Clinical trial NCT04486625
Conditions: Renal Insufficiency
Keywords: Infection
Sponsor: Pfizer
Start date: 2020-08-10; Completion date: 2021-10-18
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 1 study is being conducted to evaluate the effect of severe renal impairment on the PK, safety and tolerability of Aztreonam-Avibactam. Results from this study along with previous renal impairment data from each of the Aztreonam-Avibactam components will be used to confirm the proposed dosing adjustment in severe renal impairment which was based on modelling/simulation.

Detailed description:

Arms: arm 1: Normal renal function arm 2: Severe renal impairment (not on dialysis)
Interventions: intervention 1: Aztreonam-Avibactam intervention 2: 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 intervention 2: 675/225 mg ATM/AVI loading infusion, followed by 675/225 mg ATM/AVI extended loading infusion, then 675/225 mg ATM/AVI maintenance dose infusion every 8 hours

Protocol documents:
Prot_000.pdf: 
Aztreonam-Avibactam 
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PFIZER CONFIDENTIAL
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AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC STUDY OF 
MULTIPLE INTRAVENOUS DOSES OF AZTREONAM AND AVIBACTAM IN 
SUBJECTS WITH SEVERE RENAL IMPAIRMENT AND NORMAL RENAL 
FUNCTION
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:
C3601006
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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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
14 July 2021
Addition of an exploratory objective: To 
determine concordance/comparability of 
capillary microsample plasma 
concentrations with venous plasma
concentrations for aztreonam and 
avibactam in healthy subjects with normal 
renal function (Cohort 1).
Rationale: To facilitate collection of lower 
blood volumes for PK samples in planned 
ATM-AVI pediatric protocols, a capillary 
microsampling technique will be evaluated 
for feasibility and performance in the 
healthy volunteer cohort with normal renal 
function.
Added “temporally” as a method for 
measuring temperature, and changed the 
source of pregnancy tests kits from 
“provided by the central laboratory” to 
“provided by the investigator site”,
changes communicated to the investigator 
site in a PACL dated 07 August 2020.
Original protocol
13 June 2018
N/A


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
SCHEDULE OF ACTIVITIES..................................................................................................7
1. INTRODUCTION ...............................................................................................................12
1.1. Mechanism of Action/Indication.............................................................................12
1.2. Background .............................................................................................................12
1.3. Rationale..................................................................................................................15
1.3.1. Study Rationale...........................................................................................15
1.3.2. Dose Rationale............................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
3. STUDY DESIGN.................................................................................................................18
3.1. Study Overview.......................................................................................................18
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................20
4.1. Inclusion Criteria.....................................................................................................20
4.1.1. Specific Requirements for Healthy Subjects with Normal Renal 
Function ...........................................................................................................21
4.1.2. Specific Requirements for Subjects with Severe Renal Impairment..........21
4.2. Exclusion Criteria....................................................................................................22
4.3. Lifestyle Requirements ...........................................................................................24
4.3.1. Meals and Dietary Restrictions...................................................................24
4.3.2. Alcohol, Caffeine, and Tobacco .................................................................25
4.3.3. Activity .......................................................................................................25
4.3.4. Contraception..............................................................................................25
4.4. Sponsor’s Qualified Medical Personnel..................................................................27
5. STUDY TREATMENTS.....................................................................................................27
5.1. Allocation to Treatment ..........................................................................................27
5.2. Subject Compliance.................................................................................................27
5.3. Investigational Product Supplies.............................................................................27
5.3.1. Dosage Form and Packaging ......................................................................27
5.3.2. Preparation and Dispensing........................................................................28
5.4. Administration.........................................................................................................28


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5.5. Investigational Product Storage ..............................................................................29
5.6. Investigational Product Accountability...................................................................30
5.6.1. Destruction of Investigational Product Supplies ........................................30
5.7. Concomitant Treatment(s).......................................................................................30
6. STUDY PROCEDURES .....................................................................................................31
6.1. Screening.................................................................................................................31
6.2. Study Period ............................................................................................................33
6.2.1. Day -2 .........................................................................................................33
6.2.2. Day -1 .........................................................................................................34
6.2.3. Day 1...........................................................................................................34
6.2.4. Day 2...........................................................................................................35
6.2.5. Day 3...........................................................................................................36
6.2.6. Day 4 (end of trial [EOT])..........................................................................37
6.3. Follow-up ................................................................................................................38
6.3.1. Follow-up Contact ......................................................................................38
6.4. Subject Withdrawal.................................................................................................38
7. ASSESSMENTS..................................................................................................................39
7.1. Safety.......................................................................................................................39
7.1.1. Laboratory Tests .........................................................................................39
7.1.2. Pregnancy Testing ......................................................................................40
7.1.3. Physical Examinations................................................................................41
7.1.4. Blood Pressure and Pulse Rate ...................................................................41
7.1.5. Temperature................................................................................................42
7.1.6. Electrocardiogram.......................................................................................42
7.2. Pharmacokinetics ....................................................................................................42
7.2.1. Plasma for Analysis of Aztreonam-Avibactam..........................................42
7.2.2. Urine for Analysis of Aztreonam-Avibactam.............................................43
7.3. Blood Volume .........................................................................................................44
8. ADVERSE EVENT REPORTING......................................................................................45
8.1. Requirements...........................................................................................................45
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8.1.1. Additional Details on Recording Adverse Events on the CRF...................46
8.1.2. Eliciting Adverse Event Information..........................................................46
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................47
8.1.4. Time Period for Collecting AE/SAE Information......................................47
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................47
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................47
8.1.5. Causality Assessment .................................................................................47
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................48
8.2. Definitions...............................................................................................................48
8.2.1. Adverse Events ...........................................................................................48
8.2.2. Abnormal Test Findings .............................................................................49
8.2.3. Serious Adverse Events ..............................................................................49
8.2.4. Hospitalization............................................................................................50
8.3. Severity Assessment................................................................................................51
8.4. Special Situations ....................................................................................................51
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................51
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................53
8.4.2.1. Exposure During Pregnancy......................................................53
8.4.2.2. Exposure During Breastfeeding ................................................54
8.4.2.3. Occupational Exposure .............................................................55
8.4.3. Medication Errors and Lack of Efficacy ....................................................55
8.4.3.1. Medication Errors......................................................................55
8.4.3.2. Lack of Efficacy........................................................................56
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................56
9.1. Sample Size Determination.....................................................................................56
9.2. Efficacy Analysis ....................................................................................................56
9.3. Pharmacokinetic Analysis.......................................................................................56
9.3.1. Plasma.........................................................................................................57
9.3.2. Urine ...........................................................................................................58
9.4. Safety Analysis........................................................................................................59
9.4.1. Electrocardiogram Analysis........................................................................59


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9.5. Data Monitoring Committee ...................................................................................60
9.6. Interim Analysis ......................................................................................................60
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................60
11. DATA HANDLING AND RECORD KEEPING .............................................................60
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................60
11.2. Record Retention...................................................................................................61
12. ETHICS..............................................................................................................................62
12.1. Institutional Review Board/Ethics Committee......................................................62
12.2. Ethical Conduct of the Study ................................................................................62
12.3. Subject Information and Consent..........................................................................62
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................63
13. DEFINITION OF END OF TRIAL...................................................................................63
13.1. End of Trial in the United States...........................................................................63
14. SPONSOR DISCONTINUATION CRITERIA ................................................................64
15. PUBLICATION OF STUDY RESULTS..........................................................................64
15.1. Communication of Results by Pfizer ....................................................................64
15.2. Publications by Investigators ................................................................................65
16. REFERENCES ..................................................................................................................66
LIST OF TABLES
Table 1.
Identity of Investigational Product .......................................................................28
Table 2.
Treatment Schema ................................................................................................29
Table 3.
Safety Laboratory Tests........................................................................................40
APPENDICES
Appendix 1. Abbreviations......................................................................................................67


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections 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 subject.
Visit Identifier
Screeninga
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Follow-upl
S1
S2
Hours post dose
0
0.5
6.5
8.5
0
3
4
6-8
12-16
24
EOT
Informed consent
X
CRU confinement
X
Inclusion/exclusion criteria
X
X
Medical history
X
X
Demography
X
Physical examinationo
X
Xm
Xi
Heightb and weight
X
X
Review illegal drug/alcohol/tobacco use
X
X
Medication history
X
X
Safety laboratory 
X
X
X
X
X
Pregnancy test
X
X
Contraception check
X
X
X
Serum FSHc
X
Serologic tests: HIV, HBsAg, and 
HCVAb testing
X
Urine drug testing
X
X
eGFR assessmentd
X
X
X
Supine 12-lead ECG
X
Xe
X
Xe
X
X
Single supine blood pressure, pulse rate
and temperature
X
Xe
Xf
Xe,f
Xe,f
Xf
X
ATM-AVI loading dose (30 min 
infusion)k
X
ATM-AVI extended loading dose (3 hour 
infusion)k
Xk
ATM-AVI maintenance dose (3 hour 
infusion) q6h
X
→
→
X
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Visit Identifier
Screeninga
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Follow-upl
S1
S2
Hours post dose
0
0.5
6.5
8.5
0
3
4
6-8
12-16
24
EOT
Cohort 1 – normal renal function
ATM-AVI maintenance dose (3 hour 
infusion) q8h
Cohort 2 – severe renal impairment
X

X
Urine sampling for ATM-AVI PKg,h(see 
PK sampling schema below)
Xg


X
Blood sampling for ATM-AVI PKp (see 
PK sampling schema below)
X









X
Serious and non-serious adverse event 
monitoring
X
X
X












X
X
Prior/Concomitant treatments
X











X
Standardized mealsj
X












X
Discharge from clinic
X
Abbreviations: = ongoing/continuous event; ATM = aztreonam; AVI = avibactam; BSA = body surface area; CRU = clinical research unit; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOT = end of trial; FSH = follicle-stimulating hormone; HCVAb = hepatitis C core 
antibody; HepBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; MDRD = Modification of Diet in Renal Disease; 
PK = pharmacokinetic(s); S = Screening Visit.
a.
Subject will be screened within 28 days prior to administration of the investigational product.
b.
Height measurement only at Screening when full physical examination is performed.
c.
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. 
d.
To confirm eligibility, subjects must have stable renal function defined as 25% difference between 2 measurements of eGFR obtained, from the same 
laboratory, on 2 separate occasions during the Screening period that are at least 72 hours but no more than 14 days apart.  Additionally, difference between 
eGFR Screening 1 value and Day -2 value should be 25%.  The Day -2 eGFR values will be used for group placement.  The eGFR determination will 
utilize the MDRD formula adjusting for BSA (See Section 3.1). 
e.
Pre-dose.
f.
Temperature does not need to be collected at this timepoint.
g.
Instruct subject to void prior to administration of study treatment (pre-dose collection).  Instruct subject to void into the collection container at the end of
each collection period.
h.
Urine will be collected pre-dose on Day 3, and then during collection periods of 0-2, 2-4, 4-6, and 6-8 (Cohort 2 only) hours after dosing.
i.
Limited physical examination.
j.
See Section 4.3.1 for more details.


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Visit Identifier
Screeninga
Day -2
Day -1
Day 1
Day 2
Day 3
Day 4
Follow-upl
S1
S2
Hours post dose
0
0.5
6.5
8.5
0
3
4
6-8
12-16
24
EOT
k.
Loading dose and extended loading dose will be prepared in one infusion bag with an infusion rate change after the first 30 minutes.
l.
A follow-up contact with each subject must occur at least 28 calendar days and up to 35 calendar days after the last administration of the investigational 
product to monitor for any AEs/SAEs and to verify contraception use. Contact with the subject may be done via a phone call.
m. Full physical examination, if deferred from the screening visit.
 
o.
After the full complete physical examination (Screening or Day -2), further examinations will be performed at the discretion of the investigator.
p.
PK blood sample may be collected for the subjects who discontinue the study early for final safety assessments.
C
C
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Pharmacokinetic Sampling Schema 
Visit Identifier 
Study Day
1
2
3
4
Hours Before/After Dose
0
0.5
3.5
6.5
8.5
0
2
3
3.25
3.5
3.75
4
5
6
8
12
16
24
ATM-AVI loading dose
(30 min infusion)i
X
ATM-AVI extended loading dose
(3 hour infusion)i
Xi
ATM-AVI maintenance dose
(3 hour infusion) q6h
Cohort 1 – normal renal function
X


X
ATM-AVI maintenance dose
(3 hour infusion) q8h
Cohort 2 – severe renal impairment
X

X
Blood sampling for ATM-AVI PKk
Xa
Xb
Xc
Xa
X
Xj
X
X
X
X
X
X
X
X
X
X
Capillary sampling for ATM-AVI PKl
Cohort 1 – normal renal function
X
X
X
X
X
X
X
Trough blood sampling for ATM-AVI 
PK
Cohort 1 – normal renal function
Xd


Xe
Trough blood sampling for ATM-AVI 
PK
Cohort 2 – severe renal impairment
Xd

Xe
Urine sampling for ATM-AVI PKf,h
Cohort 1 – normal renal function
Xf







X
Urine sampling for ATM-AVI PKg,h
Cohort 2 – severe renal impairment
Xg








X
Abbreviations: ATM = aztreonam; AVI = avibactam; IV = intravenous; PK = pharmacokinetic.
a.
Predose sample collection.
b.
Collect PK blood sample within 5 min before the end of the loading dose IV infusion.
c.
Collect PK blood sample within 15 min before the end of extended loadng IV infusion.
d.
Collect maintenance pre-dose PK blood sample within 10 min before start of each maintenance dose infusion.
e.
Trough sample does not need to be collected for final maintenance dose on Day 3 as pre-dose sample will already be collected as part of intensive PK 
sampling collection.


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Visit Identifier 
Study Day
1
2
3
4
Hours Before/After Dose
0
0.5
3.5
6.5
8.5
0
2
3
3.25
3.5
3.75
4
5
6
8
12
16
24
f.
Urine will be collected pre dose on Day 3, and then during collection periods of 0-2, 2-4, and 4-6 hours after dosing.
g.
Urine will be collected pre dose on Day 3, and then during collection periods of 0-2, 2-4, 4-6, and 6-8 hours after dosing.
h.
Instruct subject to void prior to administration of study treatment (pre-dose collection).  Instruct subject to void into the collection container at the end of 
each collection period.
i.
Loading dose and extended loading dose will be prepared in one infusion bag with an infusion rate change after the first 30 minutes.
j.
Collect PK blood sample within 15 min before IV infusion stop.
k.
PK blood sample may be collected for the subjects who discontinue the study early for final safety assessments.
l.
Collect finger-prick capillary PK blood sample time-matched to venous PK blood sample for subjects in Cohort 1 – normal renal function.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Aztreonam-avibactam (ATM-AVI) is a combination product that contains the -lactam 
antibiotic aztreonam (ATM) and the non--lactam -lactamase inhibitor avibactam (AVI).  
ATM-AVI is being developed to treat infections caused by resistant Gram-negative 
pathogens, including those with metallo-lactamase (MBL)-mediated drug resistance.
1.2. Background 
The prevalence of multi-drug resistant (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 MDR Gram-negative bacteria.  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.3,4
Aztreonam 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, as well 
as several chemical side groups that interfere with degradation by MBLs.  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 is a novel, non -lactam, -lactamase inhibitor of a broad spectrum of enzymes, 
including Ambler Class A extended-spectrum -lactamases (ESBLs), Class A Klebsiella
pneumoniae carbapenemase (KPC), and Class C (AmpC) enzymes, and some Class D 
enzymes.  Its beneficial effect in combination with aztreonam occurs by inhibiting the 
enzymes that inactivate aztreonam.
Together, aztreonam and avibactam 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 MDR.
Aztreonam has been marketed as a stand-alone product under the tradename AZACTAM
for over 25 years while avibactam was approved in 2015 (US)/2016 (EU) as part of a 
combination product with ceftazdime (AVYCAZ/ZAVICEFTA).
The serum half-life of aztreonam averaged 1.7 hours (1.5 to 2.0 hours) in subjects with 
normal renal function, independent of the dose.  In healthy subjects, based on a 70 kg person, 
the serum clearance (CL) was 91 mL/min and renal clearance (CLr) was 56 mL/min; the 
apparent mean 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 q8h for 7 days to healthy subjects produced no apparent 


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accumulation of aztreonam or modification of its disposition characteristics; serum protein 
binding averaged 56% and was independent of dose.5
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 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.
The carbon-14 [14C] avibactam absorption, distribution, metabolism, and excretion (ADME) 
study showed that an average of 97% (range, 95% to 98%) of administered radioactivity was 
recovered from the urine, over 95% within 12 hours of dosing.  Avibactam is predominantly 
renally cleared and metabolism has little contribution to its excretion.  An average of 
85% (range, 67% to 101%) of administered avibactam was recovered from the urine during 
the study, with >50% being recovered within 2 hours of the start of the infusion.  CLr was 
158 mL/min suggesting active tubular secretion. 
The PK of avibactam (100 mg, single 50-mL IV infusion over 30 minutes) in renally 
impaired patients was assessed in the ceftazidime-avibactam (CAZ-AVI) program. 
Avibactam exposure, expressed by area under the curve (AUC0-), increased with increasing 
level of renal impairment by approximately 2.7-, 3.9-, 7.7-, and 21.3-fold for patients with 
mild, moderate, severe renal impairment, and end-stage renal disease (ESRD), respectively.  
This was associated with a decrease in avibactam clearance with increasing severity of renal 
impairment, which is consistent with CLr being the dominant elimination route.  The 
relationship between avibactam renal clearance and calculated creatinine clearance (CrCL) 
was found to be linear.  The impact on clearance resulted in the increasing half-life from less 
than 2 hours in subjects with normal renal function up to about 8 hours for patients with 
severe renal disease and 22 hours in patients with end-stage renal failure.  Mean Cmax also 
increased with the degree of renal impairment.  The inter-individual variability (expressed by 
the coefficient of variation [CV%]) of Cmax and area under the curve at steady-state (AUCss)
was also markedly higher in patients with renal impairment than in healthy subjects. Time to 
reach Cmax (Tmax) remained consistent at the end of infusion at 30 minutes, and Vss also 
remained roughly comparable across the groups.
The PK of aztreonam has been studied in patients with renal impairment where all subjects 
received a single 1000 mg aztreonam IV bolus dose or as a 2-min IV infusion, with frequent 
blood sampling for at least 24 h post-dose for drug concentration and PK analysis.6,7  Both
studies included a healthy control group (n=6 per study) with creatine clearance (CrCL)
80 mL/min.


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One study6 included patients with various degrees of chronic renal failure (n=12; mean SD 
CrCL 17.8 13.5 mL/min; range 4.8-49.9 mL/min). In this study the half-life (mean SD) 
was significantly increased (p<0.001) from 1.8 0.14 hours in subjects with normal renal 
function to 4.9 1.06 hours in patients with chronic renal failure.  The corresponding 
statistically significant decreases (p<0.001) in aztreonam CL were 84.2 7.8 mL/h/kg in 
subjects with normal renal function to 30.2 9.2 mL/h/kg in patients with chronic renal 
failure.
The other study7 included 4 groups (n=6/group) with CrCL of >80, mL/min, 30-79 mL/min, 
10-29 mL/min, and <10 mL/min, respectively. The half-life (mean SD) increased 
(p<0.001) with decreasing renal function, from 1.98 0.12 h (normal renal function), to 
3.42 0.80 h, 4.76 0.85 h, and 6.02 1.53 h, respectively. Aztreonam CL decreased from 
107 mL/min in subjects with normal renal function to 29 mL/min for functionally anephric 
patients. Urinary excretion (urine collected in intervals up to 48 hours post dose) of 
aztreonam was also determined in this study. Urinary recovery of aztreonam ranged from 
58% of the administered dose in normal subjects to 1.4% in uremic patients.
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.
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 subjects (aztreonam AUCss increased by 22.6%; Css,max
increased by 15.8% and Css,min was increased by 54.4% in elderly subjects).  Corresponding 
changes were observed for avibactam where AUCss increased by 32.7%; Css,max increased 
31.1% and Css,min was increased by 74.2% in elderly compared to young subjects.  Post-hoc 
modelling suggested this may be related to difference in renal function in these patients.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the ATM-AVI Investigator’s Brochure (IB).
A dual-analyte bioanalytical assay has been developed and validated for simultaneous 
analysis of aztreonam and avibactam plasma concentrations from a single microvolume 
plasma sample (minimum 5 µL of plasma) to support planned pediatric clinical trials in the 
ATM-AVI development program.  This assay enables collection of much lower blood sample 
volumes for evaluation of PK in children, including a blood microsample (≤50 µL) that may 
be collected via capillary sampling.  


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1.3. Rationale 
1.3.1. Study Rationale 
Dose adjustment for aztreonam and avibactam are warranted in renal impairment given that 
both are eliminated primarily as unchanged substances by the kidney.  This study is therefore 
being conducted to evaluate the effect of severe renal impairment on the PK, safety and 
tolerability of ATM-AVI.  Results from this study along with previous renal impairment PK 
data from each of the ATM-AVI components will be used to confirm proposed ATM-AVI 
dosing in severe renal impairment which was based on modelling/simulation.
Capillary blood microsamples will be collected from subjects in Cohort 1 (normal renal 
function) at specified time points matched to standard venous blood sample collection to 
evaluate the correlation/concordance of plasma concentrations for aztreonam and avibactam 
from microsampled capillary and venous blood collections. Results from this sub-study will 
be used to confirm the microsampling technique prior to inclusion in pediatric protocols.
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2. Dose Rationale
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.  
The ATM-AVI doses for this Phase 1 study (and proposed for Phase 3) have been selected 
based on pre-clinical and clinical data on ATM-AVI, using PK data for ATM, AVI and 
ATM-AVI and including covariate information collected in healthy volunteers and patients 
to construct a robust population PK model.  Furthermore, AVI PK and safety data together 
with PK/pharmacodynamic (PD) modelling results obtained during development of the new 
CAZ-AVI combination product Avycaz™in the US (Zavicefta® in Europe) have been taken 
into account.8,9
Dose selection (ATM-AVI) for patients with normal renal function
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.  The loading dose for patients 
with normal renal function or mild renal impairment (CrCL or GFR >50 mL/min) is 500 mg 
CCI
CCI


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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 three hour period.  
Three (3) hours after the extended loading dose is completed, a maintenance dose of 1500 mg 
ATM and 500 mg AVI is infused over 3 hours and administered every 6 hours (q6h).  The 
targeted total daily dose on Day 1 is 6500 mg ATM/2167 mg AVI.  From Day 2 onwards, the 
maximum daily dose will be 6000 mg ATM/2000 mg AVI. 
For patients with serious bacterial infections where there are limited or no treatment options, 
it is recommended for -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 a 
>90% probability of target attainment (PTA) against 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 (C3601005) 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 intra-abdominal infections (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 CrCL >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. 


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Dose selection (ATM-AVI) for patients with severe renal impairment (GFR >15 to 
30 mL/min)
In this Phase 1 study, the dose for patients with severe renal impairment (GFR >15 to 
30 mL/min) is a loading dose of 675 mg ATM plus 225 mg AVI by IV infusion over a 
30 minute period, immediately followed by an extended loading dose of 675 mg ATM plus 
225 mg AVI by IV infusion over a 3 hour period, then following a 5 hour gap, maintenance 
dose of 675 mg ATM plus 225 mg AVI by IV infusion over 3 hours q8h.
Doses for patients with impaired renal function are based on PK modeling and simulation.  
The population PK models for both ATM and AVI included data from patients with renal 
impairment which allowed the use of modeling and simulation for dose selection in Phase 2a 
and 3.  The dose selection for patients with severe renal impairment was based on the 
following criteria: matching the predicted ATM steady state area under the curve between 
time 0 and 24 hours after dose (AUC(0-24,ss)) in patients with severe renal impairment, to the 
predicted AUC(0-24,ss) in patients with normal renal function (CrCL >80 mL/min) receiving 
ATM 1500 mg/AVI 500 mg; maintaining the same 3:1 dosing ratio between ATM and AVI; 
and maintaining >90% joint PTA.  Furthermore, since the dosing ratio between ATM and 
AVI is fixed, and given the differential impact of renal impairment on the clearance of ATM 
and AVI, it was accepted that matching an area under the plasma concentration versus time 
curve (AUC) target for ATM would result in exceeding the exposure targets for AVI in 
patients with normal renal function, but should not appreciably exceed the exposure in 
patients with mild renal impairment with the standard dose. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 

To evaluate the pharmacokinetics of the 
co-administration of aztreonam and avibactam 
following multiple doses via IV infusion in subjects 
with severe renal impairment and in healthy subjects 
with normal renal function.

Total daily area under the plasma concentration time
profile from time 0 to 24 hours at steady-state
(AUC0-24,ss) and Cmax.
Secondary Endpoint(s):

Area under the plasma concentration-time profile 
from time 0 to to the time of the end of the dosing 
interval () (AUC0-), Tmax, observed concentration at 
the end of the dosing interval () (C), 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), amount of unchanged 
drug excreted into urine over dosing interval (Ae0-), 
Ae0-expressed as percent of dose (Ae0-%).
Secondary Objective(s): 
Secondary Endpoint(s): 

To evaluate the safety and tolerability of multiple doses 
of aztreonam and avibactam in subjects with severe 
renal impairment and in healthy subjects with normal 
renal function.

Safety will be assessed by physical examinations, 
adverse event (AE) monitoring, 12-lead 
electrocardiograms (ECGs), supine blood pressure and 
pulse rate, and clinical laboratory tests.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s): 


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•
To determine concordance/comparability of capillary
microsample plasma concentrations with venous plasma
concentrations for aztreonam and avibactam in healthy 
subjects with normal renal function.
 
 
•
Comparison of concentrations (capillary 
microsamples collected at specified time points 
matched to venous plasma concentrations) assessed by
X-Y and Bland-Altman (B-A) scatter plots with limits 
of agreement (LoA) for a precision assessment.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open-label, parallel-group study where an IV loading dose (30 min 
infusion) followed by multiple IV doses (3 hr infusion) of ATM-AVI will be administered to 
subjects with severe renal impairment (not on dialysis) and to healthy subjects with normal 
renal function.  Subjects with the following levels of renal function will be enrolled:
Cohort
Renal Impairment
Number of Subjects
eGFRa(mL/min)
1
None (Normal)
6
≥80
2
Severe (Not on dialysis)
5-6
>15 - ≤30
Abbreviations: BSA = body surface area; eGFR = estimated glomerular filtration rate; 
MDRD = Modification of Diet in Renal Disease.
a.
Estimate of eGFR based on the MDRD formula adjusting for BSA.  The Day -2 eGFR values will be 
used for group placement.
•
Step 1: eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) where Scr, std denotes serum creatinine measured with a standardized assay.
•
Step 2: Convert the MDRD-derived, BSA-adjusted eGFR obtained above to absolute eGFR 
(mL/min) for eligibility assessment using the following equation: 
•
eGFR (mL/min) = eGFR (mL/min/1.73 m2) × subject’s BSA where BSA is calculated as 
BSA = (Weight0.425 × Height0.725) × 0.007184.
Approximately 6 subjects will be enrolled into Cohorts 1 and 2.  Due to the potential
difficulty in recruiting subjects with eGFR ≤30 mL/min, the number of subjects to be 
enrolled in this group will be approximately 5-6 in order to have at least 5 evaluable subjects. 
The following equation from the MDRD study will be used to calculate eGFR (Scr, std denotes 
serum creatinine measured with a standardized assay for serum creatinine):
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African-American)
Note that the value of eGFR, which is directly obtained from the lab or calculated using the
equation above, is generally normalized to an average body size of 1.73 m2 for diagnosis, 
prognosis and treatment of renal disease. In terms of clearance of renally filtrated drugs 
(including secreted drugs), renal elimination capacity is related to absolute glomerular 
filtration rate (GFR) in mL/min. To use the MDRD-derived, body surface area
(BSA)-adjusted value of eGFR to obtain absolute GFR (mL/min) for renal disease 
C
C
I
C
C
I


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classification/cohort assignment, this value should be multiplied by the individual subject’s 
BSA (ie, measured BSA/1.73 m2). The BSA of an individual can be calculated by the
following formula as described below:
1. BSA = (Weight0.425 × Height0.725) × 0.007184
In summary, GFR in mL/min calculated as below will be used for group placement: 

Step 1: Obtain the MDRD-derived eGFR:

eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × 
(1.212 if African-American) where Scr, std denotes serum creatinine measured with 
a standardized assay

Step 2: Convert the MDRD-derived, BSA-adjusted eGFR obtained above to absolute 
GFR (mL/min) for eligibility assessment using the following equation: 

eGFR (mL/min) = eGFR (mL/min/1.73 m2) ×subject’s BSA where BSA is 
calculated as BSA = (Weight0.425 × Height0.725) × 0.007184
CrCL will also be estimated from a spot serum creatinine measurement using the following 
Cockcroft-Gault (C-G) equation:
2. CrCL (mL/min) = [140 – age (years)] × total body weight (kg) × (0.85 for females)
72 × serum creatinine (mg/dL)
Note that eGFR calculated by the MDRD equation will be used for group placement.  
Nevertheless, renal function will be estimated using both C-G and MDRD equations in this 
study.
All subjects must have stable renal function to enter the study. Stable renal function is 
defined as 25% difference between 2 measurements of eGFR obtained, from the same 
laboratory, on 2 separate occasions during the screening period that are at least 72 hours but 
no more than 14 days apart. Additionally, difference between eGFR Screening 1 value and 
Day -2 value should be 25%. The Day -2 eGFR value will be used for group placement.  
The CrCL value will be recorded at the same time eGFR is determined.
All screening evaluations will occur within 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 -2.  Subjects will receive a loading/extended loading dose 
followed by multiple doses of IV ATM-AVI according to Table 2 (see Section 5.4). 
Serial blood samples and urine at specified intervals will be collected pre-dose and for 
24 hours following the final maintenance dose administered on the morning of Day 3 for PK
assessments. PK samples will also be collected 0.5 and 3.5 hours after start of loading dose 
on Day 1 as well as trough samples collected just prior to administration of maintenance 


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doses over the course of the study. Subjects from Cohort 2 (severe renal impairment) will be 
recruited first.  The healthy subjects will then be recruited. An attempt will be made to 
choose such that each subject’s age is within 10 years and weight is within 15 kg of the 
mean demographics for the severe renal impairment cohort, and maintain a similar 
male/female ratio (2 subjects per gender). 
The total participation time for each subject in this study will be approximately 6 days 
(excluding Screening).
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects 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 subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Female subjects and/or male subjects who, at the time of Screening, are between the 
ages of 18 and 75 years, inclusive.

Male and female subjects of childbearing potential must agree to use highly 
effective method(s) of contraception (refer to Section 4.3.4).  A subject is of 
childbearing potential if, in the opinion of the investigator, he/she is biologically 
capable of having children and is sexually active.

Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH)
level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are
considered to be of childbearing potential.
2. Body mass index (BMI) of 17.5 to 40.5 kg/m2; and a total body weight >50 kg 
(110 lb).


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3. Stable renal function defined as 25% difference between 2 measurements of eGFR
obtained, from the same laboratory, on 2 separate occasions during the screening 
period that are at least 72 hours but no more than 14 days apart.  Additionally, 
difference between eGFR Screening 1 value and Day -2 value should be 25%.  The 
Day -2 eGFR value will be used for group placement.
4. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
5. Subjects who are willing and able to comply with all scheduled visits, treatment plan,
laboratory tests, and other study procedures.
4.1.1. Specific Requirements for Healthy Subjects with Normal Renal Function
1. Healthy as defined as no clinically relevant abnormalities identified by a detailed 
medical history, full physical examination, including blood pressure (BP) and pulse 
rate (PR) measurement, 12-lead ECG, or clinical laboratory tests.
2. Normal renal function (eGFR 80 mL/min) at Screening based on the Day -2 value,
using the MDRD formula adjusting for BSA (See Section 3.1). 
3. An attempt will be made to enroll demographically comparable to the group of 
subjects with severe impaired renal function.

Body weight within 15 kg of the mean body weight of the group of subjects with 
severe renal impairment.

Age within 10 years of the mean age of the group of subjects with severe renal 
impairment.

Gender ratio for the group similar (2 subjects per gender) to the group of 
subjects with severe renal impairment.
4.1.2. Specific Requirements for Subjects with Severe Renal Impairment
1. Good general health commensurate with the population with chronic kidney disease 
(renal impairment).
2. Documented severe renal impairment indicated by a eGFR >15 - 30 mL/min but not 
requiring hemodialysis, based on the Day -2 value, using the MDRD formula
adjusting for BSA (See Section 3.1).


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
Exclusion Criteria: All Subjects
1. A positive urine drug test.
2. Urinary incontinence without catheterization. 
3. History of regular alcohol consumption exceeding 7 drinks/week for female subjects 
or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months 
before Screening.
4. Treatment with an investigational product within 30 days (or as determined by the 
local requirement) or 5 half-lives preceding the first dose of investigational product
(whichever is longer).
5. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level
>1.0 × upper limit of normal (ULN);

Total bilirubin level >1.0 × ULN; subjects with a history of Gilbert's syndrome 
may have direct bilirubin measured if total bilirubin level >1.0 × ULN and would 
be eligible for this study provided the direct bilirubin level is ULN;

Activated partial thromboplastin time (aPTT), prothrombin time (PT) and/or 
international normalized ratio (INR) >1.0 × ULN.
6. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol (Section 4.3.4) for the 
duration of the study and for at least 28 days after the last dose of investigational 
product.
7. Use of prescription or nonprescription drugs and 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 subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. 


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For subjects with severe renal impairment, concomitant medications may be given if 
they are considered necessary for the welfare of study subjects (eg, standard therapy 
for underlying diseases), are not contraindicated with the study drug, and are unlikely 
to interfere with the PK/PD response of the study drug. Subjects must be receiving 
stable doses of these concomitant medications for at least 28 days before Screening. 
If concomitant medications are likely to interfere with the PK/PD response of the 
study drug, they may be substituted with agents that have similar pharmacological 
effects. 
Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 
(eg, probenecid) are prohibited in this study for all subjects.
8. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
9. History of sensitivity to heparin or heparin-induced thrombocytopenia.
10. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction 
to aztreonam, carbapenem, monobactam or other -lactam antibiotics, avibactam, or 
any of the excipients of the respective (investigational) medicinal products to be 
administered during the study.
11. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive 
testing for HIV, hepatitis B surface antigen (HepBsAg), or hepatitis C antibody 
(HCVAb).
12. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
13. Subjects 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 subjects who are Pfizer employees, including their family members,
directly involved in the conduct of the study.
14. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
15. Subject has past or current history of epilepsy or seizure disorders excluding febrile 
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Exclusion Criteria: Subjects with Severe Renal Impairment
1. Subjects with any significant hepatic, cardiac, or pulmonary disease.
2. Renal allograft recipients or subjects who are clinically nephrotic.
3. Screening supine 12-lead ECG demonstrating QT interval corrected by Fridericia’s 
formula (QTcF) >470 msec or a QRS interval >120 msec.  If initial QTcF exceeds 
470 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and 
the average of the 3 QTcF or QRS values should be used to determine the subject’s 
eligibility.
4. Screening supine BP 180 millimeters of mercury (mm Hg) (systolic) or 
110 mm Hg (diastolic), on a single measurement (confirmed by a single repeat, if 
necessary) following at least 5 minutes of rest.  If BP is 180 mm Hg (systolic) or 
110 mm Hg (diastolic), the BP should be repeated 2 more times and the average of 
the 3 BP values should be used to determine the subject’s eligibility.
5. Subjects requiring dialysis.
Exclusion Criteria: Healthy Subjects with Normal Renal Function
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or 
allergic disease (including clinically relevant and significant drug allergies, but
excluding untreated, asymptomatic, seasonal allergies at time of dosing).
2. Screening supine 12-lead ECG demonstrating QTcF >450 msec or a QRS interval
>120 msec.  If initial QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTcF or QRS values should 
be used to determine the subject’s eligibility.
3. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If BP is 140 mm Hg (systolic) or 90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the subject’s eligibility.
4.3. Lifestyle Requirements
The following guidelines are provided:
4.3.1. Meals and Dietary Restrictions

Subjects 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 approximately 1 hour after dosing on Day 1 (loading 
dose). On Day 3, breakfast will be provided prior to administration of the final 


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maintenance dose 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.

Lunch will be provided approximately 4-5 hours after dosing on Day 1 (loading dose) 
and Day 3 (final dose). Lunch can be given at any time on all other days.

Dinner will be provided approximately 9 to 10 hours after dosing on Day 1 (loading 
dose) and Day 3 (final dose). Dinner can be given at any time on all other days.

An evening snack may be permitted.

The continuation of a renal diet is permitted.

Subjects 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 total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake per subject 
should not exceed approximately 3200 kcal.
4.3.2. Alcohol, Caffeine, and Tobacco

Subjects 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.  Subjects may undergo an alcohol breath test or blood alcohol test at the 
discretion of the investigator.

Subjects will abstain from caffeine-containing products for 24 hours prior to the start 
of dosing until collection of the final PK sample of each study period, and at least 
3 hours prior to ECG evaluations.

Subjects will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
4.3.3. Activity

Subjects 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.
4.3.4. Contraception
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s)
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 


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investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his or her partner(s) from the permitted list of contraception 
methods (see below) and will confirm that the subject 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 subject of the need to use highly effective contraception consistently 
and correctly and document the conversation and the subject’s affirmation in the subject’s
chart (subjects 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 subject 
to call immediately if the selected contraception method is discontinued or if pregnancy is
known or suspected in the subject or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.


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4.4. 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 team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject 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 
subject’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 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product(s) are Azreonam and Avibactam.
5.1. Allocation to Treatment
The investigator will assign subject numbers to the subjects as they are screened for the 
study.  This identifying number will be retained throughout the study.  All subjects enrolled 
will receive 3 days of IV ATM-AVI according to the dose/schedule provided in the 
Section 5.4. 
5.2. Subject Compliance
Investigational product will be administered under the supervision of investigator site 
personnel.
5.3. Investigational Product Supplies
5.3.1. Dosage Form and Packaging
Aztreonam and avibactam will be provided as separate vials for reconstitution and mixed 
together in a saline bag for co-administration at the appropriate concentration for IV infusion 


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using a standard aseptic IV infusion technique (see Investigational Product Manual 
[IP Manual]).
The identity of the investigational product is provided in Table 1.
Table 1.
Identity of Investigational Product
Investigational Productsa
Dosage form and Strength
Aztreonam
Aztreonam for injection, powder for solution for infusion 2000 mg
Avibactam
Avibactam lyophilisate 600 mg/vial Concentrate for solution for infusion
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.
5.3.2. Preparation and Dispensing
See 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. 
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver 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, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.
5.4. Administration
Subjects will receive the loading dose of the investigational product at approximately 
7:30 AM (plus or minus 2 hours) 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 4.3).
On Day 1, 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 (normal renal function) or q8h (severe 
renal impairment) 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).


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Table 2.
Treatment Schema
Day
Administration 
Start Time 
(2 hrs)
Cohort 1
(Normal Renal Function)
Cohort 2
(Severe Renal Impairment)
1
7:30 AM1
30 min IV loading dose infusion 
(500/167 mg ATM/AVI)1
30 min IV loading dose infusion 
(675/225 mg ATM/AVI)1
8:00 AM1
3 hr IV extended loading (1500/500 
mg ATM/AVI)1
3 hr IV extended loading (675/225 
mg ATM/AVI)1
2:00 PM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
4:00 PM
3 hr IV maintenance infusion q8h 
(675/225 mg ATM/AVI)
8:00 PM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
2
12:00 AM
3 hr IV maintenance infusion q8h 
(675/225 mg ATM/AVI)
2:00 AM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
8:00 AM
3 hr IV maintenance infusion q6h
(1500/500 mg ATM/AVI)
3 hr IV maintenance infusion q8h
(675/225 mg ATM/AVI)
2:00 PM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
4:00 PM
3 hr IV maintenance infusion q8h 
(675/225 mg ATM/AVI)
8:00 PM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
3
12:00 AM
3 hr IV maintenance infusion q8h 
(675/225 mg ATM/AVI)
2:00 AM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
8:00 AM
3 hr IV maintenance infusion q6h 
(1500/500 mg ATM/AVI)
3 hr IV maintenance infusion q8h 
(675/225 mg ATM/AVI)
Abbreviations: ATM/AVI = aztreonam/avibactam; hr(s) = hour(s); IV = intravenous; q6h = every 6 hrs; 
q8h = every 8 hrs.
1. Loading dose and extended loading dose will be prepared in one infusion bag with an infusion rate 
change after the first 30 minutes.
5.5. Investigational Product Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
See the IP manual for storage conditions of the product once reconstituted for ATM-AVI.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 


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Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. 
5.6. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  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, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Healthy subjects with normal renal function will abstain from all concomitant treatments
(prescription or over the counter [OTC]) and herbal/dietary supplements during the study,
except for acetaminophen 1 g/dayand the treatment of AEs.  Limited use of nonprescription 
medications that are not believed to affect subject safety or the overall results of the study 
may be permitted on a case-by-case basis following approval by the sponsor.
For subjects with severe renal impairment, concomitant medications may be given if they are 
considered necessary for the welfare of study subjects (eg, standard therapy for underlying


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diseases), are not contraindicated with the study drug, and are unlikely to interfere with the 
PK/PD response of the study drug. Subjects must be receiving stable doses of these 
concomitant medications for at least 28 days before Screening.  If concomitant medications 
are likely to interfere with the PK/PD response of the study drug, they may be substituted 
with agents that have similar pharmacological effects. 
Use of oral anticoagulants and potent inhibitors of OAT1 and/or OAT3 (eg, probenecid) are 
prohibited in this study for all subjects.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects 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. STUDY PROCEDURES
6.1. Screening
Subjects will be screened within 28 days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in the Subject Information and Consent
section.  If the time between screening and dosing exceeds 28 days as a result of unexpected 
delays (eg, delayed drug shipment), then subjects do not require rescreening if the 
Day -2 laboratory results meet the eligibility criteria.
Two (2) screening visits that are at least 72 hours but no more than 14 days apart are required 
for this study.
The following procedures will be completed for Screening Visit 1:

Obtain written informed consent.

Confirm and document that the subject meets the inclusion/exclusion criteria.

Collect demography.

Collect height and weight.

Obtain medical history, including history of illegal drug, alcohol, and tobacco use.

Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 28 days prior to the planned first dose.

Obtain single supine BP, PR and temperature.


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
Conduct full physical examination. 

Collect single 12-lead ECG.

Following at least a 4-hour fast, collect blood and urine specimens for the following:

Safety laboratory tests;

Urine drug test;

Serum FSH concentration for any female subject who has been amenorrheic for at 
least 12 consecutive months;

HIV, HepBsAg, and HCVAb testing;

Serum or urine beta-human chorionic gonadotropin (-hCG) level for all female
subjects of childbearing potential;

Confirm highly effective contraception is being used;

eGFR assessment.  To confirm eligibility, subjects must have stable renal function 
defined as 25% difference between 2 measurements of eGFR obtained, from the 
same laboratory, on 2 separate occasions during the Screening period that are at 
least 72 hours but no more than 14 days apart.  Additionally, difference between 
eGFR Screening 1 value and Day -2 value should be 25%. The Day -2 eGFR
value will be used for group placement.  The eGFR determination will utilize the 
MDRD formula adjusting for BSA (See Section 3.1).  The CrCL value will be 
recorded at the same time eGFR is determined.

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” 
The following procedures will be completed for Screening Visit 2:

Following at least a 4-hour fast, collect blood sample for eGFR assessment.

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” 
To prepare for study participation, subjects will be instructed on the information in the 
Lifestyle Requirements and Concomitant Treatment(s) sections of the protocol.


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6.2. Study Period
For the study period described below, 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: 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 temperature) should be collected prior to the insertion of the 
catheter.  Blood obtained for PK samples should not be taken from the same IV line 
used to administer study drugs.
6.2.1. Day -2
Subjects will be admitted to the CRU on Day -2.  The following procedures will be 
completed following admission to the CRU:

Review inclusion and exclusion criteria.

Review changes in the subject’s medical history including medication history, illegal 
drug, alcohol and tobacco use since Screening.

Measure weight.

Obtain blood and urine samples for safety laboratory tests.  The results must have no 
clinically significant findings, as judged by the investigator, in order for a subject to 
be dosed on Day 1.

Collect urine for drug testing.

Collect serum or urine pregnancy test for female subjects of childbearing potential. 

Confirm highly effective contraception is being used.

Conduct full physical examination, if deferred from the screening visit.

Assess baseline symptoms/AEs.


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•
Assess eGFR: The Day -2 eGFR value will be used for group placement.  To confirm 
eligibility, subjects must have stable renal function defined as ≤25% difference 
between 2 measurements of eGFR obtained, from the same laboratory, on 2 separate 
occasions during the Screening period that are at least 72 hours but no more than 
14 days apart.  Additionally, difference between eGFR Screening 1 value and 
Day -2 value should be ≤25%. The eGFR determination will utilize the MDRD
formula adjusting for BSA (See Section 3.1).  The CrCL value will be recorded at the 
same time eGFR is determined.
•
Standardized meals will be provided as described in Section 4.3.
•
 
6.2.2. Day -1
The following procedures will be completed on Day -1:
•
Assess baseline symptoms/AEs.
•
Commence prior treatment monitoring.
•
Standardized meals will be provided as described in Section 4.3.1.
Subjects will begin fasting at least 4 hours prior to dosing on Day 1.
6.2.3. Day 1
Prior to dosing, the following procedures will be completed:
•
Assess baseline symptoms/AEs.
•
Collect single 12-lead ECG measurements prior to insertion of the IV catheter.
•
Collect single supine BP and PR and temperature prior to insertion of the IV catheter.
•
Collect pre-dose blood sample for PK analysis (within 1hour before start of loading 
dose infusion).
•
Monitor prior treatment.
•
After all predose procedures have been completed, administer the ATM-AVI 30 min 
loading dose infusion immediately followed by the 3 hour extended loading dose.
Loading dose and extended loading dose will be prepared in one infusion bag with an 
infusion rate change after the first 30 min (see Section 5 and Section 5.4). 
•
Standardized meals will be provided as described in Section 4.3.1.
C
C
CCI


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After dosing of loading dose infusion, the following procedures will be completed:

Obtain single 12-lead ECG measurements at 0.5 hour after dosing. (Breakfast should 
not be given prior to this ECG assessment).

Assess single supine BP and PR at 0.5 hour after dosing.

Collect blood samples for PK analysis at 0.5 (within 5 min before the end of the
loading dose IV infusion) and 3.5 (within 15 min before the end of extended load IV 
infusion) hours after start of loading dose on Day 1.  Both a venous blood sample and 
a finger-prick capillary blood sample will be collected (time-matched) from subjects
in Cohort 1 (normal renal function).

Collect maintenance pre-dose (trough) blood sample for PK analysis (within 10 min
before start of maintenance dose infusion). Both a venous blood sample and a finger-
prick capillary blood sample will be collected (time-matched) from subjects in Cohort 
1 (normal renal function).

Monitor concomitant treatment.

Administer the ATM-AVI maintenance dose infusion q6h (normal renal function) and 
q8h (severe renal impairment) (see Section 5 and Section 5.4).

Standardized meals will be provided as described in Section 4.3.1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.4. Day 2
The following procedures will be completed:

Following at least a 4-hour fast, collect blood and urine specimens for safety 
laboratory tests in the morning; obtain a fresh 6 mL urine sample for urinalysis.

Assess single supine BP and PR in the morning prior to dosing of maintenance dose
administered at approximately 8:00 AM.

Collect maintenance pre-dose (trough) blood sample for PK analysis (within 10 min
before start of each maintenance dose infusion).

Administer the ATM-AVI maintenance dose infusion q6h (normal renal function) and 
q8h (severe renal impairment) (see Section 5 and Section 5.4).

Monitor concomitant treatment.

Standardized meals will be provided as described in Section 4.3.1.


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
Assess symptoms by spontaneous reporting of AEs and by asking the subjects to
respond to a nonleading question such as “How do you feel?”
6.2.5. Day 3
The following procedures will be completed: 

Collect maintenance pre-dose (trough) blood sample for PK analysis (within 10 min
before start of each maintenance dose infusion).
Prior to dosing of final maintenance dose, the following procedures will be completed:

Following at least a 4-hour fast, collect blood and urine specimens for safety 
laboratory tests; obtain a fresh 6 mL urine sample for urinalysis.

Collect single 12-lead ECG measurements prior to insertion of the IV catheter (if 
catheter not already inserted). 

Collect single supine BP and PR prior to insertion of the IV catheter (if catheter not 
already inserted).

Breakfast will be provided prior to administration of the final maintenance dose but 
after the above procedures (safety laboratory tests, ECG, BP and PR) have been 
completed. 

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Collect maintenance pre-dose blood sample for PK analysis (within 10 min before 
start of each maintenance dose infusion).

Each subject will empty his or her bladder just prior to dosing (Dose given just prior 
to intensive PK assessment).

Monitor concomitant treatment.

After all predose procedures have been completed, administer the ATM-AVI
maintenance dose (see Section 5 and Section 5.4). 
After dosing of final maintenance dose, the following procedures will be completed:

Obtain single 12-lead ECG measurements at 3 hours after dosing.

Assess single supine BP and PR at 3 hours after dosing.

Collect venous blood samples for PK analysis at 2, 3 (within 15 min before IV 
infusion stop), 3.25, 3.5, 3.75, 4, 5, 6, 8, 12 and 16 hours after start of maintenance 


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dose infusion on Day 3.  Also collect a finger-prick capillary blood sample (time-
matched) from subjects in Cohort 1 (normal renal function) at the following times: 3
(within 15 min before IV infusion stop), 4, 5, and 6 hours after start of maintenance 
dose infusion. Trough sample does not need to be collected for final maintenance
dose on Day 3 as pre-dose sample will already be collected as part of intensive PK 
sampling collection.

Collect urine over the following intervals: 

0 to 2 hours after start of maintenance dose on Day 3;

2 to 4 hours after start of maintenance dose on Day 3;

4 to 6 hours after start of maintenance dose on Day 3;

6 to 8 hours after start of maintenance dose on Day 3 (Cohort 2 only).

Monitor concomitant medication.

Standardized meals will be provided as described in Section 4.3.1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.6. Day 4 (end of trial [EOT])
The following procedures will be completed:

Conduct limited physical examination. 

Perform single 12-lead ECG.

Obtain single supine BP and PR and temperature.

Following at least a 4-hour fast, collect blood and urine specimens for safety 
laboratory tests; obtain a fresh 6 mL urine sample for urinalysis. 

Collect blood samples for PK analysis at 24 hours after start of last maintenance dose 
infusion on Day 3.

Monitor concomitant treatment.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” 

Standardized meals will be provided as described in Section 4.3.1.


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
Discharge from CRU confinement.
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.
6.3. Follow-up 
6.3.1. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject
may be done via a phone call.
6.4. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety (see also the
Withdrawal From the Study Due to Adverse Events (see also the Subject Withdrawal
section)) or, behavioral reasons, or the inability of the subject to comply with the
protocol-required schedule of study visits or procedures at a given study site.  The early 
termination visit applies only to subjects who are randomized and then are prematurely 
withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or CRU staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return for a final visit, if applicable, and follow-up with the subject 
regarding any unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  Assessments may 
include:

Full physical examination, if there is a new or open AE or clinically significant 
abnormal physical finding from the last visit;


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
Supine BP and PR measurements;

12-lead ECG;

Blood and urine specimens for safety laboratory tests;

Blood sample for PK analysis.
If the subject withdraws from the study and also withdraws consent 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.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the Sponsor.
7. ASSESSMENTS
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 subject.  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 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.
7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests (Table 3) will be performed at times defined in
Section 6 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 concerns.


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Table 3.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
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)
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
Microscopya
FSH
Urine drug screening
β-hCGb
Hepatitis B surface antigen
Hepatitis C core antibody
Human immunodeficiency 
virus (HIV)
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
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
Serum or urine -hCG for female subjects of childbearing potential.

The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.

Subjects may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for subjects to receive 
investigational product.
7.1.2. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed at Screening and at admission on 
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A negative pregnancy test result is required before the subject may receive the ATM-AVI.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected). Pregnancy tests may 
also be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs)
or if required by local regulations.
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the investigator site in accordance with instructions provided in its 
package insert.  Subjects who have missed a menstrual period or who show an indeterminate
or positive result on the urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from
administration of investigational product and from the study.
7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
and gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Subjects 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. 
Height measurement only at screening when full physical examination is performed.
7.1.4. Blood Pressure and Pulse Rate
BP and PR will be measured at times specified in Section 6 of this protocol.  Additional 
collection times, or changes to collection times, of BP and PR will be permitted, as 
necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. BP should not be taken 
from the arm with an IV infusion.  Subjects should be instructed not to speak during 
measurements.


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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.  When the 
timing of these measurements coincides with a blood collection, BP and PR should be 
obtained prior to the nominal time of the blood collection.
7.1.5. Temperature
Temperature will be measured temporally or orally.  No eating, drinking, or smoking is 
allowed for 15 minutes prior to the measurement.
7.1.6. Electrocardiogram 
Twelve (12)-Lead ECGs should be collected at times specified in Section 6 of this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
To ensure safety of the subjects, 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 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 
subject 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).
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.
7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of Aztreonam-Avibactam
During all study periods, venous blood samples (2 mL) to provide approximately 1.0 mL of
plasma for PK analysis will be collected into appropriately labeled tubes containing Sodium 
Fluoride/Potassium Oxalate (grey top) at times specified in Section 6 of the protocol.  


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On Day 1 and Day 3, capillary blood microsamples (approximately 65 µL) to provide 30-35
µL of plasma for PK analysis will be collected from a finger-prick into capillary tubes 
containing Sodium Fluoride/Potassium Oxalate at times specified in Section 6 of the protocol
(subjects with normal renal function only). Capillary sampling will be from the second and
third finger (ie, ring and middle finger) after proper preparation and puncture of the skin.  
Details of the procedure for capillary sampling are provided in the Laboratory Manual. After 
collection, capillary tubes will be placed into appropriately labeled holders for processing. 
Sample handling details for both venous and capillary blood 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
(DCT) (eg, case report form [CRF]).
Samples will be analyzed using a validated analytical method in compliance with Pfizer & 
vendor standard operating procedures (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.
As part of understanding the PK of the investigational product, samples may be used for
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
internal exploratory purposes.  These data will not be included in the clinical study report 
(CSR).
7.2.2. Urine for Analysis of Aztreonam-Avibactam
Urine will be collected at times specified in Section 6 of the protocol.  Each subject will 
empty his or her bladder just prior to the last maintenance dose being administered at 
approximately 8:00 AM on Day 3.  Each subject will be instructed to void into the collection 
container at the end of each collection period.
Samples will be analyzed using a validated analytical method in compliance with Pfizer & 
vendor 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.


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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 investigational product, 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.
7.3. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 86 mL
for subjects with normal renal function and 81 mL for subjects with severe renal impairment.  
The actual collection times of blood sampling may change.  Additional blood samples may 
be taken for safety assessments at times specified by Pfizer, provided the total volume taken 
during the study does not exceed 550 mL during any period of 60 consecutive days.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
CCI
CCI
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Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see Section 8.2.3).  In addition, the investigator may be requested by Pfizer Safety to obtain 
specific follow-up information in an expedited fashion.  This information is more detailed 
than that recorded on the CRF.  In general, this 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 subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer 
Safety.  Any pertinent additional information must be reported on the CT SAE Report Form; 
additional source documents (eg, medical records, CRF, laboratory data) are to be sent to 
Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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 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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’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.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 


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(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
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.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;


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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met:

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result 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; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are 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.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);


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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;

Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as SAEs.  However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an SAE.  For 
example, an acute appendicitis that begins during the reporting period should be 
reported if the SAE requirements are met, and the resulting appendectomy should be 
recorded as treatment of the AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. 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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 


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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 lab 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 subject’s 
individual baseline values and underlying conditions.  Subjects 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:

Subjects 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 subjects 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).

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 subject 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, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
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 


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history, including relevant information, such as review of ethanol, acetaminophen (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) 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 live function test (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.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, 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.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 


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reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
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 includes 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 investigational product. 
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 subject with the Pregnant Partner Release of Information Form
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  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’s administration, the SAE is reported together with the exposure during breastfeeding.


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8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject 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.
8.4.3. Medication Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack 
of efficacy 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
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 immediately.
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 non-serious, are recorded on an AE page of the 
CRF. 


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.3.2. Lack of Efficacy 
Lack of efficacy in an approved indication should be reported as an SAE to Pfizer Safety.
9. DATA ANALYSIS/STATISTICAL METHODS
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. Sample Size Determination
Approximately 6 subjects will be enrolled into each the normal renal function group and the 
severe renal impairment group as described in Section 3.1.  The sample size is based on 
recommendations from the “food and drug administration (FDA) Guidance for 
Industry - Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data 
Analysis, and Impact on Dosing and Labeling”.10  Subjects who discontinue from the study 
before completing all assessments may be replaced at the discretion of the investigator and 
Sponsor.
A total of 42 capillary microsamples (7 samples per subject) will be collected from subjects 
in the normal renal function group at pre-specified time points on Day 1 and Day 3 as 
described in Section 6.2. The sample size of capillary microsamples time-matched to venous 
samples is based on recommendations from the “Land O’Lakes Microsampling workshop
organized by the American Association of Pharmaceutical Scientists (AAPS)”.11 Allowing 
for up to a 10% difference between capillary and venous plasma concentrations, between 30 
to 40 data points at minimum are recommended where the intra-sample variability (%CV) is 
<20%. Precision (%CV) is ≤10% for concentrations spanning the calibration curve of the
dual-analyte bioanalytical assay validated for simultaneous analysis of aztreonam and 
avibactam plasma concentrations from a single microvolume plasma sample.
9.2. Efficacy Analysis
Efficacy analysis is not applicable to this study. 
9.3. Pharmacokinetic Analysis
The PK concentration population is defined as all subjects treated with study drug who have 
at least 1 ATM and AVI concentration measurement.
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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Analysis of variance (ANOVA) will be used to compare the natural log transformed 
AUC0-24,ss and Cmax between the normal renal function group and the severe renal impairment 
group. The geometric least squares mean point estimate and the associated 90% confidence 
intervals (CIs) for the difference of each comparison will be estimated. 
Aztreonam and avibactam PK parameters AUC0-24,ss, Cmax, AUC0-τ, Tmax, C, t½, CL, CLr, VZ, 
Vss, Ae0-τ, Ae0-τ % will be summarized descriptively by group.
Box plots of mean, median and individual subject parameters will be made across both
groups for AUC0-24,ss,Cmax and C.  Concentrations will be listed and summarized 
descriptively by PK sampling time and group.  Summary profiles (means and medians) of the 
concentration-time data will be plotted across different groups.  Individual subject 
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 subject plots by 
time, the actual PK sampling time will be used.
Attainment of steady state will be evaluated by a graphical presentation of pre-infusion
concentration (trough) values on Days 1-3.
9.3.1. Plasma
PK parameters of aztreonam and avibactam following multiple dose administration will be 
derived from the venous plasma concentration-time profiles as follows:
Parameter
Definition
Method of Determination
AUC0-24,ss
Total daily area under the plasma 
concentration-time profile from time 0
to 24 hours at steady-state
Normal renal function (Cohort 1): 
AUC0-× 4 (= 6 hours)
Severe renal impairment (Cohort 2):
AUC0-× 3 (= 8 hours)
AUC0-
Area under the plasma 
concentration-time profile from time 0
to to the time of the end of the dosing 
interval ()b
Linear/Log trapezoidal rule
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
C
Observed concentration at the end of 
the dosing interval ()b
Observed directly from data
t½a
Terminal elimination half-life
Loge(2)/kel, where kel is the terminal phase 
rate constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only those data 
points judged to describe the terminal 
log-linear decline will be used in the 
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Parameter
Definition
Method of Determination
CL
Clearance
Dose/AUC0-
Vss
Apparent volume of distribution at 
steady-state
Volume of distribution at steady state is 
calculated as: Vss = CL × MRT
Mean residence time (MRT) is calculated 
as: MRT = AUMC0-/AUC0-- (infusion 
time/2)
Area under the first moment curve from 0
time to (AUMC0-) is calculated as: 
AUMC0-= ((t × Cest
1*)/kel) + (Cest
1*/kel
2)    
1Cest = e(-KEL × Tlast) × KELC0
Vz
Apparent volume of distribution
during terminal phase
Dose/(AUC0-× kel)
a.
If data permit.
b.
= 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
Actual PK sampling times and non-compartmental methods will be used in the derivation of 
PK parameters.
Capillary Plasma Microsamples
To determine concordance/comparability of capillary microsample plasma concentrations
with venous plasma concentrations, X-Y and Bland-Altman (B-A) scatter plots with limits of 
agreement (LoA) for a precision assessment will be used.
The Bland-Altman scatterplot will include the difference of the 2 measurements divided by 
the mean (% difference) for each sample on the vertical axis and the average of the 2
measurements on the horizontal axis. Three horizontal reference lines will be superimposed 
on the scatterplot - one line at the average percent difference between the measurements and
lines to mark the upper and lower limits of 95% CI. The same plot will be generated for 
difference of the 2 measurements (vertical axis) and the average of the 2 measurements on 
the horizontal axis.
If the 2 methods are comparable, then % differences/differences should be negligible, with 
the mean of the differences close to 0, and show no systematic variation with the mean of the 
2 measurements.
Venous and capillary observed plasma concentrations, individual subject differences and % 
differences of concentrations will be listed and summarized descriptively by PK sampling 
time.


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9.3.2. Urine
Urine PK parameters of aztreonam and avibactam following multiple dose administration of 
ATM-AVI will be derived as follows:
Parameter
Definition
Method of Determination
Ae0-
Total amount of unchanged drug excreted in the 
urine over the dosing interval ()a
Sum of amount excreted for each 
collection period.
Ae0-% 
Total amount of unchanged drug excreted in the 
urine over the dosing interval ()a, expressed as 
percent of dose
100 × (Ae0-/Dose)
CLr
Renal clearance
Ae0-/AUC0-
a.
= 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal impairment (Cohort 2).
9.4. Safety Analysis
AEs, ECGs, BP, PR, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of subjects.  Any clinical laboratory, 
ECG, BP, and PR abnormalities of potential clinical concern will be described.  Safety data 
will be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
Medical history and physical examination information 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.
9.4.1. Electrocardiogram Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
450 - 480
>480
Absolute change
30-60
>60
In addition, the number of subjects with corrected and uncorrected QT values >500 msec will 
be summarized.


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9.5. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
9.6. Interim Analysis 
No formal interim analysis will be conducted 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.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs/DCTs are accurate.  The investigator and institution
will allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, 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. 
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF/DCT should be understood to refer to either a paper 
form or an electronic data record or both, depending on the data collection method used in 
this study.


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A CRF/DCT is required and should be completed for each included subject.  The completed 
original CRFs/DCTs are the sole property of Pfizer and should not be made available in any 
form to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs/DCTs are securely stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to prevent access by 
unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs/DCTs and any other data collection forms 
(source documents) and ensuring that they are accurate, authentic/original, attributable, 
complete, consistent, legible, timely (contemporaneous), enduring, and available when 
required.  The CRFs/DCTs must be signed by the investigator or by an authorized staff 
member to attest that the data contained on the CRFs/DCTs are true.  Any corrections to 
entries made in the CRFs/DCTs or source documents must be dated, initialed, and explained 
(if necessary) and should not obscure the original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases,
data collected on the CRFs/DCTs must match those charts. 
In some cases, the CRF/DCT may also serve as the source document. In these cases, a 
document should be available at the investigator site and at Pfizer that clearly identifies those 
data that will be recorded on the CRF/DCT, and for which the CRF/DCT will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs/DCTs and hospital records), all original 
signed informed consent documents, copies of all CRFs/DCTs, safety reporting forms, source 
documents, detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The 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 shall 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 natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  


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The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject, 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 investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed, unless a waiver of 
informed consent has been granted by an IRB/EC.  The investigator will retain the original of 
each subject's signed consent document.
12.4. 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 investigational 
product, 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 subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States 
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06947387 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs/DCTs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (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 US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.


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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 US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


Aztreonam-Avibactam 
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PFIZER CONFIDENTIAL
Page 66
16. REFERENCES
1.
Lucasti C, Popescu I, Ramesh MK,et al. Comparative study of the efficacy and safety of 
ceftazidime/avibactam plus Metronidazole versus meropenem in the treatment of 
complicated intra-abdominal infections in hospitalized adults: results of a randomized,
double-blind, Phase II trial. J Antimicrob Chemother 2013;68(5):1183-92.
2.
Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug resistant, extensively 
drug-resistant and pandrug-resistant bacteria: an international expert proposal for 
interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18: 
268–81.
3.
Innovative Medicines Initiativ. http://www.imi.europa.eu/ (last accessed: 20 February 
2018).
4.
Innovative Medicines Initiative ND4BB Topic 5: Clinical development of antibacterial 
agents for Gram negative antibiotic resistant pathogens. 
https://www.imi.europa.eu/sites/default/files/archive/uploads/documents/9th_Call/ND4
BB_Topic5.pdf (last accessed: 20 February 2018).
5.
AZACTAM(US prescribing information). Bristol-Myers Squibb; 2013.  
http://packageinserts.bms.com/pi/pi_azactam.pdf. Accessed 20 February 2018.
6.
El Guinaidy MA, Nawishy S, Abd El Bary M, et al. Single-dose pharmacokinetics of
aztreonam in healthy volunteers and renal failure patients. J Chemother 
1989;1(3):164-9.
7.
Mihindu JC, Scheld WM, Bolton ND, et al. Pharmacokinetics of aztreonam in patients 
with various degrees of renal dysfunction. Antimicrob Agents Chemother 
1983;24(2):252-61.
8.
AVYCAZ(US prescribing information). Allergan; 2018.  
https://www.allergan.com/assets/pdf/avycaz_pi.
9.
ZAVICEFTA(summary of product characteristics). Pfizer; 2017.  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004027/WC500210234.pdf.
10.
Guidance for Industry: Pharmacokinetics in patients with impaired renal function   
Study design, data analysis, and impact on dosing and labeling. Draft FDA Guidance, 
March 2010.
11.
Wickremsinhe ER, Ji QC, Gleason CR, Anderson M, Booth BP.  Land O’Lakes 
Workshop on Microsampling: Enabling Broader Adoption.  The AAPS Journal
2020;22:135.


Aztreonam-Avibactam 
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Final Protocol Amendment 1, 14 July 2021
PFIZER CONFIDENTIAL
Page 67
Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
14C
carbon-14
%CV
coefficient of variation as percentage
AAPS
American Association of Pharmaceutical Scientists
Abs
absolute
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
Ae0-
total amount of unchanged drug excreted in the urine over dosing 
interval
Ae0-%
Total amount of unchanged drug excreted in the urine over dosing 
interval, expressed as percent of dose
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATM
aztreonam
ATM-AVI
aztreonam-avibactam
AUC
area under the curve
AUC0-24,ss
Total daily area under the plasma concentration time profile from 
time 0 to 24 hours at steady-state
AUC0-
area under the plasma concentration-time profile from time 0 to to 
the time of the end of the dosing interval ()
AUCss
area under the curve at steady-state
AVI
avibactam
B-A
Bland-Altman
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
C-G
Cockcroft-Gault
CAZ
ceftazidime
CAZ-AVI
ceftazidime-avibactam
CI
confidence interval
cIAI
complicated intra-abdominal infections
CK
creatine kinase
CL
Clearance


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PFIZER CONFIDENTIAL
Page 68
Abbreviation
Term
CLr
renal clearance
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CO2
carbon dioxide (bicarbonate)
CrCL
creatinine clearance
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
Cτ
observed concentration at the end of the dosing interval (τ)
CT
threshold concentration
CT
clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CTX-M
cefotaximase -M
CV%
coefficient of variation
DCT
data collection tool
DILI
drug-induced liver injury
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
ESBL
extended spectrum β-lactamase
ESRD
end-stage renal disease
EU
European Union
EudraCT
European Clinical Trials Database
FDA
food and drug administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
hCG
human chorionic gonadotropin
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IND
investigational new drug application
CCI
C
CI


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Page 69
Abbreviation
Term
INR
international normalized ratio
IP manual
investigational product manual
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
KPC
Klebsiella pneumonia carbapenemase
LFT
liver function test
LSLV
last subject last visit 
MBL
metallo-β lactamase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multidrug resistant
MDRD
Modification of Diet in Renal Disease
MIC
minimum inhibitory concentration
N/A
not applicable
NDM
New Delhi Metallo-β-lactamase
OAT
organic anion transporter
OTC
over the counter
OXA
Oxacillinase
PCD
primary completion date
PD
pharmacodynamic(s)
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
QTc
corrected QT
QTcF
QT interval corrected by Fridericia’s formula
qual
qualitative
RBC
red blood cell
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
statistical analysis plan
CCI
CCI


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Page 70
Abbreviation
Term
SCr
serum creatinine
SD
standard deviation
SOP
standard operating procedure
SRSD
single reference safety document
t½
terminal elimination half life
TBili
total bilirubin
THC
tetrahydrocannabinol
Tmax
Time for Cmax
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

SAP_001.pdf: 
Protocol C3601006 (PF-06947387) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol C3601006
AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC 
STUDY OF MULTIPLE INTRAVENOUS DOSES OF 
AZTREONAM AND AVIBACTAM IN SUBJECTS WITH 
SEVERE RENAL IMPAIRMENT AND NORMAL RENAL
FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
2.0
SAP Author: 
(FSP Statistician –
)
Date:
27-AUG-2021
PPD
PPD


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PFIZER CONFIDENTIAL
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1
July 29, 2018
Not Applicable
2
August 27, 2021
•
Section 2.2:
Addition of an exploratory objective:
To determine concordance/comparability of
capillary microsample plasma concentrations 
with venous plasma concentrations for 
aztreonam and avibactam in healthy subjects 
with normal renal function (Cohort 1).
•
Section 8.2.2:
Addition of statistical analysis methodology 
about Capillary Plasma Microsamples.
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
PPD


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................5
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................8
4. HYPOTHESES AND DECISION RULES...........................................................................8
4.1. Statistical Hypotheses ...............................................................................................8
4.2. Statistical Decision Rules..........................................................................................8
5. ANALYSIS SETS .................................................................................................................8
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................8
5.1.1. Concentration Analysis Set...........................................................................8
5.1.2. Parameter Analysis Set.................................................................................8
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................9
5.5. Treatment Misallocations..........................................................................................9
5.6. Protocol Deviations...................................................................................................9
5.6.1. Deviations Assessed Prior to Randomization...............................................9
5.6.2. Deviations Assessed Post-Randomization....................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.3. Other Endpoints.......................................................................................................10
6.3.1. PK Endpoints..............................................................................................10
6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................11


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7.1. Concentrations Below the Limit of Quantification.................................................11
7.2. Deviations, Missing Concentrations and Anomalous Values .................................11
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................12
8.1. Statistical Methods ..................................................................................................12
8.2. Statistical Analyses .................................................................................................12
8.2.1. Pharmacokinetic Analysis ..........................................................................12
8.2.2. Capillary Plasma Microsamples .................................................................13
8.3. Safety Analysis........................................................................................................14
8.3.1. Treatment and Disposition of Subjects.......................................................14
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................15
8.3.8. Other Safety Data .......................................................................................15
8.3.9. Concomitant Treatments.............................................................................15
8.3.10. Screening and Other Special Purpose Data ..............................................15
9. REFERENCES ....................................................................................................................16
10. APPENDICES ...................................................................................................................17
LIST OF TABLES
Table 1.
Group Assignment Based on eGFR (estimated glomerular filtration 
rate) Estimates ............................................................................................6
Table 2.
Noncompartmental PK Parameters...........................................................10
Table 3.
Aztreonam and avibactam PK Parameters to be Summarized 
Descriptively by Group.............................................................................12
LIST OF FIGURES
None


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APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................17


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1. AMENDMENTS FROM PREVIOUS VERSION(S)
This Statistical Analysis Plan for Study C3601006 is based on the Protocol Amendment 1,
dated 14 February 2021 as follows:

Added a tertiary/exploratory objective to Section 2.2, to determine 
concordance/comparability of capillary microsample plasma concentrations with 
venous plasma concentrations for aztreonam and avibactam.

New Section 8.2.2 added to describe additional scatter plots.
2. INTRODUCTION
Aztreonam-avibactam (ATM-AVI) is a combination product that contains the β-lactam 
antibiotic aztreonam (ATM) and the non-β-lactam β-lactamase inhibitor avibactam (AVI). 
ATM-AVI is being developed to treat infections caused by resistant Gram-negative 
pathogens, including those with metallo-β lactamase (MBL)-mediated drug resistance.
Dose adjustment for aztreonam and avibactam are warranted in renal impairment given that
both are eliminated primarily as unchanged substances by the kidney. This study is therefore
being conducted to evaluate the effect of severe renal impairment on the PK, safety and
tolerability of ATM-AVI. Results from this study along with previous renal impairment PK
data from each of the ATM-AVI components will be used to confirm proposed ATM-AVI
dosing in severe renal impairment which was based on modelling/simulation.
2.1. Study Design
This is a Phase 1, open-label, parallel-group study where an IV loading dose (30 min
infusion) followed by multiple IV doses (3 hr infusion) of ATM-AVI will be administered to
subjects with severe renal impairment (not on dialysis) and to healthy subjects with normal
renal function. Subjects with the following levels of renal function will be enrolled:
Table 1.
Group Assignment Based on eGFR (estimated glomerular filtration rate) 
Estimates
Cohort (n)
Description
Estimated eGFRa (mL/min)
1 (n=6 subjects)
None (Normal)
≥80
2 (n=5 to 6 subjects)
Severe (Not on dialysis)
>15 - ≤30
Abbreviations: BSA = body surface area; eGFR = estimated glomerular filtration rate;
MDRD = Modification of Diet in Renal Disease.
a. Estimate of eGFR based on the MDRD formula adjusting for BSA. The Day -2 eGFR values will be used for 
group placement.

Step 1: eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if African American) where Scr, std denotes serum creatinine measured with a 
standardized assay.


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
Step 2: Convert the MDRD-derived, BSA-adjusted eGFR obtained above to absolute 
eGFR (mL/min) for eligibility assessment using the following equation:

eGFR (mL/min) = eGFR (mL/min/1.73 m2) × subject’s BSA where BSA is 
calculated as BSA = (Weight0.425 × Height0.725) × 0.007184.
Approximately 6 subjects will be enrolled into Cohorts 1 and 2. Due to the potential
difficulty in recruiting subjects with eGFR ≤30 mL/min, the number of subjects to be enrolled 
in this group will be approximately 5-6 in order to have at least 5 evaluable subjects.
CLCR will also be estimated from a spot serum creatinine measurement using the following
Cockcroft-Gault (C-G) equation:
1. CLcr (mL/min) =
(mg/dL)
creatinine
serum
 x 
72
females)
for 
(0.85
 x 
(kg)
t 
body weigh
 x total
(years)]
Age
[140 
Note that eGFR calculated by the MDRD equation will be used for group placement.  
Nevertheless, renal function will be estimated using both C-G and MDRD equations in this
study.
All subjects must have stable renal function to enter the study. Stable renal function is
defined as ≤25% difference between 2 measurements of eGFR obtained, from the same
laboratory, on 2 separate occasions during the screening period that are at least 72 hours 
but no more than 14 days apart. Additionally, difference between eGFR Screening 1 value 
and Day -2 value should be ≤25%. The Day -2 eGFR value will be used for group 
placement.  The CrCL value will be recorded at the same time eGFR is determined.
The total participation time for each subject in this study will be approximately 6 days
(excluding Screening).
2.2. Study Objectives
Primary Objective

To evaluate the pharmacokinetics of the co-administration of aztreonam and 
avibactam following multiple doses via IV infusion in subjects with severe renal 
impairment and in healthy subjects with normal renal function.
Secondary Objective

To evaluate the safety and tolerability of multiple doses of aztreonam and avibactam 
in subjects with severe renal impairment and in healthy subjects with normal renal 
function.


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Tertiary/Exploratory Objective
 
•
To determine concordance/comparability of capillary microsample plasma 
concentrations with venous plasma concentrations for aztreonam and avibactam in 
healthy subjects with normal renal function.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted 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.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
C
C
I


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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 allocated to a cohort but not treated.
If a subject takes a treatment that is not consistent with the cohort they are allocated 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 Randomization
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.
5.6.2. Deviations Assessed Post-Randomization
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.
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.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events,


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PFIZER CONFIDENTIAL

laboratory data,

vital signs data,

ECG results.
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 given 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:
Table 2.
Noncompartmental PK Parameters
Matrix
PK Parameter
Analysis Scale
Aztreonam and Avibactam
Plasma
AUC0-24,ss
ln
A, D
AUC0-τ
ln
D
Cmax
ln
A, D
Tmax
R
D
t1/2*
R
D
Cτ
ln
D
CL*
ln
D
VZ*
ln
D
Vss
ln
D
Urine
CLR
ln
D
Ae0-τ
R
D
Ae0-τ (%)
R
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits, ss=steady 
state, τ = 6 hours for normal renal function (Cohort 1) and 8 hours for severe renal 
impairment (Cohort 2).
6.3.2. PD Endpoints
None.
6.4. Covariates
None.


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7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
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 for a particular renal function group with ≥3 evaluable measurements.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
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.


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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The effect of the renal impairment on PK parameters will be assessed by constructing 
90% confidence intervals around the estimated difference between each of the Test (severe 
renal impairment group) and the Reference (normal renal function group) using a one-way 
ANOVA model based on natural log transformed data.
8.2. Statistical Analyses
8.2.1. Pharmacokinetic Analysis
Analysis of variance (ANOVA) will be used to compare the natural log transformed AUC0-
24,ss and Cmax between the normal renal function group and the severe renal impairment 
group. The geometric least squares mean point estimate and the associated 90% confidence 
intervals (CIs) for the difference of each comparison will be estimated.
Aztreonam and avibactam PK parameters AUC0-24,ss, Cmax, AUC0-τ, Tmax, Cτ, t½, CL, CLr, VZ,
Vss, Ae0-τ, Ae0-τ% will be summarized descriptively by group.
Box plots of mean, median and individual subject parameters will be made across both
groups for AUC0-24,ss, Cmax and Cτ. Concentrations will be listed and summarized
descriptively by PK sampling time and group. Summary profiles (means and medians) of the
concentration-time data will be plotted across different groups. Individual subject
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 subject 
plots by time, the actual PK sampling time will be used.
The following PK parameters will be summarized by renal function group:
Table 3.
Aztreonam and avibactam PK Parameters to be Summarized 
Descriptively by Group
Parameter
Summary Statistics
AUC0-24,ss, Cmax, 
AUC0-τ, Cτ, CL, 
CLr, VZ, Vss
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
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 (AUC0-
24,ss, AUC0-τ, and Cmax) will be presented by renal function group and overlaid with geometric 
means.


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Presentations for aztreonam and avibactam concentrations will include:

A listing of all concentrations sorted by renal function group (present in heading), 
subject id 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 renal function group and 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.

Day 3 median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by renal function group (all renal function groups on the same 
plot per scale, based on the summary of concentrations by renal function group and 
time postdose).

Day 3 mean concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by renal function group (all renal function groups on the same 
plot per scale, based on the summary of concentrations by renal function group and 
time postdose).

A listing of all urine concentration interval sorted by renal function group (present in 
heading), subject ID and nominal collection duration postdose.

Attainment of steady state will be evaluated by a graphical presentation of 
pre-infusion concentration (trough) values on Days 1-3.
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.
8.2.2. Capillary Plasma Microsamples
To determine concordance/comparability of capillary microsample plasma concentrations
with venous plasma concentrations, X-Y and Bland-Altman (B-A) scatter plots with limits of
agreement (LoA) for a precision assessment will be used.
The Bland-Altman scatterplot will include the difference of the 2 measurements divided by
the mean (% difference) for each sample on the vertical axis and the average of the 
2 measurements on the horizontal axis. Three horizontal reference lines will be 
superimposed on the scatterplot - one line at the average percent difference between the 
measurements and lines to mark the upper and lower limits of 95% CI. The same plot will be 
generated for difference of the 2 measurements (vertical axis) and the average of the 
2 measurements on the horizontal axis.


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If the 2 methods are comparable, then % differences/differences should be negligible, with
the mean of the differences close to 0, and show no systematic variation with the mean of the
2 measurements.
Venous and capillary observed plasma concentrations, individual subject differences and 
% differences of concentrations will be listed and summarized descriptively by PK sampling
time.
8.3. Safety Analysis
A set of summary tables split by renal function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-06947387.
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 renal
function group.
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 by renal function group.
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 by renal
function group.
8.3.5. Laboratory Data
Laboratory data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
Supine blood pressure, pulse rate and oral temperature will be measured at the time points as 
mentioned in the schedule of activities in the protocol.


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The baseline measurement is the last predose measurement.
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the predose measurement.
Baseline values and changes from baseline for the ECG parameters QT interval, heart rate, 
QTc interval, PR interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum postdose QTc values and maximum increases
from baseline in the following categories will be tabulated by treatment:
Borderline(msec)
Prolonged(msec)
Absolute value
≥450- ≤480
>480
Absolute change
30 -≤60
>60
In addition, the number of subjects with corrected and uncorrected QT values >500 msec 
will be summarized.
If not provided, QTcF will be derived using the following formula: QTcF = QT/(RR0.33).
These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Other Safety Data
Physical examination data and medical history collected during the study will not be reported 
in the clinical study report.
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, 
serum or urine B-hCG for all females of childbearing potential, urine or blood cotinine 
concentration and HIV, HBsAg, and HCVAb testing will be obtained at Screening.
These data will not be brought in-house, and therefore will not be listed.


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9. REFERENCES
1.
FDA Guidance for Industry – Pharmacokinetics in Patients with Impaired Renal 
Function - Study Design, Data Analysis, and Impact on Dosing and Labeling.  05/98.


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC MIXED code is provided below:
proc mixed data = tab.pk covtest alpha=0.1;
class trt subjid;
model l&var = trt / S covb CL DDFM=KR;
repeated/ type=un subject=subjid group=trt R;
lsmeans trt;
estimate 'Severe vs Normal'  trt   -1  1;
ods output lsmeans = lsmeans&var;
ods output solutionf = solution&var;
run;
/* Letter assignments for trt within the estimate statement above are as follows;
A = Normal Renal Function (Reference)
B = Severe Renal Impairment (Test) */;