
For each planned timepoint, baseline values and change from baseline values will be 
summarized with descriptive statistics (using sponsor default standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the predose measurement at hour 0 taken on Day 1.
For each planned timepoint, baseline values and change from baseline values will be 
summarized with descriptive statistics (using sponsor default standards).
These data will be listed in accordance with the sponsor reporting standards.
The average of the replicate readings collected for assessment times will be calculated prior 
to summarizing the data across subjects.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
Pregnancy test, HIV, HepBsAg, HepBcAb, HCVAb testing, and History of tobacco, illegal 
drug and alcohol use will be obtained at Screening.
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9. REFERENCES
None.
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SAP_001.pdf: 
Aztreonam-Avibactam
C3601007
Final Protocol Amendment 1, December 31st, 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE I, SINGLE CENTER, OPEN-LABEL STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
AZTREONAM-AVIBACTAM ADMINISTERED AS SINGLE AND REPEATED 
INTRAVENOUS DOSES IN HEALTHY CHINESE PARTICIPANTS
Investigational Product Number:
PF-06947387
Investigational Product Name:
Aztreonam-Avibactam
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
C3601007
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Aztreonam-Avibactam
C3601007
Final Protocol Amendment 1, December 31st, 2020
PFIZER CONFIDENTIAL
Page 2
Document History
Document
Version 
Date
Summary of Changes and Rationale
Amendment
1
December 
31st, 2020
This amendment incorporates the investigator’s comments, 
protocol template revisions and content in previous PACL
(20200701).
Added Section 1. Protocol Summary and modified the 
section number and section sub-title in the following 
section for consistency with the current protocol template, 
and modified related hyperlink(s). 
Changed "subjects" to "participants" consistency with 
current protocol template. 
Modified the abbreviation of “hepatitis B core Antibody” 
as “HBcAb”, and the “hepatitis B surface antigen” as 
“HBsAg” for consistency with current protocol template. 
Modified the description of PK parameters for consistency
with current Pfizer standard. 
Section 1: 1) Added Section 1.1 Synopsis and Section 1.2 
Schema; 2) Schedule of activities: modified the “follow-up 
visit” date format to "Day 28+7" and added a footnote “l” 
to clarify protocol requirement; added a pregnancy test at 
Day 5/Early termination/discontinuation and pregnancy 
test method changed to serum or urine β-hCG test; added
time window requirement for ECG test is f15 minutes
and for Vital signs test is f10 minutes; modified some
other details in footnote e, f, h, i, j to clarify protocol 
requirements; Added another column "Early 
termination/Discontinuation" and another footnote m for 
consistency with current protocol template; 3) 
Pharmacokinetic Sampling Schema: Added footnote b to 
clarify maintenance dose administration frequency; Added
footnote i on the urine collection time points on Day 1 and 
Day 4 to avoid confusion; Added “and on Day 4, 
approximately 10 mL of pre-dose urine will be collected
before the final dose administration.” in footnote i; 
clarified the usage of pre-dose blood or urine PK sample as
“evaluation of the matrix effect on the bioanalyticalmethod 
and validation” in footnote c and i.
Section 2: 1) Added Section 2.1 study rationale; 2) Deleted
the detailed version number of IB, and changed to “current 


Aztreonam-Avibactam
C3601007
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PFIZER CONFIDENTIAL
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Version 
Date
Summary of Changes and Rationale
version” in Section 2.2 and Section 2.3.2 to align with IB 
updates; 3) Updated key conclusions of study Phase 2a
study D4910C00009/C3601001in Section 2.3 according to 
current version IB, because this study has been completed; 
4) Supplemented some study design rationale and dose 
selection rationale in Section 2.4; 5) Added Section 2.5 
Benefit/Risk Assessment according to current version of
IB for consistency with current protocol template. 
Section 3: Modified the wording in primary objective for 
clarity: “to investigate the PK profile of ATM and AVI 
after single and repeated IV infused doses of ATM-AVI”
Section 4: 1) Modified subtitle and reference section 
information in Section 4.1 for consistency with current 
protocol template; 2) Added Section 4.4.1"End of study 
definition"; 3) Modified "Adverse Events" to "Occurrence 
of an AE or any other condition posing a risk to a 
participant or jeopardizing a safe continuation of the study 
treatment for the respective participant (as judged by the 
investigator, and/or the national coordinators, and/or the 
Medical Monitor and the Study Sponsor)." in stopping 
rules.
Section 5.1, modified the inclusion criteria detailed 
requirements according to investigator's comments and 
current protocol template requirements: 1) Added the 
requirement for enrolled female and male participants 
number proportion in criteria 1; 2) Modified the healthy 
participants criteria, changed "full physical examination, 
including BP and PR" to "physical examination, vital 
signs". 3) Deleted the detail description in female 
childbearing potential in Section 5.1 and added "Refer to 
Appendix 4 for reproductive criteria for male (Section 
10.4.1) and female (Section 10.4.2) participants.". 4)Added
requirement "(both not inclusive)" after "Body mass index 
(BMI) of 17.5 to 30.5 kg/m2". 5) Modified the wording on 
criteria 5 related to signing an ICD for consistency with 
current protocol template. 
Section 5.2, modified the exclusion criteria detailed 
requirements according to investigator's comments and 
current protocol template requirements: 1) Modified
criteria 5 related to alcohol abuse or bringe drinking. 2) 


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Summary of Changes and Rationale
Deleted "including those that are known to cause PK drug 
interaction." in criteria 6 because the known cause PK drug 
interaction drug is already listed in criteria 18; 3) Separated
exclusion criteria 10 into 2 items, one is the disease that
affects ADME of ATM-AVI, and the other one is 
“Participant has known Clostridium difficile associated 
diarrhea.”, for clarity. 4) Added a sentence"CLCR will be 
calculated when the participants are selected according to 
exclusion criteria in the SoA. " in criteria 12 according to 
investigator's requirement. 5) Added more information
related to baseline 12-lead ECG procedure in criteria 13 for 
consistency with current protocol template. 6) Deleted
"liver function and coagulation tests after 48 hours. If the 
results still greater than 1.0×ULN," according to 
investigator's comments in criteria 14. 7) Modified the vital
signs examination requirement in criteria 15 according to 
investigator's comments in criteria 15. 8) Added the 
"Hepatitis B vaccination is allowed." in criteria 23 per 
current protocol template. 9) Modified the description in 
criteria 26 for consistency with the current protocol 
template. 10)Added the definition of 
allergy/Hypersensitivity in exclusion criteria 2, and added
the specific contents of dietary supplements in criteria 18 
according to ethic committee comments. 
Section 5.3 and Section 5.4: 1) Deleted the time 
requirement for breakfast on Day 2, and lunch/dinner on 
Days 1, 2, and 4 according to investigator’s requirement in 
Section 5.3.1. Because the infusion time is long and the 
food has limited impact on ATM-AVI, so this modification 
is convenient for site’s operation. 2) Modified the specific 
description for meals to "the meals for all participants 
should be standardized meals provided by CRU" in Section 
5.3.1. 3) Deleted the requirement for "Energy drinks 
containing taurine or glucuronolactone eg, Red Bull from 
72 hours before follow-up." in previous Section 4.3.2
(currently in Section 5.3.2 )for the final follow-up can be
via phone call. 4) Modified the description in Section 5.3.4 
and added Appendix 4 for contraception requirement for 
consistency with current protocol template. 5) Added
Section 5.4 screen failures based on current protocol 
template. 6) Moved "Sponsor's Qualified Medical 


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Personnel" into Section 10.1.10 for consistency with
current protocol template.
Section 6: 1) Deleted the Investigational product 
manufacturer requirement in Table 1, because the actual 
manufacturer may be changed. 2) Modified the 
administration specific time requirement in Section 6.2 and 
Table 2. Added "The single dose administration on Day 1 
as it needs to occur in the morning to allow 24 hours for 
sample collection prior to start of Day 2 dosing." to 
guarantee PK samples can be collected on time; added the 
infusion duration time window is "± 5 minutes" convenient
for site’s operation. 3) Integrated the Investigational 
product preparation, handling, storage and accountablility 
requirement in Section 6.3, added new requirement "A 
second staff member will verify the dispensing" according 
to current protocol template requirement. 4) Change the 
version of "Common Terminology Criteria for Adverse 
Events [CTCAE] v 4.03" to "v 5.0"; 5) Modified Sections
6, 6.4, 6.5, 6.6, 6.7 and 6.8 according to current protocol 
template. 
Section 7: Modified requirements related to 
"discontinuation of study intervention" in Section 7 
according to current protocol template. And deleted the 
section "study procedure" because the information has 
been covered in Schedule of Activities and Section 8. 
Section 8, was modified for consistency with current 
protocol template: 1) Added some general requirement for 
study assessment and modified the total blood sampling 
volume according to PACL; Added some detail 
requirements: 2) Modified to "pregnancy test may be urine 
or serum tests" and added another pregnancy test at the end 
of the study; 3) Modified the physical examination test 
requirement for consistency with current protocol template; 
4) Added “As much as possible, ” before “The same arm 
(preferably the dominant arm) will be used throughout the 
study.” according to investigator's comments; Added the 
requirement of “supine rest of 5 min” before BP test 
conduction; Added requirement of tympanic temperature 
measurement; 5) Changed the supine time before ECG test 
to 5 minutes; 6) Modified the time requirement to 
“Triplicate 12 lead ECGs will be obtained approximately 


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Document
Version 
Date
Summary of Changes and Rationale
within 2 to 5 minutes”; 7) Modified requirements related to 
AE and SAE in Section 8.3 for consistency with current 
protocol template; 8) Add Section 8.4 "Treatment of 
Overdose"; 9) Clarified the usage of pre-dose blood and 
urine samples and added time window for urine PK sample 
collection is 10% of nominal time interval in Section 
8.5.10) Modified Section 8.5 to Section 8.10 for 
consistency with current protocol template. 
Section 9: Modified data analysis and statistical method 
related requirements for consistency with current protocol 
template: 1) Added Section 9.1, Section 9.2 and Section 
9.3; 2) Some other modifications in Sections 9.4 to 9.6, for 
consistency with current protocol template and standard of 
PK parameters.Section 10: 1) Added Section 10 according 
to current protocol template requirement; for Section 10.2 
(Table 3), modified some detail requirements: 2)Added
additional option “carbondioxide combining power 
(CO2CP)” for total CO2 in the Chemistry safety laboratory 
tests; 3) Modified some detail requirements according to 
site practice and new protocol template: the blood sample 
volume in footnote f of Table 3, “7 mL” for serology at 
screening; added Investigators must document their review 
of each laboratory safety report; some additional wording 
for consistency with new protocol template; 4) Modified
and added new abbreviations in Section 10.7.
Updated typographical and clerical errors.
Original 
protocol
30 August 
2018
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
1. PROTOCOL SUMMARY...................................................................................................12
1.1. Synopsis ..................................................................................................................12
1.2. Schema ....................................................................................................................14
1.3. SCHEDULE OF ACTIVITIES...............................................................................15
2. INTRODUCTION ...............................................................................................................19
2.1. Study Rationale .......................................................................................................19
2.1.1. Indication....................................................................................................19
2.2. Background .............................................................................................................20
2.2.1. Metallo--Lactamases And Metallo--Lactam Resistant 
Gram-Negative Bacteria ..................................................................................20
2.2.2. Summary of Preclinical Information ..........................................................21
2.2.3. Human Experience......................................................................................21
2.3. Benefit/Risk Assessment.........................................................................................24
3. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
4. STUDY DESIGN.................................................................................................................26
4.1. Overall Design.........................................................................................................26
4.2. Scientific Rationale for Study Design.....................................................................26
4.3. Justification for Dose ..............................................................................................27
4.4. Stopping Rules ........................................................................................................28
4.4.1. End of Study Definition..............................................................................29
5. STUDY POPULATION......................................................................................................29
5.1. Inclusion Criteria.....................................................................................................30
5.2. Exclusion Criteria....................................................................................................30
5.3. Lifestyle Considerations..........................................................................................34
5.3.1. Meals and Dietary Restrictions...................................................................34
5.3.2. Alcohol, Caffeine, Tobacco and Others .....................................................34
5.3.3. Activity .......................................................................................................34
5.3.4. Contraception..............................................................................................34
5.4. Screen Failures ........................................................................................................35
6. STUDY INTERVENTION..................................................................................................35


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6.1. Study Intervention(s) Adiministered.......................................................................35
6.1.1. Dosage Form and Packaging ......................................................................35
6.1.2. Administration............................................................................................36
6.2. Preparation/Handling/Storage/Accountability ........................................................37
6.2.1. Preparation and Dispensing........................................................................38
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................38
6.3.1. Allocation to Study Intervention ................................................................38
6.4. Study Intervention Compliance...............................................................................38
6.5. Concomitant Therapy..............................................................................................38
6.6. Dose Modification...................................................................................................39
6.7. Intervention After the End of the Study..................................................................39
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................39
7.1. Discontinuation of Study Intervention ....................................................................39
7.2. Participant Discontinuation/Withdrawal From the Study.......................................40
7.2.1. Withdrawal of Consent...............................................................................40
7.2.2. Participant Replacement.............................................................................41
7.3. Lost to Follow up ....................................................................................................41
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................41
8.1. Efficacy Assessment ...............................................................................................43
8.2. Safety Assessment...................................................................................................43
8.2.1. Clinical Safety Laboratory Assessments ....................................................43
8.2.2. Pregnancy Testing ......................................................................................44
8.2.3. Physical Examinations................................................................................44
8.2.4. Weight and Height......................................................................................44
8.2.5. Vital Signs ..................................................................................................44
8.2.6. Electrocardiogram.......................................................................................45
8.3. Adverse Events and Serious Adverse Events..........................................................46
8.3.1. Time Period for Collecting AE/SAE Information......................................46
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................47
8.3.1.2. Recording Non-Serious AEs and SAEs on the CRF.................47
8.3.2. Method of Detecting AEs and SAEs ..........................................................47


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8.3.3. Follow-up of AEs and SAEs.......................................................................47
8.3.4. Regulatory Reporting Requirements for SAEs...........................................48
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................48
8.3.5.1. Exposure During Pregnancy......................................................48
8.3.5.2. Exposure During Breastfeeding ................................................50
8.3.5.3. Occupational Exposure .............................................................50
8.3.6. Cardiovascular and Death Events...............................................................50
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................50
8.3.8. Adverse Events of Special Interest.............................................................51
8.3.8.1. Lack of Efficacy........................................................................51
8.3.9. Medical Device Deficiencies......................................................................51
8.3.10. Medication Errors.....................................................................................51
8.4. Treatment of Overdose............................................................................................52
8.5. Pharmacokinetics ....................................................................................................53
8.5.1. Plasma for Analysis of ATM-AVI .............................................................53
8.5.2. Urine for Analysis of ATM-AVI................................................................54
8.6. Pharmacodynamics..................................................................................................54
8.7. Genetics...................................................................................................................54
8.8. Biomarkers ..............................................................................................................54
8.9. Immunogenicity Assessments.................................................................................54
8.10. Health economics ..................................................................................................54
9. STATISTICAL CONSIDERATIONS ................................................................................55
9.1. Statistical Hypotheses .............................................................................................55
9.2. Sample Size Determination.....................................................................................55
9.3. Analysis Sets ...........................................................................................................55
9.4. Statistical Analyses .................................................................................................56
9.4.1. General Considerations...............................................................................56
9.4.2. Pharmacokinetics Endpoints.......................................................................56
9.4.2.1. Plasma PK .................................................................................56
9.4.2.2. Urine PK....................................................................................58
9.4.3. Safety Endpoints.........................................................................................58


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9.5. Interim Analysis ......................................................................................................58
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............58
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................59
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............59
10.1.1. Regulatory and Ethical Considerations ....................................................59
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................59
10.1.2. Financial Disclosure .................................................................................60
10.1.3. Informed Consent Process ........................................................................60
10.1.4. Data Protection .........................................................................................61
10.1.5. Dissemination of Clinical Study Data ......................................................61
10.1.6. Data Quality Assurance ............................................................................62
10.1.7. Source Documents....................................................................................64
10.1.8. Study and Site Start and Closure ..............................................................64
10.1.9. Publication Policy.....................................................................................65
10.1.10. Sponsor’s Qualified Medical Personnel .................................................65
10.2. Appendix 2: Clinical Laboratory Tests .................................................................66
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................68
10.3.1. Definition of AE .......................................................................................68
10.3.2. Definition of SAE.....................................................................................69
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................70
10.3.4. Reporting of SAEs....................................................................................73
10.4. Appendix 4 Contraceptive Guidance ....................................................................75
10.4.1. Male Participant Reproductive Inclusion Criteria....................................75
10.4.2. Female Participant Reproductive Inclusion Criteria.................................75
10.4.3. Woman of Childbearing Potential ............................................................75
10.4.4. Contraception Methods.............................................................................76
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury ..........................................................78
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ...................................80
10.7. Appendix 7. Abbreviations ...................................................................................82


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11. REFERENCES ..................................................................................................................86
LIST OF TABLES
Table 1.
Identity of Investigational Product .......................................................................35
Table 2.
Treatment Schema ................................................................................................36
Table 3.
Safety Laboratory Tests........................................................................................66


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Study to Assess the Pharmacokinetics, Safety and Tolerability of 
Aztreonam-Avibactam in Healthy Chinese Participants.
Rationale: The purpose of the study is to investigate the PK characteristics, safety and 
tolerability of aztreonam-avibactam administered as single and repeated IV infusion of doses 
in healthy Chinese participants. Results from this study will be used to support clinical 
development of ATM-AVI in China and to support China registration.
Objectives and Endpoints
Primary Objective(s): 
Primary Endpoint(s): 

To investigate the PK profile of ATM and AVI after 
single and repeated IV infused doses of ATM-AVI.

For plasma concentration data, the PK parameters 
Cmax, AUC6, AUClast, AUC24, AUCinf for Day 1;
Cmax, AUCτ, AUClast, AUC24, AUC24,ss, AUCinf for 
Day 4;

For urine concentration data, the PK parameter CLr.
Secondary Endpoint(s):

For plasma concentration data, the PK parameters 
t1/2, Vss, Vz, CL, Tmax, Rac,Cmax, Rac.
Tertiary Endpoint(s):

For plasma concentration data, the PK parameters 
Cmin for Day 2, Day 3, and Day 4;

For urine concentration data, the PK parameters Aet, 
Aet%.
Secondary Objective(s): 
Secondary Endpoint(s): 

To investigate the safety and tolerability of 
ATM-AVI as single and repeated intravenous (IV)
infusions in healthy Chinese participants.

Safety and tolerability as assessed by adverse events
(AEs), physical examination, vital signs, ECGs, and
laboratory assessments.
Overall Design
This is a Phase 1, single center, single arm, open-label study to assess the PK, safety and
tolerability of ATM and AVI after single and repeated IV infusion of doses ATM-AVI in 
healthy Chinese participants. 


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Number of Participants
A maximum of approximately 12 healthy male and female Chinese participants will be 
enrolled to study intervention such that approximately 9 evaluable participants complete the 
study. 
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process.  Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Intervention Groups and Duration
All participants are scheduled to receive ATM-AVI single dose administration on Day 1 and 
repeated dose administration on Day 2 to Day 4 by IV infusion. 
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
All data analyses will be descriptive.
ATM and AVI PK parameters (Cmax, AUC6, AUClast, AUC24, AUCinf for Day 1, Cmax, AUCτ, 
AUC24, AUC24,ss, for Day 4, CLr, t1/2, Vss, Vz, CL, Tmax, Rac,Cmax, Rac, Aet, Aet%) will be 
summarized descriptively for Day 1 and Day 4. Cmin for Day 2, Day 3, and Day 4 will be 
summarized.
The plasma and urine concentration data will be listed and summarized descriptively by PK 
sampling time for Day 1 and Day 4. Summary profiles (means and medians) of the 
concentration-time data will be plotted for Day 1 and Day 4. Individual participant
concentration-time profiles will be also presented. For summary statistics and summary plots 
by sampling time, the nominal PK sampling time will be used; for individual participant plots 
by time, the actual PK sampling time will be used.
 
Safety data (AEs, vital signs, ECGs and laboratory data) will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate. 
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1.2. Schema


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1.3. SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENT 
AND PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with 
the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the participant.
Study Plan
Screening
Treatment phase
Follow-upl
Early
termination/
Discontinuation
Day
-28 to -2
-1
1
2
3
4
5
28+7 after 
last dose
Informed consenta
X
CRU confinement
X




X
Inclusion/exclusion criteria
X
X
Medical history 
X
X
Medication history
X
X
History of tobacco, illegal drug and 
alcohol use
X
X
Physical examination
Xb
Xc
Xd
Xm
Demography, height and weighte
X
X
Pregnancy testf
X
X
X
X
Contraception check
X
X
X
X
Serum FSHg
X
Urine drug testing
X
X
Safety laboratory (chemistry, hematology,
coagulation, and urinalysis)
X
X
X
X
X
X
12-lead ECGh
X
X
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
HIV, HBsAg, HBcAb, HCVAb testing
X
Single dose ATM-AVI administration (3 
hour infusion)
X


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Study Plan
Screening
Treatment phase
Follow-upl
Early
termination/
Discontinuation
Day
-28 to -2
-1
1
2
3
4
5
28+7 after 
last dose
ATM-AVI loading dose (30 min
infusion)
X
ATM-AVI extended loading dose (3 hour
infusion)
X
ATM-AVI maintenance dose (3 hour
infusion) q6h
X
X
X
PK blood sampling (see
PK sampling schema below)
X
X
X
X
X
X
PK urine sampling (see
PK sampling schema below)
X
X
X
Prior/Concomitant treatment(s)
X
→
→
→
X
X
Local tolerability
Assessmentj
X
X
X
X
X
X
Standardized mealsk
X
→
→
→
→
X
X
CRU discharge 
X
X
Serious and non-serious adverse event 
monitoring
X
→
→
→
→
→
→
X
X
Abbreviations:  = ongoing/continuous event; ATM = aztreonam; AVI = avibactam; CRU = clinical research unit; ECG = electrocardiogram; FSH = follicle-stimulating 
hormone; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HIV = human immunodeficiency virus; PK = 
pharmacokinetic; q6h = every 6 hours.
a.
Informed consent must be obtained prior to undergoing any study specific procedure and may occur prior to the screening period which will be up to 28 days prior to 
administration of the investigational product.
b.
Conduct full physical examination, further examinations will be performed at the discretion of the investigator; if deferred, conduct limited physical examination at 
screening and the full physical examination should be performed on Day -1.
c.
Conduct full physical examination, if deferred from the screening visit, further examinations will be performed at the discretion of the investigator; otherwise, limited 
physical examination will be conducted.
d.
Limited physical examination.
e.
Collect demography, height and weight information at screening, and collect height and weight at Day -1. 
f.
Serum or urine beta-human chorionic gonadotropin (β-hCG) level for all female participants of childbearing potential.
g.
To be conducted for females who have achieved postmenopausal status, defined as cessation of regular menses for at least 12 consecutive months with no alternative 
pathological or physiological cause.
h.
Single 12-lead ECG will be done at screening and repeated if abnormal, see exclusion criterion 12 in Section 5.2 Single 12-lead ECG will also be done on Day -1. Perform 
triplicate baseline 12-lead ECG on Day 1 prior to dosing, single ECG will be performed at the end of infusion (withinf15 minutes) on Day 1. On Day 2, obtain single 


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Study Plan
Screening
Treatment phase
Follow-upl
Early
termination/
Discontinuation
Day
-28 to -2
-1
1
2
3
4
5
28+7 after 
last dose
12-lead ECG measurements at 0.5 hour after administration of loading dose infusion (withinf15 minutes). On Day 4, single ECG will be taken prior to last dose infusion 
and at the end of last dose (withinf15 minutes) infusion. On Day 5, single ECG will be taken at the end of treatment phase prior to blood sample collection.
i.
Vital signs include blood pressure (BP), pulse rate (PR) and body temperature.  Single BP should be taken with the participant in the supine position after the participant has 
been resting quietly for approximately 5 minutes.  On Day 1, vital signs will be taken prior to infusion, and only BP and PR at the end of infusion (withinf10 minutes).  On 
Day 2, vital signs (except body temperature) will be taken prior to loading dose infusion, and at the end of loading dose infusion (withinf10 minutes). On Day 3, vital 
signs will be taken prior to infusion (Second maintenance dose infusion on Day 3). On Day 4, vital signs (except body temperature) will be taken prior to last dose infusion, 
and at the end of last dose infusion (withinf10 minutes). On Day 5, vital signs will be taken at the end of treatment phase prior to blood sample collection.
j.
Assessment performed on Day 1 before the start of the infusion and at the end of the infusion; on Days 2 through 4 before the start and at the end of each infusion; and on 
Day 5 before blood sample collection.
k.
See section 5.3 or more details.
l.
Follow-up visit occurs on Day 28 (the visit time window is 28+7 days). Follow- up visit can be via telephone. 
m.
Full physical examination, if there is a new or open AE or clinically significant abnormal physical finding from the last visit. If there is no new or open AE or clinically 
significant abnormal physical finding from the last visit, a limited physical examination is needed. 


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Pharmacokinetic Sampling Schema 
Visit Identifier
Study Day
Day 1
Day 2
Day 3
Day 4
Day 5
Hours
0
2
3
3.25
3.5
4
5
6
8
12
16
0
0.5 3.5
6.5
12.5
ATM-AVI single dose
(3 hour infusion)
  X
ATM-AVI loading dose
(30 min infusion)a
X
ATM-AVI extended loading dose
(3 hour infusion)
Xa
ATM-AVI maintenance dose
(3 hour infusion) q6hb
Xb
→b
→b
Xb
Blood sampling for ATM-AVI PK
Xc
X
Xd
X
X
X
X
X
X
X
X
Xc
Xe
Xf
Xg
Xc
Urine sampling for ATM-AVI PKi
Xi
→
→
→
→
→→
→
→
Xi
Xi
Abbreviation: →= ongoing/continuous event; ATM = aztreonam; AVI = avibactam; IV = intravenous; PK = pharmacokinetic q6h = every 6 hours. 
a.
Loading dose and extended loading dose will be prepared in one infusion bag with an infusion rate change after the first 30 minutes. 
b.
Total of 8 maintenance doses administration from Day 2 to Day 4, two maintenance doses on Day 2, four maintenance doses on Day 3, two maintenance doses on Day 
4.  
c.
Pre-dose sample collection. Only on Day 1, the pre-dose blood sample is to be collected within 1 hour before infusion with volume of about 10 mL (about 6 mL will 
be used for evaluation of the matrix effect on the bioanalytical method and validation as appropriate, and 4 mL for pharmacokinetics analysis). On Day 2, the 
pre-dosesample collection is the 24 hour sample for Day 1. On Day 5, the sample collection is the 24 hour sample for Day 4.
d.
Collect PK blood sample within 15 min before IV infusion stop.
e.
Collect PK blood sample within 5 min before the end of the loading dose IV infusion.
f.
Collect PK blood sample within 15 min before the end of extended loadng IV infusion.
g.
On Day 4, collect 
blood sample for PK analysis 
; after administration of final infusion, collect blood 
samples at 2, 3 (within 15 min before end of IV infusion), 3.25, 3.5, 4, 5, 6, 8, 12 and 16 hours.
h.
 
i.
Urine will be collected on Day 1 and Day 4, pre-dose and after dosing during collection periods of 0-2, 2-4, 4-6, 6-8 and 8-12 hours. Instruct participant to void prior to 
administration of investigational product.  On day 1, approximately 20 mL of pre-dose blank urine will be colletected for bioanalytical method evaluation and 
validation as appropriate.  On Day 4, approximately 10 mL of pre-dose urine will be collected before the final dose administration. Instruct participant to void into the 
collection container at the end of each collection period.
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2. INTRODUCTION
Aztreonam (ATM), with more than 30 years of use worldwide, is an established injectable
antibiotic indicated for the treatment of various infections caused by susceptible 
Gram-negative bacteria. It has a unique monocyclic -lactam nucleus that makes it 
structurally different from other -lactam antibiotics (including penicillins and 
cephalosporins), as well as several chemical side groups that interfere with degradation by 
metallo--lactamases (MBL). In this way, activity against MBL (Class B) producing 
pathogens is possible, although potential inactivation by Class A, C, or D -lactamases 
remains problematic.
Avibactam (AVI) is a novel, non β-lactam, β-lactamase inhibitor of a broad spectrum of 
enzymes, including Ambler Class A extended spectrum β-lactamases (ESBL), Class A 
Klebsiella pneumoniae carbapenemase (KPC), and Class C (AmpC) enzymes, and some 
Class D enzymes, notably oxacillinase-48 (OXA-48), a problematic carbapenemase in the 
European Union (EU) and Middle East. AVI’s -lactamase inhibition occurs through 
formation of a covalent bond between AVI and enzyme. Alone, AVI has no meaningful 
antibacterial activity; rather, its beneficial effect in combination with ATM occurs by 
rendering inactive those enzymes that inactivate ATM.
Together, ATM and AVI have the potential to address the unmet need for safe and effective
agents to combat MBLs and other problematic -lactamases, such as ESBLs and KPCs, 
which may be co-expressed with MBLs and contribute to a multiple-drug resistant (MDR)
phenotype.
2.1. Study Rationale 
The purpose of the study is to investigate the Pharmacokinetic characteristic, safety and 
tolerability of aztreonam-avibactam administered as single and repeated IV infusion of doses 
in healthy Chinese participants.
Results from this study will be used to support clinical development of ATM-AVI in China 
and to support China registration.
2.1.1. Indication
The combination product referred to as ATM-AVI is being developed for the treatment of 
serious infections caused by susceptible Gram-negative bacteria for which there are limited 
or no treatment options. These include infections caused by MBL-producing pathogens that 
can also co-produce ESBLs, KPC and/or AmpC -lactamases. Relevant to the clinical 
development of the study therapy is the fact that ATM-AVI has shown excellent activity in 
pre-clinical studies against a broad range of Gram-negative pathogens, including several of 
the most problematic MDR pathogens (see current aztreonam-avibactam Investigator’s 
Brochure for further details).


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2.2. Background 
2.2.1. Metallo--Lactamases And Metallo--Lactam Resistant Gram-Negative Bacteria
The incidence of MDR bacteria is increasing worldwide. This has become a significant 
public health threat as there are fewer, or even sometimes no, effective antimicrobial agents 
available for infections caused by MDR bacteria.1,2 In particular, ongoing surveillance 
studies have demonstrated an increasing frequency of antibiotic resistance among 
Gram-negative pathogens. New antibiotics or combinations of existing antibiotics with 
resistance enzyme inhibitors are urgently needed to provide treatment options for patients 
with infections known or suspected to be caused by MDR Gram-negative pathogens.3
One of the most common resistance mechanisms in Gram-negative pathogens is the 
production of ESBLs.1 Infections due to ESBL-producing organisms present a major 
therapeutic dilemma especially as isolates are also increasingly expressing resistance to other 
first line agents such as fluoroquinolones or aminoglycosides, leaving few available options 
for therapy. ESBL are found in a significant percentage of Enterobacteriaceae (including E. 
coli, Klebsiella pneumoniae, Enterobacter, Citrobacter, Proteus, Morganella morganii, 
Serratia marcescens, and Shigella dysenteriae). They can also be found in Pseudomonas 
aeruginosa although they do not contribute significantly to resistance in this organism.
Carbapenems are the preferred treatment option for serious infections due to such MDR 
Gram-negative pathogens but carbapenemases have steadily accumulated in the 
Enterobacteriaceae with the epidemiology of carbapenem resistant Enterobacteriaceae 
(CRE) characterized by large heterogeneity in genotypes (with >20 reported resistance gene 
families, such as New Delhi Metallo-β-lactamase (NDM), KPC, Verona Integron encoded
metallo--lactamase (VIM, a type of Class B β-lactamase), OXA-48.4 The expression of 
MBLs such as VIM and NDM-1, in addition to other resistance mechanisms, is of increasing 
concern as the treatment options are extremely limited.
A particular threat is posed by a family of MBLs known as NDM. NDM-1-producing 
pathogens have already been reported in a number of countries outside of the regions where 
the first producing strains were identified in 2009 (India, Pakistan, Sweden, UK), including 
Australia, Singapore, Taiwan, and the United States. The recent emergence of NDM-1 has 
caused particular concern in the international infection community, as the genetic element 
encoding NDM-1 is able to rapidly spread amongst bacteria in both community and hospital 
settings.
The spread of resistance due to the ESBL cefotaximase-M (CTX-M, a type of Class A 
β-lactamase) may provide a useful model for the spread of NDM-1 as the blaNDM-1 gene is 
found on the same promiscuous ST131 clone as CTX-M. In particular, organisms that 
produce NDM-1 have spread geographically and are now seen in community-acquired 
infections, similar to the spread of CTX-M, which has reached endemic levels in much of 
Asia, Europe, and South America. These pathogens have become endemic in the Indian 
subcontinent, where they have been detected in the environment.5


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A representative example of a serious Gram-negative infection includes complicated 
intra-abdominal infection (cIAI). Most commonly, Enterobacteriaceae are isolated in cIAI. 
For therapy, the current Guidelines of the Infectious Diseases Society of America6
recommend surgical intervention along with broad spectrum single agent 
(β-lactam/β-lactamase inhibitor, carbapenem) or combination antibiotic regimens 
(metronidazole plus cephalosporin or aztreonam or fluoroquinolone). Specific regimens are 
recommended for higher risk patients with severe or postoperative nosocomial 
intraabdominal infections where resistant pathogens such as Enterococcus spp. or 
Pseudomonas aeruginosa may occur.
The combination product ATM-AVI is being developed for intravenous (IV) treatment of 
serious infections caused by Gram-negative pathogens producing MBLs in addition to other 
β-lactamases. Commonly, such organisms termed MDR show non-susceptibility to at least 
3 classes of antibiotics.
2.2.2. Summary of Preclinical Information
The preclinical toxicological evaluation of AVI comprised single- and repeat-dose toxicity 
studies of up to 3 months duration in rats and dogs, studies to assess genetic and reproductive 
toxicology (male and female fertility in rats, embryo-foetal development in the rat and 
rabbit), local tolerance studies, an in vitro phototoxicity study, and immunotoxicology and 
hemolytic-potential studies. These studies show that AVI is well tolerated in preclinical 
species and is not associated with target organ toxicity with the exception of local tolerance 
issues when administered via a peripheral vein. These local tolerance issues are not seen 
when AVI is administered intravenously via a central vein in surgically prepared animals.
For further information please refer to the current aztreonam-avibactam Investigators 
Brochure.
2.2.3. Human Experience
Aztreonam alone is an established injectable antibiotic indicated for the treatment of various 
infections caused by susceptible Gram-negative bacteria. Additional information regarding 
ATM is available in the approved prescribing information.7
The serum half-life of aztreonam averaged 1.7 hours (1.5 to 2.0 hours) in participants with
normal renal function, independent of the dose. In healthy participants, based on a 70 kg 
person, the serum clearance (CL) was 91 mL/min and renal clearance (CLr) was 56 mL/min; 
the mean apparent volume of distribution at steady-state (Vss) averaged 12.6 L, 
approximately equivalent to extracellular fluid volume. Intravenous (IV) administration of a 
single 500 mg or 1000 mg dose of aztreonam every 8 hours (q8h) for 7 days to healthy 
participants produced no apparent accumulation of aztreonam or modification of its 
disposition characteristics; serum protein binding averaged 56% and was independent of 
dose.
To date, human experience with AVI comes from Phase I to Phase III studies in which AVI 
was administered either as a single agent or in combination with other antibiotics 


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(ceftazidime or ceftaroline) in other clinical development programmes. From these 
programmes, the clinical pharmacology of AVI has been well characterised.
Avibactam demonstrated approximately linear pharmacokinetics (PK) across the dose range
studied for single IV administration with a 30-min infusion time (50 to 2000 mg avibactam
alone) and time-invariant PK across the dose range studied for multiple IV doses with a
30 min infusion time (500 to 1000 mg avibactam). Following IV administration, the
maximum observed plasma concentration (Cmax) of avibactam is achieved at the end of 
infusion, after which plasma concentrations decline in a multi-exponential manner. The 
half-life of avibactam ranged from 1.4 to 3 hours and resulted in little or no accumulation 
upon repeated administration (q8h for up to 10 days).
At the time of developing this Clinical Study Protocol, 92 healthy volunteers have been 
dosed with the investigational medicinal product (ie, ATM-AVI, placebo or ATM-AVI
separately), in a Randomised, Double-blind, 3-Part Phase I study in Healthy Young and 
Elderly Participants (D4910C00001). Key aztreonam-avibactam PK findings in this Study 
are as follows:

Comparison of exposure parameters (Cmax and area under the curve [AUC]) between 
the combination or individual therapy (ie, ratio of aztreonam-avibactam/aztreonam 
and aztreonam-avibactam/avibactam) in a statistical model (not powered) produced
estimates and 90% confidence intervals [CI]s which indicated that single-dose PK of 
aztreonam or avibactam was not affected when it was co-administered compared to 
separate administrations.

Systemic exposure of both avibactam and aztreonam increased in a dose-proportional 
manner in the studied dose range, following multiple dosing exposure of both 
aztreonam and avibactam; it was similar on Day 1 compared to Day 11, showing 
there was minimal accumulation and providing supportive evidence of a lack of 
drug-drug interaction.

Data indicate avibactam displays approximately linear PK over the studied dose range 
(375 to 600 mg) following multiple doses administered as a 1- to 3-hour infusion 
every 6 hours (q6h) in healthy young participants.

Consistent plasma PK and urinary excretion data were obtained for aztreonam
(1500 to 2000 mg) and avibactam (375 to 600 mg) administered alone or in
combination (1 to 3 hours IV infusion) after single doses and multiple doses. No drug 
accumulation was observed and linear PK was observed for both aztreonam and 
avibactam. Renal clearance accounted for the most part of plasma clearance,
indicating urinary excretion of unchanged drug as the primary elimination pathway
for both aztreonam and avibactam.

At steady state (Day 10 of dosing q6h) statistical comparison (analysis of variance
[ANOVA]) showed a difference in PK of avibactam when it was co-administered 
with aztreonam in elderly versus young participants (aztreonam area under the curve 


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at steady-state [AUCss] increased by 22.6%; observed maximum plasma 
concentration at steady state (Css,max) increased by 15.8% and observed minimum 
plasma concentration at steady state (Css,min) was increased by 54.4% in elderly 
participants). Corresponding changes were observed for avibactam where AUCss
increased by 32.7%, Css,max increased by 31.1% and Css,min increased by 74.2% in 
elderly compared to young participants. Post-hoc modeling suggested this may be 
related to difference in renal function in these patients.

In cohorts of 8-10 patients, the proportion of healthy volunteers who developed 
transaminase excursions decreased after reduction of both of aztreonam and 
avibactam doses, and extension of the infusion time. Post-hoc PK modeling of 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by exposure 
did not suggest a relationship between avibactam concentration and ALT increases.
A Phase 2a study D4910C00009/C3601001 was completed to investigate the PK, safety, and 
tolerability of ATM-AVI in patients with a serious bacterial infection (ie, cIAI) and to 
support dose selection for the Phase 3 studies. Assessment of treatment outcome was a 
secondary objective. 34 adult patients with cIAI and requiring surgical intervention were
treated with ATM-AVI in this single-arm study. Key aztreonam-avibactam PK findings in 
this study are as follows:

Following the end of a 3 hour infusion of aztreonam-avibactam maintenance dose 
regimen on Day 4 (steady-state), aztreonam and avibactam plasma concentrations 
declined with a mean t½ (within the 6 hour dosing interval) of 2.3 to 2.8 and 1.8 to 2.2 
hours, respectively. Geometric mean Vss and CL were approximately 20 L and 6.4 
L/h, respectively for aztreonam and 23.7-26.0 L and 10.1-10.5 L/h, respectively for 
avibactam.

Exposures of aztreonam and avibactam achieved in the cIAI patients were consistent 
with the predicted exposures (Cmax and AUC24,ss) for both avibactam dose groups 
based on the updated population PK models used to define the doses for Study 
D4910C00009/C3601001.

Since the population PK models performed well, it gives assurance that the exposures 
for the dosing regimens for patients with moderate and severe renal impairment, are 
adequately well predicted.
Both avibactam and aztreonam were shown to be a substrates of the human organic anion
transporter (OAT) proteins OAT1 and OAT3.
In various Phase 1/2a studies, it has been shown that there are no PK interactions between
ceftazdime (CAZ) and AVI, CAZ-AVI and metronidazole, ceftaroline and avibactam, or
aztreonam and avibactam, which validates the use of data from these individual components
to support the ATM-AVI program.


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Based on the mechanisms clearance summarized above, there are no ethnic associated 
differences in clearance expected.
In the completed Phase 1 study for ATM-AVI in healthy participants (Study D4910C00001),
ATM-AVI was considered well tolerated, with a safety profile similar to that expected with
aztreonam monotherapy. The most common adverse effects (AEs) reported in the ATM-AVI 
treatment arms were headache, liver function test (LFT) abnormal, diarrhea, and 
infusion/cannula site pain/reaction, which are all expected events for aztreonam. Elevations 
in liver transaminases were seen in a number of healthy participants who received aztreonam 
in combination with avibactam. None of the liver transaminase elevations was associated 
with signs or symptoms of hepatic dysfunction, and all cases rapidly resolved after cessation 
of therapy.
In the completed Phase 2a study (Study D4910C00009/C3601001), the overall observed  
patterns of AEs is in line with that described for aztreonam alone in the UK summary of  
product characteristics (SmPC) and United States Package Insert(USPI) for AzactamTM. 
Based on the available safety and efficacy data for ATM-AVI, the expected benefit-risk 
profile of the medicinal product remains favorable, and supports the further development of 
the compound in patients with serious infections.  
Additional information for this combination may be found in the single reference safety 
document (SRSD), which for this study is the ATM-AVI Investigator’s Brochure (IB).
2.3. Benefit/Risk Assessment
ATM-AVI is not expected to provide any clinical benefit to healthy participants.  This study 
is designed primarily to generate PK, safety and tolerability, and pharmacokinetic data for 
further clinical development.
Aztreonam has been in use worldwide for more than 30 years, and its safety profile is well 
characterized.  Preclinical toxicity and safety profiles for avibactam, along with early clinical 
findings, suggest no serious liabilities with avibactam alone or when used in combination 
with other antibiotics.
Increases in transaminase levels are expected for ATM-AVI on the basis of the aztreonam 
labeling. In Section 4.8 (“Undesirable effects”) of the UK aztreonam SmPC9, AEs of 
transaminases increased are listed as expected events occurring at an unknown frequency and 
are considered to be “usually reversing during therapy and without overt signs or symptoms 
of hepatobiliary dysfunction”.  The LiverTox aztreonam monograph (US National Library of 
Medicine 2017) quotes the frequency from literature of asymptomatic serum 
aminotransferase elevations as common during high dose, IV aztreonam therapy (10% to 
38%).  Although data are limited at this stage of development in the ATM-AVI clinical 
program, the transaminase elevations observed in the completed Studies D4910C00001 and 
D4910C00009/C3601001 show a similar pattern to that expected with aztreonam 
monotherapy, ie, generally asymptomatic, mild, and reversible.  Post hoc exposure-response 
analyses for AST and ALT elevations in Study D4910C00001 do not suggest that avibactam 
contributes to the expected effect of aztreonam on AST and ALT.  


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Hepatitis and jaundice are also listed as expected events in the aztreonam SmPC occurring 
rarely (1/10,000 to <1/1000). Drug-induced liver injury is considered an important 
potential risk for ATM-AVI.
While increases in transaminase levels are not currently considered expected adverse drug 
reactions (ADRs) with avibactam alone, increases in transaminase levels are noted as 
expected ADRs for aztreonam and thus for ATM-AVI.  Currently, this finding does not alter 
the benefit-risk profile for ATM-AVI.  However, liver-related AEs and increases in serum 
transaminases will continue to be kept under close surveillance in the studies within the 
ATM-AVI clinical program and managed appropriately.  This will include risk mitigation 
measures in the individual clinical study protocols, such as liver function test monitoring and 
the use of individual patient liver-specific withdrawal criteria.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ATM-AVI may be found in the investigator’s brochure, which is 
the SRSD for this study.
3. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 

To investigate the PK profile of ATM and AVI after 
single and repeated IV infused doses of ATM-AVI.

For plasma concentration data, the PK parameters 
Cmax, AUC6, AUClast, AUC24, AUCinf for Day 1;
Cmax, AUCτ, AUClast, AUC24, AUC24,ss, AUCinf for 
Day 4;

For urine concentration data, the PK parameter CLr.
Secondary Endpoint(s):

For plasma concentration data, the PK parameters 
t1/2, Vss, Vz, CL, Tmax, Rac, Cmax, Rac.
Tertiary Endpoint(s):

For plasma concentration data, the PK parameters 
Cmin for Day 2, Day 3, and Day 4;

For urine concentration data, the PK parameters Aet, 
Aet%.
Secondary Objective(s): 
Secondary Endpoint(s): 

To investigate the safety and tolerability of 
ATM-AVI as single and repeated intravenous (IV)
infusions in healthy Chinese participants.

Safety and tolerability as assessed by adverse events
(AEs), physical examination, vital signs, ECGs, and
laboratory assessments.


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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, single center, open label study to assess the PK, safety and tolerability of 
ATM and AVI after single and repeated IV infusion of doses ATM-AVI in healthy Chinese 
participants. 
Twelve (12) healthy male and female Chinese participants, aged 18 to 55 years, inclusive, 
will be recruited in this study in order to have at least 9 participants complete the study 
procedures and have sufficient post-dose PK samples to calculate PK parameters.
The study will consist of a screening phase, a treatment phase and a follow-up phase. All 
screening evaluations will occur within up to 28 days prior to administration of the
investigational product. All participants will provide informed consent and undergo 
screening evaluations to determine their eligibility. Eligible participants will check into the 
Clinical Research Unit (CRU) on Day -1. Participants will receive a 3 hour IV infusion of 
1500 mg ATM plus 500 mg AVI as a single dose on Day 1. 24 hrs later (Day 2), participants 
will receive a loading/extended loading dose followed by multiple maintenance doses of
ATM-AVI IV infusion. The loading dose in this study is 500 mg ATM plus 167 mg AVI 
infused over a 30 minute period, immediately followed by an extended loading dose of 1500 
mg ATM plus 500 mg AVI over a 3 hour period. Three (3) hours after the extended loading 
dose is completed, a maintenance dose of 1500 mg ATM and 500 mg AVI will be infused 
over 3 hours and administered q6h.
Serial blood samples and urine samples at specified intervals will be collected pre-dose and 
for 24 hours following the single dose administration on Day 1 and final maintenance dose 
administered on the morning of Day 4 for PK assessments. PK samples will also be 
collected 0.5 and 3.5 hours after start of loading dose on Day 2 as well as trough samples 
collected just prior to administration of specific maintenance doses (please refer to Schedule 
of Activities. 
Participants will be monitored for safety during the screening and treatment phases and at 
least 28 and up to 35 calender days after the last dose of investigational product.
The total participation time for each participant in this study will be up to 68 days.
4.2. Scientific Rationale for Study Design
Currently, a Phase 1 (D4910C00001) and a Phase 2a (D4910C00009/C3601001) study are 
completed, and a pivotal Phase 3 (C3601002) study is ongoing, and a Phase 1 study in the 
participants with renal impairment (C3601006) and a supplemental Phase 3 (C3601009) 
study is planned.
In order to facilitate development of ATM-AVI in China, this study will investigate the PK,
safety and tolerability  after single and repeated IV infused doses of ATM with AVI to 
healthy male and female Chinese participants.  This study will be the first time to investigate 
PK profile of ATM when dosed in combination with AVI, evaluate the PK exposure of ATM 


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when combined with AVI, and determine safety and tolerability of this combination in 
Chinese participants. No control or reference group is needed, and no blinding is 
needed.Among enrolled participants, the number of female or male participants should be no 
less than 1/3 of the total participants. In order to investigate comprehensively ATM-AVI PK 
characteristics of Chinese participants, and confirm whether there are differences between 
participants of different genders.
Human reproductive safety data are limited for ATM and AVI, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound. Female 
participants with childbearing potential are permitted to join the study.  Therefore, the use of 
a highly effective method of contraception is required (see Appendix 4).
Blood and urine are to be collected for PK parameter calculations, including renal clearance 
of ATM and AVI.
4.3. Justification for Dose
The intention for ATM-AVI is that it will be active against clinically isolated Gram-negative 
bacteria for which there are limited or no treatment options when dosed in a fixed 3:1 ratio
(ATM:AVI=3:1)_.  The ATM-AVI doses for this Phase I study have been selected based on 
pre-clinical and clinical data on ATM-AVI, using PK data for aztreonam, avibactam and 
ATM-AVI and including covariate information collected in healthy participants and as 
presented in the Investigator’s Brochure.  Furthermore, PK and safety data together with 
PK/PD modelling results obtained during development of the new ceftazidime-avibactam 
(CAZ-AVI) combination product Zavicefta have been taken into account.8
At the time of dose selection for the start of this study, PK data for both ATM and AVI were 
available from a Phase I study with 66 healthy volunteers and a Phase 2a study receiving 
ATM-AVI (D4910C00001 and D4910C00009/C3601001 as displayed in the Investigator’s 
Brochure) and were used in development of a population PK model. 
In this Phase 1 study, the dosing regimen is the same as that administered in Cohorts 2 and 
3 of the Phase 2a study and what is being evaluated in Phase 3.  On Day 1, participants will 
receive a 3 hour IV infusion of a single dose of 1500 mg ATM plus 500 mg AVI. On Day 2,
participants will receive a loading/extended loading dose followed by multiple doses of 
ATM-AVI IV infusion. The loading dose is 500 mg ATM plus 167 mg AVI infused over a 
30 minute period, immediately followed by an extended loading dose of 1500 mg ATM plus 
500 mg AVI over a 3 hour period. Three (3) hours after the extended loading dose is 
completed, a maintenance dose of 1500 mg ATM and 500 mg AVI will be infused over 
3 hours and administered q6h till morning of Day 4. 
For patients with serious bacterial infections where there are limited or no treatment options,
it is recommended for β-lactams to rapidly achieve target attainment and steady state
concentrations while prolonging time above the minimum inhibitory concentration (MIC)
with extended infusion time and shorter dosing intervals.  The rationale for the selected dose
regimen is based on the objective of obtaining optimal exposure to achieve 
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(PK/PD) targets for both ATM and AVI which have been identified from non-clinical data.  
The PK/PD targets are:

Maintain unbound ATM concentrations above an MIC for 60% of the dosing interval;

Maintain unbound AVI concentrations above a threshold concentration (CT) of
2.5 mg/L for 50% of the dosing interval.
The dose has been selected to achieve >90% PTA at an ATM-AVI MIC of 8 mg/L.
Population PK models have been constructed using the following data: ATM PK data from
the literature, ATM and AVI PK data from the Phase 1 study of the ATM-AVI development 
program, and AVI PK data from the Zavicefta development program (AVI in combination 
with CAZ) which included a substantial amount of PK data in patients.  Most recently, the 
PK model was updated using PK and covariate data from patients with complicated cIAI in 
the Phase 2a study.  The PK models were used in Monte Carlo simulations of 5000 patients 
to select a dosing regimen which achieved a >90% joint PTA for ATM and AVI based on 
PK/PD targets.
In Cohort 1 of the Phase 2a study in patients with cIAI (and creatinine clearance
[CLCR] >50 mL/min) the dosing regimen was selected based on the Phase 1 safety data and 
PK/PD modeling above, ie, a loading dose (500 mg ATM plus 137 mg AVI by IV infusion) 
over a 30 minute period, was immediately followed by a maintenance infusion of 1500 mg 
ATM plus 410 mg AVI over a 3 hour period [q6h]).
The safety and PK data from 10 patients in Cohort 1 (who completed all safety and PK
assessments) was reviewed by a Scientific Advisory Committee (SAC). Based on assessment 
of the safety and PK data in Cohort 1, Cohort 2 was subsequently initiated using a higher 
AVI dose (a loading dose of 500 mg ATM plus 167 mg AVI by IV infusion over a 30 minute 
period, immediately followed by a dose of 1500 mg ATM plus 500 mg AVI by IV infusion 
over a 3 hour period q6h [maintenance infusion]).  Following the review of PK and safety 
data from 10 patients in Cohort 2 by the SAC, the higher AVI dose was continued in 
Cohort 3.  The higher AVI dose was selected as it provides a higher PTA for AVI using the 
PK/PD targets as described above compared to the lower AVI dose.
The PK of ATM and AVI observed in the cIAI patients in Phase 2a study
(D4910C00009/C3601001) confirm the maintainance dosing regimen of 1500 mg ATM/500 
mg AVI infused over 3 hours q6h for further evaluation in the Phase 3 program.
4.4. Stopping Rules 
Participants may be discontinued from investigational product (IP) in the following 
situations: 

Subject decision. The subject is at any time free to discontinue treatment, without
prejudice to further treatment;

Positive pregnancy test at any time during the study;


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
Occurrence of an AE or any other condition posing a risk to a participant or 
jeopardizing a safe continuation of the study treatment for the respective participant
(as judged by the investigator, and/or the national coordinators, and/or the Medical 
Monitor and the Study Sponsor).

Hepatic disorder:

alanine aminotransferase (ALT) >3x upper limit of normal (ULN);

alkaline phosphatase (ALP) >2x ULN;

Total bilirubin >2x ULN.

Severe non-compliance to study protocol;

Incorrect enrollment;

Subject lost to follow-up.
4.4.1. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled follow-up (can be via a phone call) shown in the 
SCHEDULE OF ACTIVITIES, and the investigator has reviewed the final safety data and 
have determined that no additional evaluation is required.
The end of the study is defined as the date of the last follow-up (can be via a phone call) of 
the last participant shown in SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Investigators should keep a record, ie, subject screening log, of volunteers who entered
prestudy screening.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Healthy Chinese female participants and/or male participants who, at the time of 
signing ICD, are between the ages of 18 and 55 years, inclusive. Among enroll 
participants, the number of female or male participants should be no less than 1/3 of
the total participants.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Healthy is defined as no clinically relevant abnormalities identified by a detailed 
medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG),
or clinical laboratory tests.  
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures.
Weight:
4. Body mass index (BMI) of 17.5 to 30.5 kg/m2 (both not inclusive); and a total body 
weight >50 kg (110lb).
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).


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2. Known history of severe allergy to betalactam and/or L-arginine. History of severe 
allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as 
judged by the principal investigator (PI) or history of hypersensitivity to drugs with a
similar chemical structure or class to ATM or AVI. History of food allergy.

Allergy is a disorder characterized by an adverse local or general response 
from exposure to an allergen. The serious allergy includes anaphylaxis, 
angioedema and bronchospasm, hypersensitivity or any serious reactions. 
Hypersensitivity is an inappropriate immune response to generally harmless 
antigens, representing a continuum from minor to severe manifestations.
Assessment of allergy/hypersensitivity are based on investigator’s 
discretion10.
3. Any clinically significant illness, medical/surgical procedure, or trauma within
4 weeks prior to the first administration of IP.
4. Current evidence of drug abuse or history of drug abuse within one year of
enrollment, and/or positive results of urine drug and alcohol test at screening and at 
admission.
5. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.  Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a regular rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).    
6. Use within 14 days (or 5 half-lives, whichever is longer) prior to the first study dose
or intended use of any over-the-counter (including St. John’s Wort or any herbal
products) or prescription medication.
7. Has received another new chemical entity (defined as a compound which has not
been approved for marketing) or has participated in any other clinical study that
included drug treatment within 30 days (on the condition that 5 half-lives of the
compound is <30 days) of screening in this study. The period of exclusion begins at 
the time of the last follow-up visit of the prior study.
8. Has participated in a clinical study of a biologic within 6 months of screening.
9. Treatment in the previous 3 months with any drug with well defined toxicity potential 
to a major organ.
10. Presence or sequelae of liver or kidney disease, or other conditions known to interfere 
with the absorption, distribution, metabolism, or excretion of drugs.
11. Participant has known Clostridium difficile associated diarrhea.


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12. Estimated Creatinine clearance 80 mL/min calculated by Cockcroft-Gault equation.
CLCR will be calculated when the participants are selected according to exclusion 
criteria in the SoA.
13. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTc interval 
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
infarction, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). Screening 
supine 12-lead ECG demonstrating a corrected QT (QTc) interval >450 msec or a 
QRS interval >120 msec. If the baseline uncorrected QT interval is >450 msec, this 
interval should be rate corrected using the Fridericia method and the resulting QTcF
should be used for decision making and reporting. If QTc exceeds 450 msec, or QRS 
exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 
QTc or QRS values should be used to determine the participant’s eligibility.
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding participants.
14. Any clinically significant abnormalities in physical examination, ECG, clinical
chemistry, hematology, coagulation, or urinalysis results, as judged by the 
Investigator. If the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 
/total bilirubin (TBili)/alkaline phosphatase (ALP) is greater than 1.0 × ULN,
activated partial thromboplastin time (aPTT), prothrombin time (PT) and/or
international normalized ratio (INR) >1.0 × ULN at screening, the volunteer must be 
excluded and deemed a screen failure. Healthy volunteers with clinically determined 
Gilbert’s syndrome must be excluded.
15. Abnormal vital signs, after 5 minutes supine rest, defined as any of the following:

Systolic blood pressure (SBP) >140 mmHg;

Diastolic blood pressure (DBP) >90 mmHg;

Pulse rate <40 or >99 beats per minute.
16. Pregnant female participants; breastfeeding female participants; fertile male 
participants and female participants of childbearing potential who are unwilling or 
unable to use a highly effective method of contraception as outlined in this protocol 


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(Section 10.4.4 ) for the duration of the study and for at least 28 days after the last 
dose of investigational product.  
17. Known history of past or current epilepsy or seizure disorders, excluding febrile
seizures of childhood.
18. Use any of prescription or nonprescription drugs or dietary supplements within 7 days 
or 5 half-lives (whichever is longer) prior to the first dose of investigational product.  
As an exception, acetaminophen/paracetamol may be used at doses of 1 g/day.  
Limited use of nonprescription medications that are not believed to affect participant
safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. 
Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 (eg, 
probenecid) are prohibited in this study for all participants.
The dietary supplements include such ingredients as vitamins, minerals, herbs, amino 
acids, and enzymes according to FDA website11.
19. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
20. Smoker of more than 5 cigarettes/day or equivalent use of nicotine products during
the previous 3 months.
21. Consumption of grapefruit or grapefruit-containing products within 7 days of the first 
study dose.
22. History of sensitivity to heparin or heparin-induced thrombocytopenia.  
23. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive 
testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or hepatitis C antibody (HCVAb). Hepatitis B vaccination is allowed.
24. Unwilling or unable to comply with the criteria in the Life Considerations 
(Section 5.3) of this protocol.
25. Participants who are 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 participants who are Pfizer employees, including their family 
members, directly involved in the conduct of the study.
26. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and at least 1 hour prior to ECG evaluations.

Breakfast will be provided prior to administration of the single dose on Day 1 or final
dose on Day 4 but after the pre-dose safety laboratory tests, ECG, BP and PR
procedures have been completed. Breakfast can be given at any time on all other
days.

Participants will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of 
investigational product until collection of the final PK blood sample.

While confined,the meals for all participants should be standardized meals provided 
by CRU. 
5.3.2. Alcohol, Caffeine, Tobacco and Others

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample of each study 
period.  Participants may undergo an alcohol breath test or blood alcohol test at the 
discretion of the investigator.

Energy drinks containing taurine or glucuronolactone eg, Red Bull from 72 hours 
before admission and during the residential periods.

Refrain from consumption of xanthine-containing foods or beverages (including all 
caffeine-containing products ) within 24 hours preceding investigational product
infusion until collection of the final PK sample of each study period, and at least 3 
hours prior to ECG evaluations.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.3. Activity
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 


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participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4)and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the Schedule of Activities, the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception).  In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study.  Screen failure data are collected and remain as 
source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For this study, the investigational product(s) are avibactam and aztreonam.
Investigational product will be prepared using standard aseptic IV infusion preparation using
saline. An IV infusion will be used.
6.1. Study Intervention(s) Adiministered
6.1.1. Dosage Form and Packaging
Aztreonam and avibactam will be provided by Pfizer as separate vials for reconstitution and 
mixed together in a saline bag for co-administration at the appropriate concentration for IV 
infusion using a standard aseptic IV infusion technique (see Investigational Product Manual
[IP Manual]) at CRU.
The identity of the investigational product is provided in Table 1. 
Table 1.
Identity of Investigational Product
Investigational
Product a
Dosage form and strength
Aztreonam
Aztreonam for injection, powder for solution for infusion 2 g.
Avibactam
Avibactam lyophilisate for concentrate for solution for infusion 600 mg.
a. Aztreonam and Avibactam will be supplied by Pfizer Global R&D as separate vials for reconsititution and mixed 
together in a saline bag for co-administration at the appropriate concentration for intravenous infusion.


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6.1.2. Administration
Participants will receive the single dose of the investigational product on Day 1. No fasting 
is required in respect to dosing as ATM-AVI is administed intravenously. Fasting will only 
be required prior to safety laboratory and ECG assessments (see Section 5.3). The single dose 
administration on Day 1 needs to occur in morning to allow 24 hours for sample collection 
prior to start of Day 2 dosing.
On Day 2, the loading dose and extended loading dose will be prepared in 1 infusion bag.
The infusion pump will be programmed to administer the loading dose of ATM-AVI over
30 minutes followed by a rate change to administer the extended loading dose over 3 hours.
This is followed by maintenance infusions dosed q6h according to the treatment schedule 
described in Table 2. The infusion line will be flushed according to local site procedure to 
ensure complete delivery of the dosing solution. The details of the IV infusion will be 
described in the IP manual. The start and stop time of each infusion will be recorded in the
case report form  (CRF).
Table 2.
Treatment Schema
Day 
Infusion Duration Time
(5 minutes)
Dosing regimen
1
3 hr
Single dose infusion (1500/500 
mg ATM-AVI)
2
30 min
IV loading dose infusion (500/167 
mg ATM-AVI)a
3 hr
3 hr IV extended loading 
(1500/500 mg ATM-AVI)a
3 hr
IV maintenance infusion q6h
(1500/500 mg ATM-AVI) (h2)
3
3 hr
IV maintenance infusion q6h
(1500/500 mg ATM-AVI) (h4)
4
3 hr
IV maintenance infusion q6h
(1500/500 mg ATM-AVI) (h2)
Abbreviations: ATM-AVI = aztreonam-avibactam; hr(s) = hour(s); IV = intravenous; q6h = every 6 hrs.
a.
Loading dose and extended loading dose will be prepared in one infusion bag with an infusion rate
change after the first 30 minutes.
The start and stop time of the infusion will be recorded. Time 0 is the time when the 
investigational product infusion begins. The infusion rate and volume infused will be 
recorded. The full contents of the infusion bag must be administered.  
Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements.


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6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual or other specified location.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. See the IP manual for storage conditions of the study intervention once reconstituted 
and/or diluted.
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
Investigational Product Accountability Log (IPAL) or sponsor-approved equivalent.  
All study interventions will be accounted for using a study intervention accountability 
form/record.  
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.  All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.


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Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
Refer to the IP manual for instructions on how to prepare the investigational product for
administration.  Both aztreonam and avibactam vials are for single-use. Investigational
product should be prepared and dispensed by an appropriately qualified and experienced
member of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner,
pharmacy assistant/technician, or pharmacist) as allowed by local, state, and institutional
guidance. A second staff member will verify the dispensing.
Within this protocol, preparation refers to the investigator site activities performed to make
the investigational product ready for administration or dispensing to the subject by qualified 
staff.  Dispensing is defined as the provision of investigational product, concomitant 
treatments, and accompanying information by qualified staff member(s) to a healthcare 
provider, participantin accordance with this protocol.  Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator will assign subject numbers to the participants as they are screened for the
study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
This identifying number will be retained throughout the study. All participants enrolled will 
receive 4 days of IV ATM-AVI according to the dose/schedule provided in the Section 6.1.2.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.  
6.5. Concomitant Therapy
Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 (eg, probenecid) are
prohibited in this study for all participants.
Participants must not receive any antipyretic medications on Day -1 prior to the body 
temperature assessments.


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Participants must not receive any premedications for the purpose of suppressing infusion 
related reactions. 
Fever or chills should not routinely be managed with any antipyretic medications unless body 
temperature is greater than or equal to 38C (ie, Grade 1 Common Terminology Criteria for 
Adverse Events ([CTCAE], v5.0) and/or clinically indicated in the opinion of the 
investigator.
Participants will abstain from all concomitant treatments, except for the treatment of 
AEs. Limited use of nonprescription medications that are not believed to affect participant
safety or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are women of childbearing potential (WOCBP) (see Appendix 4).
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments.
6.6. Dose Modification 
Not applicable.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation).  Reasons for definitive discontinuation of study 
intervention include the following :safety consideration, or behavioral reasons, or the 
inability of the participant to comply with the protocol-required schedule of study visits or 
procedures at a given investigator site.  
Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for a complete early discontinuation visit.  See the SCHEDULE OF 
ACTIVITIES for data to be collected at the time of discontinuation of study intervention and 
follow-up for any further evaluations that need to be completed.


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In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, post-treatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SCHEDULE OF ACTIVITIES for assessments to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding
their reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 


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information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.2.2. Participant Replacement
Participants who do not receive the full dose of ATM-AVI, for whom significant protocol 
violations are identified or who withdraw from the study may be replaced at the discretion of 
the investigator upon consultation with the Sponsor.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SCHEDULE OF ACTIVITIES.  
Protocol waivers or exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.


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Adherence to the study design requirements, including those specified in the SCHEDULE 
OF ACTIVITIES, is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study.  If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
Participants screened for another study may participate in this study provided they meet the 
participant selection criteria and informed consent for this study is obtained by the 
investigator, or delegate.  Screening data from another study will be considered sufficient if 
those data satisfy the requirements of this protocol.  Procedures required by this protocol will 
only be done if they were not performed as part of the requirements for the other study.  
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For the study period described in the SoA, when multiple procedures are scheduled at the 
same time point(s) relative to dosing, the following chronology of events should be adhered 
to, where possible.

ECGs: obtain prior to vital sign measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection;

BP/PR/body temperature (if applicable): obtain as close as possible to the scheduled 
time, but prior to blood specimen collection;

PK blood specimens: obtain at the scheduled time;

Other procedures: obtain all other procedures as close as possible to the scheduled 
time, but may be obtained before or after blood specimen collection.
When an IV catheter is utilized for blood sample collections, ECGs and vital sign 
assessments (PR, BP and body temperature) should be collected prior to the insertion of the 
catheter. Below blood sample collection requirements are applicable to all related 


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procedures during the study.  Blood samples must be drawn from the arm contralateral 
to the arm in which the infusion will be administered.  In no case may blood samples be 
obtained via the catheter through which the investigational product was administered.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior
to initiation of the study.
The total blood sampling volume for male participants in this study is approximately
176 mL, and is approximately 186.5mL for female participants of childbearing potential 
(another 10.5mL may be collected for Serum β-hCG test) or 179.5mL for female participants 
who are amenorrheic for at least 12 consecutive months with no alternative pathological or 
physiological cause (another 3.5mL for FSH test). And if the blood sample is collected with 
in-dwelling catheter, 1ml of blood will be discarded before sample collection. The actual 
collection times of blood sampling may change from SoA.  Additional blood samples may be 
taken for safety assessments at times specified by Pfizer or at the discretion of investigators, 
provided the total volume taken during the study does not exceed 550 mL during any period 
of 60 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations (Section 5.3) and Concomitant Therapy (Section 6.5) of the 
protocol.
8.1. Efficacy Assessment
Not applicable. 
8.2. Safety Assessment
Planned time points for all safety assessments are provided in the SCHEDULE OF 
ACTIVITIES.  Unscheduled clinical laboratory measurements may be obtained at any 
time during the study to assess any perceived safety issues.
8.2.1. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the 
SCHEDULE OF ACTIVITIES for the timing and frequency.  All protocol-required 
laboratory assessments, as defined in Appendix 2, must be conducted in accordance with the 
laboratory manual and the SCHEDULE OF ACTIVITIES. Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 


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repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.2. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the 
SCHEDULE OF ACTIVITIES.  Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced and a second negative pregnancy test result 
will be required at the baseline visit prior the participant’s receiving investigational product.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected) and at the end of the 
study. Pregnancy tests may also be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations.If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required.  In such 
cases, the participant must be excluded if the serum pregnancy result is positive.
8.2.3. Physical Examinations
A complete physical examination will include, at a minimum, general check (including head, 
ears, eyes, nose, mouth), skin and musoca, chest examination (including heart and lung 
examinations), lymph nodes, and gastrointestinal, musculoskeletal (limbs and spine), and 
neurological systems. 
A limited physical examination will include, at a minimum, assessments of general 
appearance, the respiratory and cardiovascular systems, and participant-reported symptoms. 
Physical examinations may be conducted by a physician. 
8.2.4. Weight and Height
Height and weight will also be measured and recorded as per the SCHEDULE OF 
ACTIVITIES. For measuring weight, a scale with appropriate range and resolution is used 
and must be placed on a stable, flat surface. Participants must remove shoes, bulky layers of 
clothing, and jackets so that only light clothing remains.  They must also remove the contents 
of their pockets and remain still during measurement of weight. 
8.2.5. Vital Signs
BP, PR and body temperature will be measured at times specified in the SoA of this protocol.  
Additional collection times, or changes to collection times, of BP, PR and body temperature
will be permitted, as necessary, to ensure appropriate collection of safety data.


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Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mmHg after approximately 5 minutes of supinerest.  As much as 
possible, the same arm (preferably the dominant arm) will be used throughout the study. BP 
should not be taken from the arm with an intravenous infusion. Participants should be 
instructed not to speak during measurements.  
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and PR is acceptable; however, when done 
manually, PR will be measured in the brachial/radial artery for at least 30 seconds. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Temperature will be measured with tympanic method. No eating, drinking, or smoking is 
allowed for 15 minutes prior to the measurement.
8.2.6. Electrocardiogram 
12-Lead ECGs should be collected at times specified in the SoA of this protocol.
All scheduled ECGs should be performed after the participant has rested quietly for at least 
5 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained within approximately 2 to 5 minutes; the average of 
the triplicate ECG measurements collected at nominal time point on Day 1 will serve as each 
participant’s time-controlled baseline QTc value.  
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTc interval is increased by 45 msec from 
the baseline, or an absolute QTc value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTc values from these repeated ECGs remains above 
the threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTc values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement. 
If the average of QTc values from the triplicate measurements remains above the threshold 
value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG must be 
repeated at least hourly until QTc values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner, at the discretion of the investigator).


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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 6.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days after the last administration of the investigational product.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.


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Investigators are not obligated to actively seek AE or SAE after the participant has concluded 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Non-Serious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.


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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or 
infusion.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study intervention and untilthe 
pregnancy completion (or until pregnancy terminaiton).

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form.  Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed 
to study intervention (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider 
who reports that she is breastfeeding after having been exposed to the study 
intervention by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF.  However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable


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8.3.8. Adverse Events of Special Interest
Not applicable
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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8.4. Treatment of Overdose
For this study, any dose of ATM or AVI in excess of that specified in Table 2, Treatment 
Schema will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study intervention 
(whichever is longer).  
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 24h from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).  
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.


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8.5. Pharmacokinetics
8.5.1. Plasma for Analysis of ATM-AVI
Whole blood samples (4 mL, with exception of additional 6 mL of the pre-dose blood sample
only on Day 1 for evaluation of the matrix effect on the bioanalyticalmethod and validation) 
to provide a minimum of 1.5 mL plasma for PK analysis will be collected into appropriately 
labeled tubes containing Sodium Fluoride/Potassium Oxalate  at times specified in the SoA
of the protocol.  Sample handling details are provided in the Laboratory Manual.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF). Pre-dose PK samples on Day 1 should be taken no more than 1 hour prior to 
infusion. Collection of samples more than 10 hours after dose administration that are
obtained ≤1 hour away from the nominal time relative to dosing will not be captured as a 
protocol deviation, as long as the exact time of the sample collection is noted on the source 
document and the data collection tool (eg, CRF). 

Samples will be used to evaluate the PK of ATM and AVI. The only exception was 
the10 mL pre-dose blood sample collected in Day 1, which will be divided into 2 
tubes (1 tube contains 4 mL to evaluate PK of ATM and AVI, and 1 tube contains 
6mL to evaluate the matrix effect on the bioanalytical method evaluation and 
validation).  

Samples collected for analyses of ATM and AVI plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after 
the study, for metabolite identification and/or evaluation of the bioanalytical method, 
or for other internal exploratory purposes. These data will not be included in the CSR.

Genetic analyses will not be performed on these plasma samples.  Participant 
confidentiality will be maintained.

Samples collected for measurement of plasma concentrations of ATM and AVI will 
be analyzed using a validated analytical method in compliance with applicable SOPs.  

The PK samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from 
the PK sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor. On a case-by-case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.


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8.5.2. Urine for Analysis of ATM-AVI
Urine will be collected at times specified in the SoA of the protocol.  Each participant will 
empty his or her bladder just prior to dosing on Day 1 and Day 4. On day 1, approximately
20 mL of pre-dose blank urine sample will be collected for bioanalytical method evaluation
and validation as appropriate. On Day 4, approximately 10 mL of pre-dose (last maintance 
dose) urine sample will be collected for PK analysis.Each participant will be instructed to 
void into the collection container at the end of each collection period. Samples obtained 
within 10% of the nominal time interval (eg, f12 minutes when collection urine PK sample 
within 120 minutes) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).
Samples will be analyzed using a validated analytical method in compliance with Pfizer and 
vendor SOPs. Sample handling details are provided in the Laboratory Manual.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the ATM and AVI, urine samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method.  These data will be 
used for internal exploratory purposes and will not be included in the CSR.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study. 
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.


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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their
analyses will also be reflected in a protocol amendment.
9.1. Statistical Hypotheses
There are no statistical hypotheses for this study.
9.2. Sample Size Determination
There is no statistical hypothesis for this study, therefore, the study sample size is not based 
on statistical calculations. The sample size has been chosen based on the need to fulfill the 
National Medical Products Administration (NMPA) requirement for a PK study to support 
the registration in China. A sufficient number of participants will be screened to achieve 12 
participants enrolled to study intervention and at least 9 participants complete the study 
procedures and have sufficient post-dose PK samples to calculate PK parameters.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled to study 
intervention 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process.  
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Pharmacokinetics
The PK concentration population is defined as all enrolled
and treated participants who have at least 1 ATM and AVI 
concentration.
The PK parameter population is defined as all enrolled and
treated participants who have at least 1 of the ATM and AVI 
PK parameters of interest.
Safety
All participants enrolled to study intervention and who take at 
least 1 dose of study intervention (ATM-AVI).  Participants 
will be analyzed according to the product they actually 
received.


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9.4. Statistical Analyses
9.4.1. General Considerations
Aztreonam (ATM) and AVI PK parameters partial AUC, area under the plasma 
concentration-time profile from time 0 to 6 hours [AUC6] and area under the plasma 
concentration-time profile from time 0 to 24 hours [AUC24] for Day 1, area under the plasma 
concentration-time profile from time 0 to to the time of the end of the dosing interval (τ)
(AUCτ), total daily area under the plasma concentration-time profile from time 0 to 24 hours 
at steady-state (AUC24,ss) for Day 4, area under the plasma concentration-time profile from 
time zero extrapolated to infinite time (AUCinf), area under the plasma concentration-time 
profile from time zero to time of the last quantifiable concentration (Clast) (AUClast), 
maximum observed plasma concentration (Cmax), time for Cmax (Tmax), terminal elimination 
half life (t½), clearance (CL), renal clearance (CLr), apparent volume of distribution during 
terminal phase (Vz), apparent volume of distribution at steady-state (Vss), accumulation ratio 
for Cmax (Rac,Cmax): Cmax (Day 4)/Cmax (Day 1), accumulation ratio for AUC following 
multiple dosing (Rac), total amount of unchanged drug excreted in the urine over dosing 
interval [Aet], total amount of unchanged drug excreted in the urine over dosing interval, 
expressed as percent of dose [Aet %] will be summarized descriptively for Day 1 and Day 4.
Minimum observed plasma concentration (Cmin) for Day 2, Day 3, and Day 4 will be 
summazied.
Concentrations will be listed and summarized descriptively by PK sampling time for Day 1 
and Day 4. Summary profiles (means and medians) of the concentration-time data will be 
plotted for Day 1 and Day 4. Individual participant concentration-time profiles will be also 
presented. For summary statistics and summary plots by sampling time, the nominal PK 
sampling time will be used; for individual participant plots by time, the actual PK sampling 
time will be used.
Safety data (AEs, vital signs, ECGs and laboratory data) will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate.
9.4.2. Pharmacokinetics Endpoints
9.4.2.1. Plasma PK
PK parameters of aztreonam and avibactam following single and multiple dose 
administration will be derived from the concentration-time profiles as follows:
Parameter
Definition
Method of Determination
AUC6
Area under the plasma
concentration-time profile from time 0
to 6 hours
Linear/Log trapezoidal rule
CCI


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Parameter
Definition
Method of Determination
AUC24
Area under the plasma 
concentration-time profile from time 0 to 
24 hours
Linear/Log trapezoidal rule
AUC24,ss
Total daily area under the plasma
concentration-time profile from time 0
to 24 hours at steady-state
AUC*4
AUClast
Area under the plasma 
concentration-time profile from time 
zero to time of the last quantifiable 
concentration (Clast)
Linear/Log trapezoidal rule
AUC
Area under the plasma
concentration-time profile from time 0 to 
to the time of the end of the dosing
interval (), where hours
Linear/Log trapezoidal rule
AUCinfa
Area under the plasma 
concentration-time profile from time 
zero extrapolated to infinite time
AUClast + (Clast*/kel), where Clast* is 
the predicted plasma concentration at 
the last quantifiable time point 
estimated from the log-linear 
regression analysis
Cmax
Maximum observed plasma 
concentration
Observed directly from data
Cmin
Minimum observed plasma 
concentration during dosing interval
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
CLa
Clearance
Dose/AUCinf
t½a
Terminal elimination half-life
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression through at least 
3 data points in the terminal phase of 
the log-linear concentration-time 
curve. Only those data points judged 
to describe the terminal log-linear 
decline will be used in the regression
Vssa
Apparent volume of distribution at
steady-state
Volume of distribution at steady state 
is calculated as: Vss = CL × MRT
Vza
Apparent volume of distribution
during terminal phase
Dose /(AUCinf*kel)
Rac, Cmax
Accumulation ratio for Cmax
Cmax (Day 4)/Cmax (Day 1)
Rac
Accumulation ratio for AUCfollowing 
multiple dosing
AUC(Day 4) /AUC6 (Day 1)
a.
If data permit.
Actual PK sampling times and non-compartmental methods will be used in the derivation of
PK parameters.


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9.4.2.2. Urine PK 
Urine PK parameters of aztreonam and avibactam following single and multiple dose 
administration of ATM-AVI will be derived as follows:
Parameter
Definition
Method of Determination
Aet
Total amount of unchanged drug excreted 
into urine from time 0 to time t.
Sum of amount excreted for each
collection period. Calculated as the 
product of the urine volume and the urine 
concentration. The amount will be 
calculated and reported for each collection 
interval and cumulatively.
Aet%
Total amount of unchanged drug excreted in 
the urine from time 0 to time t, expressed as
percent of dose.
100 × (Aet/Dose).
CLr
Renal clearance.
Aet/AUCt for single dose;
Ae/AUCat steady-state on Day 4.
9.4.3. Safety Endpoints
AEs, ECGs, BP, PR, body temperature, and safety laboratory data will be reviewed and 
summarized on an ongoing basis during the study to evaluate the safety of participants.  Any 
clinical laboratory, ECG, BP, PR, and body temperature abnormalities of potential clinical 
concern will be described.  Safety data will be presented in description, tabular and/or 
graphical format and summarized descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.
9.5. Interim Analysis
No formal interim analysis is planned for this study. However, as this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating dose-escalation decisions, facilitating 
PK/PD modeling, and/or supporting clinical development.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a data monitoring committee (DMC).


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.


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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.


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10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code.  Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred.  All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code.  The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification.  In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a  
product, regardless of the geographical location in which the study is conducted. These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.


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EudraCT
Pfizer posts results on EudraCT for all Pfizer-sponsored interventional studies in accordance 
with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the the corresponding study results are posted to 
www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.


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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the study 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.


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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee if requested to do so by the responsible IRB/EC or if such termination is required 
to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements.  The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.


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10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Investigator Site Master File.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant study 
numbers, contact information for the investigator site, and contact details for a contact center 
in the event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 


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a Pfizer CRU, the contact number is not intended for use by the participant directly, and if a 
participant calls that number, he or she will be directed back to the investigator site.
10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SCHEDULE 
OF ACTIVITIES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory, or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical laboratory measurements may be 
obtained at any time during the study to assess any perceived safety issues.
Table 3.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysisa
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
aPTT
PT
INR
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate) 
or carbondioxide 
combining power 
(CO2CP)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyb
Urine drug screeningc
β-hCGd
FSHe
Serologyf panel to 
include: 

Hepatitis B surface 
antigen

Hepatitis B core 
antibody

Hepatitis C core 
antibody

Human 
immunodeficiency 
virus
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels


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Table 3.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysisa
Other
a.
Obtain a fresh 10 mL urine sample for urinalysis.
b.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site specific).
d.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC.  Serum or urine -hCG for female participants of childbearing potential.
e.
Only females who are amenorrheic for at least 12 consecutive months with no alternative pathological or 
physiological cause.
f.
Serology at screening only, additional 7 mL blood sample required.
Investigators must document their review of each laboratory safety report.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator.  Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.


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d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; 
and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must 


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be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP
supplemental form for 
EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 


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
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is 
assessed as severe should not be confused with an SAE.  Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.


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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.


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
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4 Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3);
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
least 28 days after the last dose of study intervention, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention(s). If a 
highly effective method that is user dependent is chosen, a second effective method of 
contraception, as described below, must also be used.  The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first dose 
of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).


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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.  
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  In addition, a

High FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
4. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.


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5. Intrauterine device.
6. Intrauterine hormone-releasing system.
7. Bilateral tubal occlusion.
8. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days.
9. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation.

Oral;

Intravaginal;

Transdermal;

Injectable.
10. Progestogen-only hormone contraception associated with inhibition of ovulation.

Oral;

Injectable.
11. Sexual abstinence.

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
In addition, one of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;


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
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments Potential 
Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study.  However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.6. Appendix 6: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from 
baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to 
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.7. Appendix 7. Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
ADME
absorption, distribution, metabolism, and excretion
ADR
adverse drug reaction
AE
adverse event
Aet
total amount of unchanged drug excreted in the urine from time 0 to 
time t
Aet%
total amount of unchanged drug excreted in the urine from time 0 to 
time t, expressed as percent of dose
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AmpC
A Class C β-lactamase (Amp = ampicillin)
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATM
aztreonam
ATM-AVI
aztreonam-avibactam
AUC
area under the curve
AUC6
area under the plasma concentration-time profile from time 0 to 6 
hours
AUC24
area under the plasma concentration-time profile from time 0 to 24
hours
AUC24,ss
total daily area under the plasma concentration-time profile from time 
0 to 24 hours at steady-state
AUC
area under the plasma concentration-time profile from time 0 to to the 
time of the end of the dosing interval ()
AUCinf
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to 
time of the last quantifiable concentration (Clast)
AUCss
area under the curve at steady-state
AV
atrioventricular
AVI
avibactam
BA
bioavailability
BE
bioequivalence
-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BUN
blood urea nitrogen


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Abbreviation
Term
C-G
Cockcroft-Gault
CAZ
ceftazidime
CAZ-AVI
ceftazidime-avibactam
CFR
Code of Federal Regulations
CI
confidence interval
cIAI
complicated intra-abdominal infection
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL
clearance
CLCR
creatinine clearance
CLr
renal clearance
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CO2
carbon dioxide (bicarbonate)
CO2CP
carbondioxide combining power
CRE
carbapenem resistant Enterobacte
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
Css,max
observed maximum plasma concentration at steady state
Css,min
observed minimum plasma concentration at steady state
CT
threshold concentration
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTX-M
cefotaximase-M
DBP
diastolic blood pressure
DCT
data collection tool
DILI
drug-induced liver injury
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EMA
European Medicines Agency
ESBL
extended spectrum -lactamase
EU
European Union
EudraCT
European Clinical Trials Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase


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Abbreviation
Term
GFR
glomerular filtration rate
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
INR
international normalized ratio
IP
investigational product
IP Manual
Investigational Product Manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
KPC
Klebsiella pneumonia carbapenemase
LBBB
left bundle branch block
LFT
liver function test
LSLV
last subject last visit 
MBL
metallo-lactamase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multiple-drug resistant
MIC
minimum inhibitory concentration
N/A
not applicable
NDM
New Delhi Metallo--lactamase
NMPA
National Medical Products Administration
OAT
organic anion transporter
OXA
oxacillinase
PCD
primary completion date
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PK/PD
pharmacokinetic/pharmacodynamic
PR
pulse rate
PT
prothrombin time
PTA
probability of target attainment
q6h
every 6 hours
q8h
every 8 hours


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Abbreviation
Term
QTc
corrected QT interval
QTcF
QTcF corrected using the Fridericia’s formula
qual
qualitative
RAUC
accumulation ratio for AUC following multiple dosing
RBC
red blood cell
RCmax
accumulation ratio for Cmax (RCmax): Cmax (Day 4)/Cmax (Day 1)
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SCr
serum creatinine
SmPC
Summary of Product Characteristics
SOA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
t½
terminal elimination half life
TBili
total bilirubin
THC
tetrahydrocannabinol
Tmax
time for Cmax
UK
United Kingdom
ULN
upper limit of normal
US
United States
VIM
Verona Integron encoded metallo--lactamase
Vss
apparent volume of distribution at steady-state
Vz
apparent volume of distribution during terminal phase
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
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ceftazidime/avibactam plus Metronidazole versus meropenem in the treatment of 
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double-blind, Phase II trial. J Antimicrob Chemother 2013;68(5):1183-92.
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Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug resistant, extensively 
drug-resistant and pandrug-resistant bacteria: an international expert proposal for 
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Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of Infections Due to MDR 
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Nordmann P, Poirel L. Strategies for identification of carbapenemases-producing 
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Walsh TR, Weeks J, Livermore SM, Toleman MA. Dissemination of NDM-1 positive 
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Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, et al. 
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Children: Guidelines by the Surgical Infection Society and the Infectious Diseases 
Society of America. Clinical Infectious Diseases 2010; 50:133–64.
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AZACTAM (US prescribing information). Bristol-Myers Squibb; 2013.
http://packageinserts.bms.com/pi/pi_azactam.pdf. Accessed Sep 2018.
8.
ZAVICEFTA(summary of product characteristics). Pfizer; 
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ER Squibb & Sons Limited. Azactam (ATM) 1g or 2g Powder for Solution for Injection 
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CTCAE Criteria as attached [page 48]; Tintinalli's Emergency Medicine: A 
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Definition of dietary supplements. https://www.fda.gov/food/dietary-
supplements/dietary-supplement-products-ingredients