Conditions: Pseudomonas Aeruginosa Respiratory Tract Infection/Colonization Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 149
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and efficacy of a 14-day course versus a 28-day course of aztreonam for inhalation solution (AZLI) in pediatric participants with new onset Pseudomonas aeruginosa respiratory tract infection or colonization.

Detailed description:

Arms:
arm 1: 75 mg/ml of aztreonam will be administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days. arm 2: 75 mg/ml of aztreonam will be administered TID for 28 days.

Interventions: intervention 1: AZLI intervention 2: Placebo
Intervention descriptions: intervention 1: Administered via the PARI Altera® Nebulizer System. Participants \< 2 years will receive via the SmartMask® Baby, 2 to \< 6 years via the SmartMask Kids® and \> 6 years via the nebulizer mouthpiece. intervention 2: Administered via the PARI Altera® Nebulizer System. Participants \< 2 years will receive via the SmartMask® Baby, 2 to \< 6 years via the SmartMask Kids® and \> 6 years via the nebulizer mouthpiece.

Protocol document:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
and Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
Randomized, Double-Blind, Phase 3B Trial to Evaluate the Safety and 
Efficacy of2 Treatment Regimens of Aztreonam 75 mg Powder and 
Solvent for Nebulizer Solution/ Aztreonam for Inhalation Solution 
(AZLI) in Pediatric Subjects with Cystic Fibrosis (CF) and New Onset 
Respiratory Tract Pseudomonas aeruginosa (PA) Infection/Colonization 
A,ztreonam ,Lysine for fseudomonas INfection ,Eradication 2 (ALPINE 2) 
Study 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA, 94404 
064402 
2016-002749-42 
NCT03219164 
For the treatment of new onset respiratory tract P seudomonas aeruginosa 
infection/ colonization 
GS-US-205-1850 
Name: 
Telephone: 
Mobile: 
Fax 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
11 November 2016 
31 March 2017 
06 November 2017 
15 April 2020 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an Investigator, 
potential Investigator, or consultant, for review by you, yow- staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol. You will not disclose any of the information to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................15
1.1.
Background ............................................................................................................................................15
1.2.
Aztreonam for Inhalation Solution (AZLI) ............................................................................................16
General Information .............................................................................................................16
Preclinical Pharmacology and Toxicology...........................................................................17
Clinical Trials of AZLI.........................................................................................................17
1.3.
Rationale for This Study ........................................................................................................................17
1.4.
Risk/Benefit Assessment for the Study..................................................................................................18
1.5.
Compliance ............................................................................................................................................19
2.
OBJECTIVES.....................................................................................................................................................20
3.
STUDY DESIGN................................................................................................................................................21
3.1.
Endpoints ...............................................................................................................................................21
3.2.
Study Design..........................................................................................................................................21
3.3.
Study Treatments ...................................................................................................................................23
3.4.
Duration of Treatment............................................................................................................................24
3.5.
Discontinuation Criteria.........................................................................................................................24
3.6.
Source Data............................................................................................................................................24
3.7.
Biomarker Testing..................................................................................................................................25
Biomarker Samples to Address the Study Objectives:.........................................................25
4.
SUBJECT POPULATION..................................................................................................................................26
4.1.
Number of Subjects and Subject Selection ............................................................................................26
4.2.
Inclusion Criteria....................................................................................................................................26
4.3.
Exclusion Criteria...................................................................................................................................27
4.4.
Screen Failure Criteria and Rescreening................................................................................................28
4.5.
Randomization Criteria ..........................................................................................................................28
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................29
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................29
Planned Primary Endpoint Unblinding ................................................................................29
Procedures for Breaking Treatment Codes...........................................................................29
5.2.
Description and Handling of Study Drug...............................................................................................30
Reconstitution.......................................................................................................................30
Formulation..........................................................................................................................30
Packaging and Labeling .......................................................................................................30
Storage and Handling...........................................................................................................31
5.3.
Dosage and Administration of Study Drug ............................................................................................31
5.4.
Bronchodilator Use ................................................................................................................................31
5.5.
Prior and Concomitant Medications.......................................................................................................32
Prohibited Concomitant Medications...................................................................................33
Allowed Concomitant Medications......................................................................................33
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.6.
Devices...................................................................................................................................................33
PARI Altera® Nebulizer System ..........................................................................................33
5.7.
Study Drug and Device Accountability..................................................................................................34
Study Drug and Device Return or Disposal .........................................................................35
6.
STUDY PROCEDURES ....................................................................................................................................36
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................36
6.2.
Study Assessments.................................................................................................................................36
6.3.
Pretreatment Assessments......................................................................................................................41
Screening Visit .....................................................................................................................41
Day 1 Assessments...............................................................................................................41
Randomization .....................................................................................................................43
6.4.
Initial Eradication Phase.........................................................................................................................43
Day 14 ..................................................................................................................................43
Day 29/Week 4.....................................................................................................................43
Week 6 and Week 8 .............................................................................................................44
6.5.
Follow-up Culture Phase........................................................................................................................44
Week 16 through Week 100.................................................................................................44
Week 112/End of Study .......................................................................................................45
6.6.
Assessments for Premature Discontinuation from Study.......................................................................45
6.7.
Unscheduled Visits.................................................................................................................................46
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................46
6.9.
Details of Scheduled Assessments .........................................................................................................47
Medical History....................................................................................................................47
Physical Examination/Modified Physical Examination, Vital Signs, and 
Height and Weight Measurements .......................................................................................47
Clinical Observation.............................................................................................................47
Samples for Laboratory Tests...............................................................................................48
Pregnancy Test.....................................................................................................................49
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................50
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................50
Adverse Events.....................................................................................................................50
Serious Adverse Events........................................................................................................50
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................51
Assessment of Causality for Study drugs and Procedures....................................................51
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events.......................................................................................................................................52
7.4.
Gilead Reporting Requirements.............................................................................................................53
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................54
7.6.
Toxicity Management ............................................................................................................................54
7.7.
Special Situations Reports......................................................................................................................55
Definitions of Special Situations..........................................................................................55
Instructions for Reporting Special Situations.......................................................................55
8.
STATISTICAL CONSIDERATIONS................................................................................................................57
8.1.
Analysis Objectives and Endpoints........................................................................................................57
Analysis Objectives..............................................................................................................57
Primary Endpoint .................................................................................................................57
Secondary Endpoint .............................................................................................................57
8.2.
Planned Analyses ...................................................................................................................................58
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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Primary Analysis..................................................................................................................58
Final Analysis.......................................................................................................................58
8.3.
Analysis Conventions.............................................................................................................................58
Analysis Sets ........................................................................................................................58
8.4.
Data Handling Conventions ...................................................................................................................59
8.5.
Demographic Data and Baseline Characteristics ...................................................................................59
8.6.
Efficacy Analysis ...................................................................................................................................59
Primary Analysis..................................................................................................................59
Secondary Analyses .............................................................................................................60
8.7.
Safety Analysis.......................................................................................................................................60
Extent of Exposure...............................................................................................................61
Adverse Events.....................................................................................................................61
Laboratory Evaluations ........................................................................................................61
Other Safety Evaluations......................................................................................................61
8.8.
Biomarker Analysis................................................................................................................................62
8.9.
Sample Size............................................................................................................................................62
9.
RESPONSIBILITIES..........................................................................................................................................63
9.1.
Investigator Responsibilities ..................................................................................................................63
Good Clinical Practice..........................................................................................................63
Financial Disclosure.............................................................................................................63
Institutional Review Board/Independent Ethics Committee Review and 
Approval...............................................................................................................................63
Informed Consent.................................................................................................................63
Confidentiality......................................................................................................................64
Study Files and Retention of Records ..................................................................................64
Case Report Forms...............................................................................................................65
Investigator Inspections........................................................................................................66
Protocol Compliance............................................................................................................66
9.2.
Sponsor Responsibilities ........................................................................................................................66
Protocol Modifications.........................................................................................................66
Study Report and Publications .............................................................................................66
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................67
Payment Reporting...............................................................................................................67
Access to Information for Monitoring..................................................................................67
Access to Information for Auditing or Inspections ..............................................................67
Study Discontinuation..........................................................................................................67
10.
REFERENCES ...................................................................................................................................................68
11.
APPENDICES ....................................................................................................................................................72
Appendix 1.
Investigator Signature Page....................................................................................................73
Appendix 2.
Management of Clinical and Laboratory Adverse Events......................................................74
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................75
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF IN-TEXT TABLES
Table 6-1.
Study Procedures Table..........................................................................................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema:........................................................................................................................23


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Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences Europe Ltd., Gilead Sciences, Inc.1 
1333 Lakeside Drive, Foster City, CA, 94404, USA 
Randomized, Double-Blind, Phase 3B Trial to Evaluate the Safety 
and Efficacy of 2 Treatment Regimens of Aztreonam 75 mg Powder 
and Solvent for Nebulizer Solution / Aztreonam for Inhalation 
Solution (AZLI) in Pediatric Subjects with Cystic Fibrosis (CF) and 
New Onset Respirato1y Tract Pseudomonas aernginosa (PA) 
Infection/Colonization 
A,ztreonam ,Lysine for J!seudomonas INfection E,radication 2 
(ALPINE 2) Study 
064402 
2016-002749-42 
NCT03219164 
Approximately 85 sites globally. 
The primaiy objective of this study is to evaluate the safety and 
efficacy of a 14-day course vs a 28-day course of AZLI 75 mg three 
times a day (TID) in subjects with new onset PA respirato1y tract 
colonization/infection as detennined by PA eradication over a 28-
day post-treatment follow-up period. 
The secondaiy objectives of this study are as follows: 
• 
To evaluate the time from primaiy eradication to PA recmTence 
over a 108-week post-treatment follow-up period 
• 
To compare the efficacy of AZLI 75 mg TID for 14 days vs 
historical pooled tobramycin nebulizer solution (TNS) two times 
a day (BID) for 28 days as detennined by PA eradication over a 
28-day post-treatment follow-up period 
• 
To evaluate the time to PA recmTence for a sub-group of 
subjects matching the population in the TNS ELITE Study 
{Ratjen 2009} over a 108-week post-treatment follow-up period 
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Study Design:
This is a randomized, double-blind, multi-center study in pediatric
subjects age 3 months to less than 18 years with CF and newly
detected PA respiratory tract colonization/infection. The study
schedule will consist of a minimum of 13 visits: Screening, Day 1 
(Baseline and Randomization), Day 29, Weeks 6, 8, 16, and at 
12-week intervals thereafter through Week 112. Subjects may be 
screened up to 14 days prior to the Baseline visit to determine 
eligibility for participation in the study. Screening and Baseline may 
occur on the same day for subjects.
Initial Eradication Phase (Primary Endpoint):
At the Baseline visit (Day 1), eligible subjects will be randomized to
a 28-day course of AZLI 75 mg TID or a 14-day course of AZLI
75 mg TID followed by a 14-day course of placebo to match (PTM)
TID. Note: For the purpose of this protocol, AZLI and PTM will 
both be considered “study drug treatment”. After completing study 
drug treatment, subjects will be followed through Week 8 for safety
and recurrence of PA (cultures obtained at Day 29, Week 6, and 
Week 8).
Follow-Up Culture Phase:
Following the end of the Initial Eradication Phase, subjects will 
continue in the Follow-Up Culture Phase, with study visits and PA
cultures obtained at week 16 and then every 12 weeks for 112 
weeks total study duration.
Re-Treatment Phase:
Subjects with PA recurrence after study drug treatment should be 
re-treated with a standard of care antipseudomonal antibiotic 
regimen at the discretion of the Investigator. A non-exclusive list of 
re-treatment regimen options include:

Inhaled AZLI (Cayston®) 75 mg TID x 28 days

Inhaled tobramycin 300 mg BID x 28 days

Inhaled colistin 2 million units BID x 28 days (with or without oral 
ciprofloxacin)

Any intravenous (IV) antibiotic regimen (with or without 
additional inhaled or oral antibiotics)

Other antipseudomonal antibiotic regimen at the discretion of 
the Investigator (to be documented)
For the first PA recurrence, subjects will be followed and re-
cultured at the end of re-treatment, 4 weeks post re-treatment, and 
every 12 weeks thereafter through Week 112. If subjects have 
subsequent PA recurrences post re-treatment they will be treated at 


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the Investigator’s discretion and have continued follow-up cultures 
collected every 12 weeks through Week 112.
The total study period will be 112 weeks (4 weeks study drug 
treatment + 4 weeks Initial Eradication Phase + 104 weeks 
Follow-Up Culture Phase).
Number of Subjects 
Planned:
Approximately 140 randomized subjects.
Target Population:
Pediatric subjects age 3 months to less than 18 years with CF and 
newly detected PA respiratory tract colonization/infection.
Duration of 
Treatment:
Subjects will receive either AZLI 75 mg administered TID for 
28 days or AZLI 75 mg administered TID for 14 days followed by
PTM TID for 14 days. Study treatment will be administered in a 
blinded fashion. Subjects will be followed through Week 8 for
safety and recurrence of PA, and through Week 112 for additional 
comparative analyses. Subjects with PA recurrence after study drug
treatment will be re-treated at the Investigators’ discretion. All 
subjects will be followed for PA recurrence during the Initial 
Eradication and Follow-Up Culture Phases.
Total study duration is 112 weeks.
Diagnosis and Main 
Eligibility Criteria:
Main Inclusion Criteria:

Male or female aged 3 months to less than 18 years

Diagnosis of CF as determined by the 2008 CF Consensus 
Conference criteria:
Sweat chloride level ≥60 mEq/L by quantitative pilocarpine 
iontophoresis;
or a genotype with 2 identifiable mutations consistent with
CF;
or an abnormal nasal transepithelial potential difference
(NPD), and 1 or more clinical features consistent with CF

Documented new onset of positive respiratory tract culture for
PA within 30 days of Screening defined as either first lifetime
documented PA-positive culture, or PA recovered after at least a
2-year history of PA-negative respiratory cultures (at least
2 cultures per year)

FEV1 ≥ 80% predicted (for subjects ≥6 years of age who can 
reliably perform spirometry assessments)

Clinically stable with no evidence of acute significant
respiratory symptoms that would require administration of IV
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Main Exclusion Criteria:

Use of IV or inhaled antipseudomonal antibiotics within 2 years
of Screening

Use of oral antipseudomonal antibiotics for a respiratory event
within 30 days of study entry (Screening visit)

History of intolerance to inhaled short acting β2 agonists

History of lung transplantation

Current requirement for daily continuous oxygen 
supplementation or requirement of more than 2 L/minute at 
night

Hospitalization for a respiratory event within 30 days prior to 
Screening

Changes in bronchodilator, corticosteroid, dornase alfa, 
or hypertonic saline medications within 7 days prior to 
Screening

Significant changes (per investigators discretion) in 
physiotherapy technique or schedule within 7 days prior to 
Screening

Abnormal renal or hepatic function results at most recent test 
within the previous 12 months, defined as
AST or ALT >5 times upper limit of normal (ULN), or
Serum creatinine > 2 times ULN for age

Presence of a condition or abnormality that would compromise 
the subject’s safety or the quality of the study data, in the 
opinion of the Investigator

Known hypersensitivity to aztreonam, its metabolites, or 
formulation excipients in AZLI

Respiratory cultures performed within 24 months prior to 
Screening that are positive for ANY Burkholderia spp. or
Non-tuberculous Mycobacteria (NTM)
Study Procedures/
Frequency:
Study visits for all subjects will occur at Screening, Day 1, Day 29, 
and Weeks 6, 8, 16, 28, 40, 52, 64, 76, 88, 100, and 112. Special 
consideration for the pediatric study population will be maintained 
for all study procedures throughout the study (refer to Section 6.2). 
Study procedures to be performed are as follows:
Complete Physical Exam: Screening and at Week 112 or the Early 
Termination (ET) visit
Body Weight, Height and Vital Signs: Screening
Blood Draw for Serum Chemistry and Hematology: Screening (if 
not available within previous 12 months to assess eligibility)


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Blood Draw for Antipseudomonal Antibodies: Screening (if not 
available within previous 24 months)
Respiratory Sample Collection for Microbiology: All study visits.
If the subject is not able to spontaneously expectorate sputum at a
study visit, alternative methods of lower respiratory tract specimen 
collection may be performed as per the site’s local standard of care 
(eg induced sputum, cough swab, nasopharyngeal aspiration, 
laryngeal suction). If a lower respiratory specimen cannot be 
obtained, an oropharyngeal (throat) swab may be taken, although
this will limit microbiology testing.
Nasal swab for Bacteria and Virus Detection: Day 1
Spirometry (for subjects ≥6 years old who can reliably perform 
spirometry assessments): Screening, Day 1 (pre- and post-dose), 
and every subsequent visit
Clinical Observations for study drug-induced adverse events (for 
subjects < 6 years old and subjects 6 years of age and older who 
cannot reliably perform spirometry assessments): Including chest 
auscultation, respiratory rate, and oxygen saturation: Day 1 pre- and 
post-dose
Test Product, Dose, 
and Mode of 
Administration:
Subjects will receive either AZLI 75 mg administered TID for 
28 days or AZLI 75 mg administered TID for 14 days followed by 
PTM for 14 days. Both treatment regimens to be delivered via the 
PARI Altera® Nebulizer System for 28 days. For the purpose of this 
protocol, AZLI and PTM are both considered “study drug 
treatment”.
Study drug treatment is recommended to be administered to subjects 
aged:

< 2 years via the SmartMask® Baby,

2 to < 6 years via the SmartMask Kids®, and

≥ 6 years via the nebulizer mouthpiece
Investigator has the discretion to select the appropriate mask or 
mouthpiece for each subject in order to optimize fit and delivery.
Subjects should be instructed to administer a bronchodilator (BD) 
prior to taking each dose of study drug (see Section 5.4).
Reference Therapy, 
Dose, and Mode of 
Administration:
PTM administered TID using the same administration procedure as 
for AZLI.


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Criteria for 
Evaluation:
Respiratory tract cultures positive or negative for PA following a
14-or 28-day course of AZLI.
Safety:
Safety endpoints will include adverse events (AEs), airway
reactivity (study drug-induced bronchospasm) as determined by 
post-dose spirometry or clinical observations.
Efficacy:
The primary objective of this study is to evaluate the proportion of 
subjects with PA eradication for each treatment group through 
28 days following the end of AZLI treatment. During the Initial 
Eradication phase, PA cultures will be monitored at all study visits 
through 28 days after cessation of study drug treatment; 
microbiological cultures will be obtained at Screening, Day 1, 
Day 29, and Weeks 6 and 8.
Secondary objectives include the evaluations of the time to 
recurrence of PA from primary eradication over the 108-week 
post-treatment follow-up period. Primary eradication is defined as 
all PA-negative cultures through 28 days post AZLI treatment. 
Cultures will be obtained at week 16 and then at 12-week intervals 
during the follow-up time frame.
Statistical Methods:
The Evaluable Analysis Set will include all randomized subjects 
who complete the AZLI treatment with at least 75% compliance and 
do not use any anti-PA antibiotics while on study treatment with 
AZLI. Missing PA culture data will be adjudicated before data 
unblinding based on available PA culture results.
The Safety Analysis Set will include all randomized subjects who 
receive at least 1 dose of study drug.
Primary analysis of the primary endpoint is the test of noninferiority 
of 14-day treatment compared to 28-day treatment with AZLI based 
on the Evaluable Analysis Set.
The proportion of subjects with primary PA eradication defined as 
all PA-negative tests through 28 days post-AZLI treatment for each 
treatment group (Week 6 for subjects in 14-day treatment group and 
Week 8 for subjects in 28-day group) and the difference between 
treatment groups will be presented with 2-sided 95% confidence 
intervals (CI).
The unblinded primary analysis of the primary endpoint will be 
conducted after all evaluable subjects have completed Study 
Week 8, or Study Week 16 if Week 8 culture data are missing, or 
are early terminated, and the data have been cleaned and finalized 
for the analysis.
Noninferiority of the 14-day treatment regimen will be claimed if 
the 1-sided 97.5% lower confidence limit of the treatment difference 


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in the proportion of PA-negative subjects through 28 days 
post-treatment is above the noninferiority margin of -20%.
Safety will be assessed by AEs and airway reactivity (study drug 
induced bronchospasm) as determined by post-dose spirometry or 
clinical observations. Safety data will be summarized by descriptive 
statistics.
Sample Size:
A maximum feasible sample size of 130 evaluable subjects 
(65 subjects per treatment arm) will provide 75% power to show 
that treatment with AZLI for 14 days is not inferior to treatment 
with AZLI for 28 days with a -20% noninferiority margin at a 
1-sided significance level of 0.025, assuming PA eradication rates 
for both AZLI treatment groups is 75%.
Assuming a non-evaluable rate of 5% to 7%, up to 140 subjects will 
be enrolled to obtain 130 evaluable subjects for the efficacy 
analyses. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS
American Thoracic Society
AZLI
aztreonam for inhalation solution
BAL
bronchoalveolar lavage
BD
bronchodilator
BID
twice a day
BMI
body mass index
BUN
blood urea nitrogen
CF
COVID-19
cystic fibrosis
coronavirus disease 2019
CRF
case report form
CI
confidence interval
CRO
clinical research organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
eCRF
electronic case report form
EDC
electronic data capture
ET
Early Termination
FDA
Food and Drug Administration
FEF
forced expiratory flow
FEV
forced expiratory volume
FVC
forced vital capacity
GCP
Good Clinical Practice
HEENT
head, ears, eyes, nose and throat
IB
investigator brochure
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
IWRS
interactive web response system
MIC
minimum inhibitory concentrations
MRSA
methicillin-resistant S. aureus
MSSA
methicillin-sensitive S.aureus
MT
mid-turbinate


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NTM
non-tuberculous mycobacteria
OP
oropharyngeal
PA
Pseudomonas aeruginosa
PIP
pediatric investigation plan
PTM
PVE
placebo to match
Pharmacovigilance & Epidemiology (formerly Drug Safety and Public Health [DSPH])
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SmPC/PI
summary of product characteristics/product information
SOP
standard operating procedures
SUSAR
suspected unexpected serious adverse reaction
TID
three times a day
TNS
tobramycin nebulizer solution
ULN
upper limit of normal
vs
versus


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1.
INTRODUCTION
1.1.
Background
Cystic fibrosis (CF) affects an estimated 100,000 people worldwide. {Cystic Fibrosis Worldwide 
2016} In Europe, approximately 29,000 people are estimated to have CF.{McCormick 2010}
In the United States (US), similar numbers of individuals are affected. {Cystic Fibrosis 
Foundation 2015} CF is the most common life-shortening genetic disorder in Caucasians. 
The incidence in European Caucasians is estimated at 1 case per 2500 live births. 
Approximately 66% of European patients are conservatively estimated to be children (< 18 years 
of age); however, estimates can vary widely and McCormick J et al. reported 56% are pediatric 
patients.{European Lung Foundation 2007, McCormick 2010} Average life expectancy across 
Europe ranges from the early 30s to approximately 40 years of age.{Cystic Fibrosis Trust 2007, 
Cystic Fibrosis Worldwide 2016, European Lung Foundation 2007, Vaincre la Mucoviscidose 
2006} In the US in 2014, the median age of death for CF patients was 29.1 years and 
approximately 5% of these deaths occurred in pediatric patients < 18 years old. The median 
predicted survival age in the US in 2014 was 39.3 years. {Cystic Fibrosis Foundation 2015}
However, throughout many areas of the world life expectancy for patients with CF varies greatly 
depending on access to care. {Cystic Fibrosis Worldwide 2016}.
CF is an autosomal recessive disease characterized by a defective CF transmembrane receptor 
gene, resulting in abnormal ion transport across cell membranes. The viscous airway secretions 
in CF patients provide an environment for chronic bacterial infection that leads to progressive, 
obstructive pulmonary disease. CF patients are particularly susceptible to pulmonary infections 
with organisms such as Pseudomonas aeruginosa (PA), Staphylococcus aureus, Achromobacter 
species (spp.), Burkholderia spp., Stenotrophomonas maltophilia, and Haemophilus influenzae. 
Acquisition of specific pathogens, namely PA and Burkholderia spp., can significantly alter the 
clinical course of the patient with CF.{Courtney 2004, Treggiari 2007} Infected patients 
experience progressive obstruction of the airways and loss of lung function that is due in large 
part to the inflammatory response to chronic bacterial infection. Loss of pulmonary function is 
the primary cause of death in patients with CF.{Cystic Fibrosis Foundation 2015, European 
Lung Foundation 2007} In 2014, 84% of all deaths were due to respiratory failure or 
complications of lung transplantation, the only definitive therapy for end-stage CF lung disease.
{Cystic Fibrosis Foundation 2015}.
The most significant bacterial pathogen associated with CF pulmonary disease is PA. {Gibson 
2003a} PA infection is a significant predictor of mortality and has also been associated with 
higher rates of pulmonary function decline.{Henry 1992, Pamukcu 1995} Relative lung function, 
expressed as the percentage of Forced Expiration Volume in 1 second (FEV1) predicted, is the 
strongest clinical predictor of mortality in CF. Patients with an FEV1 below 30% of their 
predicted value have a 2-year mortality rate greater than 50%. Corey et al. showed that patients 
who died earlier in life had experienced significantly higher rates of lung function decline than 
longer lived patients. {Corey 1997, Kerem 1992}.


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Lung function is better in the pediatric CF population compared to adult CF patients. {Cystic 
Fibrosis Foundation 2008, Wiedemann 2001}In US CF patients < 18 years, approximately 
65% have normal or mildly impaired lung function (FEV1 ≥70%), 30% have moderate lung 
function impairment (FEV1 40%-69%), and 5% have severe lung function impairment 
(FEV1 < 40%). Median FEV1 % predicted remains normal from age 6 to 12 and progressively 
declines in adolescents. Further declines in FEV1 are observed in adults.
In general, pediatric CF patients have a lower incidence of PA airway infection compared to 
adults. In the European Union (EU), approximate prevalences are 24% in 0 to 4 year olds, 
25% in 5 to 9 year olds, 40% in 10 to 14 year olds, and 50% in 15 to 19 year olds. In the US, 
approximate prevalences are 20% in children <6 years old; 25% in 6 to 10 year olds; 40% in 
11 to 17 year olds, and 60-75% in ≥18 year olds {Cystic Fibrosis Foundation 2015}. These PA
infection rates have been decreasing over the past decade, with the greatest decline seen in 
adolescents.
Initial infection with PA can occur at any age in the CF population. Some patients may avoid 
PA infection until the third decade of life, while others experience chronic PA infection within 
the first decade of life. While PA has been detected in infants < 1 year of age, this is a relatively 
rare occurrence. In a bronchoscopy study of newly diagnosed CF infants < 6 months of age, 
0 out of 46 subjects had a positive respiratory culture for PA.{Ho 1998} Reported incidences of 
PA in CF infants at 1 year of age, as documented by bronchoalveolar lavage fluid cultures, 
ranged from 6%, to 18%.{Abman 1991, Burns 2001}.
Initial infection with PA, prior to the development of chronic infection, has been characterized as 
a window of opportunity for PA eradication. Early and aggressive antibiotic treatment of initial 
PA infection in young patients with CF has been observed to improve pulmonary function and 
delay the onset of chronic PA infection, thus increasing survival. {Doring 2004, Frederiksen 
1996} Multiple PA eradication studies have been published subsequently, utilizing a variety of 
treatment regimens, including inhaled, inhaled plus oral, and IV antibiotics. Despite differing 
study designs, definitions of eradication and follow-up times, similar rates of PA eradication
have been reported. {Schelstraete 2013}.
Eradication of PA at initial detection is now a treatment strategy used by most CF centers.
{Zemanick 2010} Recently published guidelines by the Cystic Fibrosis Foundation (CFF) 
strongly recommend inhaled antibiotic therapy for new onset PA infection. Inhaled tobramycin is 
the CFF recommended treatment, however, no inhaled antibiotic has a labeled indication for 
treatment of new onset PA infection in CF patients. {Mogayzel 2014}.
1.2.
Aztreonam for Inhalation Solution (AZLI)
General Information
Gilead Sciences, Inc. (Gilead) has developed aztreonam for inhalation solution (AZLI), 
a lyophilized formulation of the monobactam antibiotic aztreonam, for the treatment of 
CF patients with PA infection. AZLI is specifically designed for inhalation therapy with lysine as 
an excipient. AZLI was first approved for marketing under the trade name Cayston® in Canada 
on 11 September 2009 for use in CF patients with chronic pulmonary PA infections and is 
currently approved in 36 countries, including the United States, Canada, Australia, Switzerland, 
and the European Union.
 


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Although the spectrum of activity of aztreonam is similar to that of tobramycin and gentamicin, 
{Brewer 1991} because the mechanism of action of monobactams is different than that of the 
aminoglycosides treatment with AZLI provides clinicians with an additional option to avoid 
bacterial resistance. Furthermore, aztreonam has been shown to have activity against 
aminoglycoside-resistant CF pathogens. {Shawar 1999} Finally, extensive clinical use of 
parenteral aztreonam has demonstrated a safety profile, which lacks the toxic effects (both acute 
and cumulative) characteristic of the aminoglycosides, and unlike other members of the 
beta-lactam class, aztreonam is rarely immunogenic. {Adkinson 1990, Adkinson 1984, Brewer 
1991, Saxon 1984, Saxon 1985}.
AZLI is a reconstituted product that consists of the sterile lyophilized powder of aztreonam 
(75 mg aztreonam and 52.5 mg lysine monohydrate) mixed with 1 mL of sterile, 0.17% w/v
saline diluent immediately prior to aerosolization. In clinical trials, AZLI is delivered using the 
Investigational eFlow® Nebulizer System (nebulizer) manufactured by PARI. The eFlow is a 
single-patient, multi-use device that uses a vibrating perforated membrane to generate an aerosol 
with a relatively mono-dispersed particle spectrum (the average mass median diameter is 3.5 μm 
with a geometric standard deviation of approximately 1.6), which is well suited for lower airway 
drug deposition. {Newman 1985} Previous studies indicate that the eFlow is capable of rapid 
delivery of AZLI to the lungs taking only 2 to 3 minutes.
For further information on AZLI, refer to the current Investigator’s Brochure (IB) for AZLI and 
Summary of Product Characteristics/Product Information (SmPC/PI).
Preclinical Pharmacology and Toxicology
Extensive preclinical pharmacology and toxicology studies of AZLI have been conducted to 
identify local and systemic adverse effects associated with AZLI administration. 
These individual preclinical studies are discussed in detail in the IB. To date, no clinically 
relevant adverse effects have been reported in any of these studies.
Clinical Trials of AZLI
Results of completed trials can be found in the AZLI IB.
1.3.
Rationale for This Study
Initial acquisition of PA typically involves nonmucoid strains that are generally susceptible to 
antipseudomonal antibiotics. Studies of various antibiotic regimens have demonstrated the ability 
to eradicate early PA infection and maintain a significant infection-free interval. {Frederiksen 
1997, Gibson 2007, Ratjen 2001, Ratjen 2009, Valerius 1991, Wiesemann 1998} Consensus 
treatment guidelines recommend early and aggressive attempts to eradicate recently acquired PA, 
in order to prevent the establishment of chronic infection and the associated progressive decline 
in lung function. {Mogayzel 2014}.
Existing treatments authorized for pediatrics are not satisfactory and alternative methods with an 
improved expected benefit-risk balance are needed. Despite the currently available inhaled 
antibiotics (TNS and colistin, which are not labeled for the treatment of initial PA infection) 
pediatric CF patients continue to suffer significant morbidity and mortality due to PA airway 
infection.
 
 


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AZLI is a monobactam with a different mechanism of action than aminoglycoside antibiotics. 
AZLI has demonstrated significant reductions in PA sputum density in CF patients with chronic 
PA infection. This potent antibacterial effect justifies additional study of AZLI for eradication of 
initial PA infection in pediatric patients 3 months to less than 18 years.
In GS-US-205-0162, a single-arm, open-label Phase 2 study of AZLI in CF pediatric subjects 
with new onset PA infection {Freiberg 2013, Tiddens 2015}, 105 pediatric subjects aged 
3 months to < 18 years (24 subjects aged 3 months to < 2 years; 25 subjects aged 2 to < 6 years; 
56 subjects aged 6 to < 18 years) with CF and documented initial/new onset PA infection
/colonization received Cayston 75 mg 3 times a day for a single course of 28 days.
Of the 101 evaluable subjects, 89.1% (n = 90) were free of PA at the end of treatment (Day 28) 
and 75.2% (n = 76) were free of PA 1 month after the end of treatment (Day 56). Of the 
79 subjects evaluable for the primary endpoint, 58.2% were PA culture negative at all 
post-treatment time points through 6 months following end of treatment. These eradication rates 
are consistent with success rates reported in the literature for various antibiotic regimens, 
including other inhaled antibiotics studied for eradication.
The current study will address key issues in the management of pediatric CF subjects with new 
onset PA infection:
1) The primary comparison of 14 days vs 28 days of AZLI treatment will provide evidence that 
a shorter AZLI regimen is effective as an initial treatment for PA eradication, which has 
significant implications for treatment adherence in young subjects.
2) A re-treatment phase for PA culture positive patients during the follow-up period will 
provide insights into the treatment of patients with primary eradication treatment failure; this 
long-term follow-up period will provide natural history data on the management strategies 
aimed at maintaining patients free of chronic PA infection.
This study is required as part of an approved Pediatric Investigation Plan (PIP) for AZLI in the
EU (EMEA-000827-PIP01-09-M04). The AZLI PIP was originally approved in October 2010; a
modification was subsequently approved on 29 January 2016.
1.4.
Risk/Benefit Assessment for the Study
Chronic PA infection has devastating consequences for CF patients, in terms of persistent 
pulmonary symptoms, frequent acute pulmonary exacerbations often requiring hospitalization 
and treatment with IV antibiotics, and progressive lung function decline ultimately leading to 
lung transplantation and/or death. Prior to the establishment of chronic infection, there is an 
opportunity to eradicate new onset PA infection with inhaled anti-pseudomonal antibiotic 
treatment, with the goal of delaying the onset of chronic PA infection. This can preserve lung 
function, reduce symptom progression, and prolong survival.


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The PA eradication rates in Study GS-US-205-0162 {Tiddens 2015} have demonstrated the 
ability of a 28-day treatment course of AZLI to eradicate new onset PA infection, with rates 
comparable to other regimens of inhaled antibiotics. The adverse events reported for 
AZLI-treated subjects in this study are similar to the safety profile documented for pediatric 
subjects with chronic PA infection.
Previous studies have shown that AZLI is well tolerated in the pediatric population age 
6 to 17 years old. Delivery time of 2-3 minutes via the Investigational eFlow® Nebulizer System
(eFlow nebulizer) should enhance compliance, particularly in the pediatric population.
The risk of a shorter (14-day) treatment course compared to the standard 28-day course is a 
sub-optimal rate of PA eradication. This risk of eradication failure in this study is obviated 
(in both treatment arms) by the frequency of repeat culturing to detect eradication failure and the 
re-treatment with additional antibiotics per the investigators’ discretion, which is the standard of 
care in clinical practice. However, if the 2 treatment arms are shown to be similar in the ability to 
eradicate new onset PA, this will support shorter treatment duration for initial eradication 
treatment with AZLI, and will be of benefit to pediatric CF patients (and parents/caregivers) in 
terms of reduced treatment burden and improved adherence to this treatment regimen.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice, and all 
applicable regulatory requirements.


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2. 
OBJECTIVES 
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The prima1y objective of this study is to evaluate the safety and efficacy of a 14-day course vs a 
28-day course of AZLI 75 mg three times a day (TID) in subjects with new onset PA respirato1y 
tract colonization/infection as detennined by PA eradication over a 28-day post-treatment 
follow-up period. 
The secondaiy objectives of this study are as follows: 
• 
To evaluate the time from primaiy eradication to PA recmTence over a 108-week 
post-treatment follow-up period 
• 
To compare the efficacy of AZLI 75 mg TID for 14 days vs historical pooled tobramycin 
nebulizer solution (TNS) twice daily (BID) for 28 days as detennined by PA eradication over 
a 28-day post-treatment follow-up period 
• 
To evaluate the time to PA recmTence for a sub-group of subjects matching the population in 
the TNS ELITE Study {Ratjen 2009} over a 108-week post-treatment follow-up period 
I 
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STUDY DESIGN 
3.1. 
Endpoints 
The prima1y endpoint of this study is: 
Final 
Arnendment3 
• 
The propo1t ion of subjects with PA-negative cultures through 28 days post-treatment in the 
14-day treatment group vs 28-day treatment group 
The secondaiy endpoints of this study are: 
• 
Time from prima1y eradication to PA recmTence over a 108-week post-treatment follow-up 
period 
• 
The proportion of subjects with PA-negative cultures through 28 days post-treatment in the 
14-day treatment group vs historical pooled data for PA eradication at 28 days post-treatment 
in subjects treated with TNS 
• 
Time to PA recmTence for a sub-group of subjects matching the population in the TNS 
ELITE Study over a 108-week post-treatment follow-up period 
I 
I 
I 
3.2. 
Study Design 
This is a randomized, double-blind, multi-center study in pediatric subjects age 3 months to less 
than 18 years with CF and newly detected PA respirato1y tract colonization/infection. Subjects 
will be randomized in 1: 1 ratio in to AZLI 28-day or AZLI 14-day treatment aim. 
The randomization will be stratified by age group (3 months to 2 years, 2 to 6 years, and 6 to 
18 years). 
The study schedule will consist of a minimum of 13 visits: Screening/Baseline (Day 1), Day 29, 
Weeks 6, 8, 16, and at 12-week intervals thereafter through Study Week 112. Subjects may be 
screened up to 14 days prior to the Baseline visit to dete1mine eligibility for pait icipation in the 
study. Screening and Baseline may occur on the same day for subjects. 
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Initial Eradication Phase (Primary Endpoint):
At the Baseline visit (Day 1), eligible subjects will be randomized to a 28-day course of AZLI
75 mg TID or a 14-day course of AZLI 75 mg TID followed by a 14-day course of PTM TID.
Note: For the purpose of this protocol, AZLI and PTM will both be considered “study drug 
treatment”.
After completing study drug treatment, subjects will be followed through Week 8 for safety and
recurrence of PA (cultures obtained at Day 29, Week 6, and Week 8).
Follow-Up Culture Phase:
Following the end of the Initial Eradication Phase, subjects will continue in the Follow-Up 
Culture Phase, with study visits and PA cultures obtained at Week 16 and then every 12 weeks 
after that for 112 weeks total study duration.
Re-Treatment Phase:
Subjects with PA recurrence after study drug treatment should be re-treated with a standard of 
care antipseudomonal antibiotic regimen at the discretion of the Investigator. A non-exclusive 
list of re-treatment regimen options include:

Inhaled AZLI (Cayston®) 75 mg TID x 28 days

Inhaled tobramycin 300 mg BID x 28 days

Inhaled colistin 2 million units BID x 28 days (with or without oral ciprofloxacin)

Any intravenous (IV) antibiotic regimen (with or without additional inhaled or oral 
antibiotics)

Other antipseudomonal antibiotic regimen at the discretion of the Investigator (to be 
documented)
For the first PA recurrence, subjects will be followed and re-cultured at the end of re-treatment, 
4 weeks post re-treatment, and every 12 weeks thereafter through Week 112. If subjects have 
subsequent PA recurrences post re-treatment they will be treated at the Investigator’s discretion 
and have continued follow-up cultures collected every 12 weeks through Week 112.
The total study period will be 112 weeks (4 weeks study drug treatment + 4 weeks Initial 
Eradication Phase + 104 weeks Follow-Up Culture Phase).


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Figure 3-1.
Study Schema:
3.3.
Study Treatments
Subjects will be randomized at Day 1 and receive either AZLI 75 mg administered TID 28 days 
or AZLI 75 mg administered TID for 14 days followed by PTM TID for 14 days. Both treatment 
regimens to be delivered via the PARI Altera® Nebulizer System for 28 days. For the purpose of 
this protocol, AZLI and PTM will both be considered “study drug treatment”.
Study drug treatment is recommended to be administered to subjects aged:

< 2 years via the SmartMask® Baby,

2 to < 6 years via the SmartMask Kids®, and

≥6 years via the nebulizer mouthpiece
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The Investigator has the discretion to select the appropriate mask or mouthpiece for each subject 
in order to optimize fit and delivery. If the Investigator feels subjects over the age of 6 years are 
not ready to use the Altera® standard nebulizer mouthpiece, they may use a SmartMask for drug 
delivery. Additionally, if subjects under the age of 6 years are able to demonstrate the ability to 
use a mouthpiece, it is recommended they use the Altera® standard nebulizer mouthpiece for 
optimal drug delivery.
AZLI and PTM will be packaged separately in 14-day dosing cartons. On Day 1 all subjects will 
receive two cartons: Carton 1 and Carton 2.
Carton 1 contains the product required for administration on Day 1 to 14. Carton 1 only contains
AZLI 75mg TID.
At Day 14 subjects will start Carton 2 which contains the vials required for administration on 
Days 15 to 28. Carton 2 will contain either blinded AZLI 75 mg TID or PTM TID. 
Subject treatment allocation for Carton 2 will be determined by randomization on Day 1.
Use of non-study antipseudomonal antibiotics is prohibited during the 28-day treatment period. 
Subjects who violate this criterion will be withdrawn from the study. These subjects will come 
for an Early Termination (ET) visit and be followed for 30 days and/or until all ongoing adverse 
events resolve. Subjects who do not violate the criteria of Evaluable Analysis Set will be 
included in the primary efficacy analysis. If at any time after the 28-day treatment period the 
physician determines that a subject requires antipseudomonal antibiotics, the subject will not be 
withdrawn from the study but an unscheduled visit will be scheduled to document treatment.
3.4.
Duration of Treatment
Randomized subjects will complete 28 days of daily dosing. Subjects will have their final visit 
108 weeks after the last dose. The total study duration is 112 weeks.
3.5.
Discontinuation Criteria
For discontinuation criteria refer to Section 6.8.
3.6.
Source Data
The subject identification number and randomization number captured by the interactive web 
response system (IWRS) are considered source data. All other information entered into the 
electronic data capture (EDC) requires source documentation to be available for verification.


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3.7.1. 
Bio marker Testing 
Biomarker Samples to Address the Study Objectives: 
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Blood and respirato1y samples (sputum and swabs) will be collected in this study and these 
samples may be used to evaluate the association of explorato1y systemic and/or tissue specific 
biomarkers with study drug response, including efficacy and/or adverse events as well as to 
increase knowledge and understanding of the biology of CF or related diseases or the validation 
of a companion diagnostic for AZLI. The specific analyses will include, but will not be limited 
to, antipseudomonal antibodies. PA-specific antibody titers will be obtained at Screening if no 
results are available within 24 months. Because biomarker science is a rapidly evolving area of 
investigation, and adverse events in particular are difficult to predict, it is not possible to specify 
prospectively all tests that will be done on the specimens provided. The testing outlined below is 
based upon the cunent state of scientific knowledge. It may be modified during or after the end 
of the study to remove tests no longer indicated and/or to add new more applicable tests. Any 
future testing must be approved by local authorities as applicable according to specific local 
regulations. 
1111 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 140 subjects will be enrolled in this study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Male or female aged 3 months to less than 18 years at screening
2) Diagnosis of CF as determined by the 2008 CF Consensus Conference criteria {Farrell 
2008}:
sweat chloride level ≥60 mEq/L by quantitative pilocarpine iontophoresis;
or a genotype with 2 identifiable mutations consistent with CF;
or an abnormal nasal transepithelial potential difference (NPD), and 1 or more clinical 
features consistent with CF
3) Documented new onset of positive respiratory tract culture for PA within 30 days of
Screening defined as either first lifetime documented PA-positive culture, or PA recovered
after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year)
4) FEV1 ≥80% predicted (for subjects ≥6 years of age who can reliably perform spirometry 
assessments)
5) Clinically stable with no evidence of acute significant respiratory symptoms that would
require administration of IV antipseudomonal antibiotics, oxygen supplementation, or
hospitalization
6) A negative serum pregnancy test is required for female subjects of child bearing potential
who have a positive urine pregnancy test at screening
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 3
8) Lactating females must agree to discontinue nursing before administration of study drug
9) Subjects and/or parent/guardian must be able to give written informed consent prior to study 
related procedures


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Use of IV or inhaled antipseudomonal antibiotics within 2 years of Screening
2) Use of oral antipseudomonal antibiotics for a respiratory event within 30 days of study entry
(Screening visit)
3) History of intolerance to inhaled short acting β2 agonists
4) History of lung transplantation
5) Administration of any investigational drug or device within 28 days prior to Screening
6) Concurrent use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone 
per day or 20 mg prednisone every other day
7) Current requirement for daily continuous oxygen supplementation or requirement of more 
than 2 L/minute at night
8) Hospitalization for a respiratory event within 30 days prior to Screening
9) Changes in bronchodilator, corticosteroid, dornase alfa, or hypertonic saline medications 
within 7 days prior to Screening
10) Significant changes (per investigators discretion) in physiotherapy technique or schedule 
within 7 days prior to Screening
11) Abnormal hepatic or renal function results at most recent test within the previous 12 months, 
defined as
AST or ALT >5 times upper limit of normal (ULN), or
Serum creatinine > 2 times ULN for age
12) Presence of a condition or abnormality that would, in the opinion of the Investigator, 
compromise the subject’s safety or the quality of the study data
13) Known hypersensitivity to aztreonam, its metabolites, or formulation excipients present in 
AZLI
14) Respiratory cultures performed within 2 years prior to Screening that are positive for ANY 
Burkholderia spp. or NTM


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4.4.
Screen Failure Criteria and Rescreening
Any consented subject who is excluded from the study before enrollment at Baseline (Day 1) 
visit is considered a screen failure. Subjects may only be re-screened once for study eligibility. 
The re-screen may not occur on the same day as the initial screening visit. All screen failures 
must be documented with the reason for the screen failure stated as noted below:

Subject failed to meet all of the study inclusion criteria or met any of the exclusion criteria 
prior to randomization (Day 1)

Subject withdrew consent

Other (specify)
4.5.
Randomization Criteria
Any enrolled subject that has remained clinically stable is eligible for randomization to study 
drug if the following criteria are met:

Has not received antipseudomonal antibiotics for a respiratory event within 30 days of study
entry (Screening visit) and through Baseline (Day 1) visit

Has not received any IV or inhaled antipseudomonal antibiotics within 2 years of study entry
(Screening visit) and through Baseline (Day 1) visit

Has not developed a condition requiring hospitalization or other change in clinical status
which, in the opinion of the Investigator, precludes the subject’s ability to continue
participation in the study


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An IWRS will be employed to manage subject randomization and enrollment, shipping of study 
drug, and dispensing of study drug.
During the randomized phase subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment. Specified personnel may be unblinded based on 
their study role. Study drug will be dispensed by the study pharmacist, or designee, in a blinded 
fashion to the subjects. Individuals in Clinical Packaging & Labeling or Clinical Supply 
Management who have an Unblinded Inventory Manager role in the IWRS system for purposes 
of study drug inventory management will remain unblinded. Individuals in Pharmacovigilance & 
Epidemiology (PVE) responsible for safety signal detection, IND safety reporting and/or 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs) may be 
unblinded to individual case data and/or group level summaries. External (ie, contract research 
organizations) Biostatisticians and Programmers will be unblinded for data monitoring 
committee (DMC). Regulatory Quality and Compliance personnel in Research and Development 
may also be unblinded for purposes of supporting Quality Assurance activities and/or Regulatory 
Agency inspections.
Planned Primary Endpoint Unblinding
In order to assess the primary efficacy endpoint for regulatory planning purposes and/or 
submission, Gilead personnel will be unblinded to subject-level treatment codes after all subjects 
have completed Week 8, or Week 16 if Week 8 visit culture data are missing, or are early 
terminated and the data have been cleaned and finalized for the analysis. Unblinded treatment-
level summaries may be shared externally. Unblinding procedures for analyses will be followed 
as specified in Gilead SOPs. Investigators, site personnel, and subjects will remain blinded to 
subject-level treatment codes until the completion of the study.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the Investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the Investigator contact the Gilead
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the case report 
form/electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The Investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
 
 


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Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the Investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead PVE may independently unblind cases for expedited reporting of suspected unexpected 
serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drug
Reconstitution
Study drug must be reconstituted using the supplied diluent by the subject or the subject’s 
caregiver. Adequate supplies of study drug and diluent will be provided to the subject at 
baseline. Detailed instructions for reconstitution are available in Study Drug Information 
Booklet. Once constituted, it should be used immediately.
Formulation
5.2.2.1.
AZLI Formulation:
AZLI will be supplied as vials of sterile lyophilized powder containing 75 mg aztreonam as 
aztreonam lysine. Diluent for AZLI will be supplied in ampules, each of which contains 1 mL of 
sterile 0.17% w/v sodium chloride solution. When the diluent is added to the lyophilized powder, 
the final product is 75 mg/ml of aztreonam with a pH of 4.5 to 6.0.
5.2.2.2.
Placebo to Match (PTM):
The PTM will be supplied as vials of lyophilized sterile powder containing lactose monohydrate 
and sodium chloride and will be identical in physical appearance to AZLI vials. Diluent for PTM
is the same as for AZLI and will be supplied in ampules, each of which contains 1 mL of sterile
0.17% w/v sodium chloride solution.
Packaging and Labeling
AZLI and PTM will be supplied in 2 mL amber glass vials with a siliconized rubber stopper and 
an over-seal cap closure.
Study drug will be packaged in two 14-day dosing cartons. Carton 1 contains AZLI (42 vials) 
required for administration on Day 1 to 14. Carton 2 will contain either AZLI (42 vials) or PTM 
(42 vials) required for administration on Days 15 to 28. Carton 1 and Carton 2 will both be given 
to subjects after randomization on Day 1. In each carton there will be 6 additional vials of study 
drug treatment in case administration of the study drug is compromised for any reason 
(eg, spillage of vial contents prior to nebulizer use). Adequate diluent will be provided in a 
separate carton for 28 days of study drug treatment.
 
 
 


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Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice – Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
Storage and Handling
AZLI or PTM should be stored at 2°C to 8°C (36°F to 46°F). Storage conditions are specified on 
the label. Until dispensed to the subjects, all study drug should be stored in a securely locked 
area, accessible only to authorized site personnel. To ensure the stability and proper 
identification, study drug (s) should not be stored in a container other than the container in which 
they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of Study Drug
Subjects will receive either AZLI 75 mg administered TID for 28 days or AZLI 75 mg
administered TID for 14 days followed by PTM administered TID for 14 days. Both treatment 
regimens will be delivered via the PARI Altera® Nebulizer System provided to each subject.
Subjects, and/or the subject’s caregiver, should be instructed to administer a bronchodilator prior 
to taking each dose of study drug (see Section 5.4). For subjects taking multiple inhaled 
therapies, the recommended order of administration is as follows: bronchodilator, mucolytics, 
and lastly, study drug.
The first dose of study drug will be administered in the clinic during the Baseline (Day 1) 
visit. After the first dose, subjects will administer study drug (in the morning, afternoon, 
and evening/night) at home. Doses are to be taken a minimum of 4 hours apart. If a dose is 
missed, all daily doses should be taken as long as they are at least 4 hours apart.
5.4.
Bronchodilator Use
All subjects, and/or the subject’s caregiver, should be instructed to refrain from using 
short-acting inhaled Bronchodilators (BDs; such as albuterol) within 4 hours prior to each study 
visit (unless used for rescue).
At Baseline (Day 1) visit, subjects should administer a short-acting BD in the clinic 15 to 
30 minutes prior to spirometry and within 1 hour prior to in-clinic study drug administration. 
Subjects should also be instructed to administer their routine short-acting BD prior to each study 
drug dose at home.
Subjects who do not routinely use BDs should be prescribed an appropriate BD by the 
Investigator for use during the study drug treatment periods. This BD use should be recorded on 
the Concomitant Medications and Therapies eCRF.
 


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Subjects who routinely use either short-acting and/or long acting inhaled BDs should adhere to 
the following guidelines for at-home use:

If a subject normally administers a long-acting inhaled BD twice daily, the subject, and/or the 
subject’s caregiver, will be advised to ensure that a long-acting BD has been used at least 
30 minutes before treatment and no more than 12 hours prior to study drug administration at 
home, or

If a subject normally administers a long-acting inhaled BD once daily, the subject, and/or the 
subject’s caregiver, will be advised to ensure that the long-acting BD has been used at least 
30 minutes before treatment and no more than 24 hours prior to study drug administration at 
home, or

If a subject does not normally administer a long-acting inhaled BD, the subject, and/or the 
subject’s caregiver, will be instructed to administer a short-acting inhaled BD at least 
15 minutes before treatment and no more than 4 hours prior to study drug administration at 
home.
All subjects who normally use a BD should continue their use as prescribed, however, 
subjects should be instructed to refrain from using a short-acting inhaled BD within 4 hours of 
each study visit (unless used for rescue), and from using a long-acting inhaled BD within 
12 hours of each study visit if the BD is used twice daily, or within 24 hours of each study visit if 
the BD is used once daily. If a subject has taken a BD treatment within 4 hours (short-acting) or 
12 hours (long-acting) of a study visit, this should be noted in the CRF and no BD should be 
given at that study visit.
If part of their regularly prescribed therapy, subjects may be permitted to use a combination of 
long-acting and short-acting BDs during the study.
5.5.
Prior and Concomitant Medications
Concomitant medications are any prescription medications, over-the-counter preparations, 
or therapies used by the subject between Screening and Week 112 or early termination.
Use of concomitant medication or treatment required for the clinical management of subjects 
will be at the Investigator’s discretion.
Use of hypertonic saline therapy is permitted. Subjects must be on a stable chronic regimen from 
Screening to Day 29 (no changes in or initiation of regimen).
At Screening, concomitant medications and therapies including airway clearance techniques will 
be recorded. All antibiotics given in the past 24 months prior to screening should be recorded. 
All medications, indications for use, dose (amount, dose units, frequency, and route of 
administration), and dates of administration must be recorded. At subsequent visits, subjects will 
be questioned about any changes in their medications or concomitant therapy.


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Prohibited Concomitant Medications
Use of concomitant medications or treatments required for the clinical management of subjects 
will be at the Investigator’s discretion unless otherwise specified here or in the exclusion criteria:

Concurrent use of oral antipseudomonal antibiotics for a respiratory event or any IV or 
inhaled antibiotics for any indication (excluding chronic, stable treatment with a macrolide) 
is prohibited from Screening to Day 28. Use of these specific types of antibiotics during this 
period will require study withdrawal and conduct of an ET Visit, as described in Section 3.3.

Changes in chronic bronchodilator, corticosteroid, azithromycin, or bronchial hygiene 
therapy are prohibited within 28 days of Baseline.

The use of any investigational drug or device other than those designated in this study is 
prohibited within 28 days prior to Baseline and through Day 56. Subjects who complete 
study drug treatment and follow-up cultures for the primary endpoint (through Day 56) are 
allowed to participate in other investigational drug trials. The one restriction is entry into 
another inhaled antibiotic trial unless, and until, the first positive post-treatment culture for 
PA is obtained. (This is to preserve the PA culture-negative study population for the time to 
PA recurrence endpoint).
Allowed Concomitant Medications
After Day 29, Investigators may prescribe non-study antibiotics to any subject who is 
experiencing worsening respiratory signs and/or symptoms, or for a positive PA respiratory 
culture. It should be noted that the use of non-study antipseudomonal antibiotics is prohibited 
during the 28-day study drug treatment phase. Subjects requiring treatment with additional
antipseudomonal antibiotics during the study drug treatment phase will be withdrawn from the 
study, as described in Section 3.3. In the event of worsening respiratory symptoms between 
study visits, the subject should return to the clinic for an Unscheduled Visit in order to be 
evaluated for treatment with non-study antibiotics. In addition to completing the Unscheduled 
Visit procedures, the prescribing physician must record the subject’s specific worsening 
respiratory symptoms in source documents and then in the eCRF. If necessary for appropriate 
management of the subject, and for timely treatment with antibiotics, this visit can be conducted 
over the phone. If the subject will be withdrawn from the study, the Early Termination Visit 
should be scheduled as soon as possible following the call.
If the requirement for non-study antibiotics is identified during a regular scheduled study visit, 
the specific respiratory symptoms indicating need for antibiotics must be documented as 
described above. In either case, the subject will be allowed to continue study participation.
5.6.
Devices
PARI Altera® Nebulizer System
The Altera® Nebulizer System (manufactured by PARI GmbH, Starnberg, Germany) will be 
used to deliver study drug. The Altera® Nebulizer System consists of an eBase controller unit 
 
 
 


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and the Altera® Nebulizer Handset to deliver the study drug. Gilead Sciences will supply a 
nebulizer system for each eligible subject. The nebulizer is to be used by the subject for the 
administration of study drug only.
AZLI or PTM is recommended to be administered to subjects aged:

< 2 years via the SmartMask® Baby,

2 to < 6 years via the SmartMask Kids®, and

≥6 years via the nebulizer mouthpiece
The Investigator has the discretion to select the appropriate mask or mouthpiece for each subject 
in order to optimize fit and delivery.
The Investigator, study coordinator, or research nurse will instruct the subject and/or 
parent/guardian on use of the nebulizer and breathing technique prior to the first dose. 
Nebulizer accessories for use in the trial and instructions for use, cleaning, and disinfecting will 
be supplied to each subject.
At the Baseline visit, subjects and/or subjects’ parent/guardian should:

Read the Altera® instructions for use

Be instructed by the study coordinator on how to breathe with the Altera®

Demonstrate to the study coordinator that he/she can disassemble, clean, sterilize, 
and reassemble the Altera®
A functionality test is performed on the Altera® prior to each subject’s first dose to ensure that 
the unit was not damaged during shipment.
5.7.
Study Drug and Device Accountability
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug vials, diluent ampules, nebulizers, and masks. This includes acknowledgement of receipt of 
each shipment of study drug, nebulizers, handsets, and masks (quantity and condition). All used 
and unused study drug, solvent/diluent ampules, nebulizers, sterilizers, and masks dispensed to 
subjects must be returned to the site.
Study drug and device accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, and the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, and the initials of the 
person recording the information.


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Study Drug and Device Return or Disposal
Where possible, study drug (and diluent) and devices (Altera® nebulizers, sterilizers and masks) 
will be destroyed at the site. If the site has appropriate Standard Operating Procedures (SOPs) 
for study drug and device destruction, the site may destroy used study drug and devices 
(empty vials, ampules, and nebulizers) and unused study drug supplies in accordance with the 
SOPs, after the monitor has completed study drug and device accountability. If the site does not 
have acceptable procedures in place for study drug and device destruction, arrangements will be 
made between the site and Gilead (or Gilead’s representative) for return of study drug and study 
drug supplies.
At the start of the study, the study monitor will evaluate each study center’s disposal procedures 
and provide instruction for return or destruction of unused study drug and study drug supplies. 
If unused study drug and study drug supplies will be destroyed on site, a copy of the site’s SOP 
for study drug destruction will be obtained for central files.
If study drug is destroyed on site, the Investigator must maintain accurate records for all study 
drug vials destroyed. Records must show how the identification and quantity of each unit 
destroyed, the method of destruction, and person who disposed of the study drug. All study drug
records must be submitted to Gilead at the end of the study. Upon study completion, a copy of 
the study drug and device accountability forms must be filed at the site. Another copy will be 
returned to Gilead.
 


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form and described in the text that follows. Additional information is provided in the 
study procedures manual.
The Investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). Missed visits/procedures due to the coronavirus disease
2019 (COVID-19) pandemic will be documented as deviation from the protocol due to the 
COVID-19 pandemic. 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to randomization/enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, 
and study eligibility has been confirmed, eligible subjects will be randomized to study treatment 
as described in Section 3.3.
The study center will not be activated and allowed to Screen subjects until:

The Institutional Review Board (IRB) or Ethics Committee (EC) have reviewed and 
approved the study and the informed consent document

All required regulatory documents have been submitted to and approved by Gilead or the 
CRO

A master services agreement and/or study agreement is executed

The site initiation meeting has been conducted by the Gilead clinical monitor (or designee). 
The initiation meeting will include a review of the protocol, the IB, and the Investigator’s
responsibilities
6.2.
Study Assessments
This study consists of a minimum of 13 scheduled visits with total study duration of 112 weeks.
The study procedures to be conducted for each subject enrolled in the study are described in the
following sections. In addition, Table 6-1 presents the study procedures in tabular form.
Refer to the lab manual for information on collection and shipment of all required study samples.
Care must be taken by the Investigator to minimize any possible pain and distress that subjects
may experience as a result of study participation. Additionally, whenever possible the
Investigator should take action to try to ensure the comfort of subjects. The degree of burden to


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subjects in this trial has been evaluated and is not significantly more than that involved in routine
CF care and treatment. The level of anticipated risk to minors is minimal; however,
Investigators should attempt to reduce subject discomfort whenever possible. The following
study procedures may have a potential for risk of discomfort, distress, or embarrassment:
blood sampling, sputum sampling, nasal sampling, pulmonary function testing, physical exams,
and collections of body weight and/or height. Methods to reduce discomfort from blood sample
collection include the use of numbing cream prior to venipuncture to lessen the discomfort of the
subject.
If the subject is not able to spontaneously expectorate sputum at a study visit, alternative 
methods of lower respiratory tract specimen collection may be performed as per the site’s local 
standard of care (eg induced sputum, cough swab, nasopharyngeal aspiration, laryngeal suction). 
If a lower respiratory specimen cannot be obtained, an oropharyngeal (throat) swab may be
taken, although this will limit microbiology testing. A mid-turbinate (MT) swab will be used to 
collect a nasal sample and is less invasive than a nasal oropharyngeal swab.
The following considerations are suggested in order to minimize distress and anticipation of 
pain:

Investigators are advised to provide an age appropriate explanation to the child of all study
procedures involved in this trial

Whenever possible, separation of the child from the parent/legal representative should be 
avoided, or if this is not possible, a member of the study team should accompany the child to
provide reassurance

Prior to the child’s participation, the parent/legal representative and the child will be 
informed of which procedures are related to the study, and which are part of the child’s 
routine CF care
The frequency of study visits and the study procedures monitoring safety ensure that a pediatric
subject’s level of risk, and burden will be closely monitored during his or her participation in the
trial. Additional visits may occur if needed, at the discretion of the Investigator.
Overall, Investigators must continually monitor the risk for potential distress and suffering
during a child’s participation. During the follow-up culture phase study visits may be scheduled
to coincide with routine quarterly clinic visits, so as to not be overly burdensome to the 
subjects/families.
Follow-up visits (from Week 16 to Week 100 and not including Week 112 or the ET visit) can be 
performed at home by qualified CF specialist nurses if this is standard of care at the clinic and 
appropriate cultures can be obtained and processed.


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Table 6-1.
Study Procedures Table
Day/Week
Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
ET
Unscheduled
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
Written Informed Consent
X
Inclusion/Exclusion Criteria
X
Xf
Subject Demographics
X
Medical History
X
Complete Physical Examination
X
X
X
Modified Physical Examination
X
X
X
X
X
X
Body Weight, Height and Vital 
Signs
X
X
Hematology and Serum Chemistry
Xa
Blood for Biomarkersi
X
Respiratory Sample for 
Microbiologyn
X
X 
(pre-dose)
X
X
X
X
X
X
X
Nasal Swab for Microbiology
X 
(pre-dose)
Urine Pregnancy Testc
X
X 
(pre-dose)
X
X
Xe
X
Randomization
X


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Day/Week
Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
ET
Unscheduled
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
Instruct Subject on Study Drug 
Administration, Dosing, and 
Storage and on Proper 
Operation/Cleaning of Altera®
X
Administer Study Treatment in 
Clinic
X
Administer Study Treatment at 
Home, 3 times per day
X
Xl
Administer short-acting β2 agonist
X
X
(pref and 
post-dose)
X
X
X
X
X
X
X
Clinical Observations for study 
drug-induced adverse eventsb
X 
(pre and 
post-dose)
Dispense Study Treatment Kits,
Sterilizer, Altera® Nebulizer 
System (eBase & handset, mask if 
applicable), and Dosing Log
X
CCI


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Day/Week
Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
ET
Unscheduled
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
Collect device system 
components(eBase Unit, Handset 
and Mask if applicable), Used and 
Unused Drug Vials, and Dosing 
Log
X
Xj
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Adverse Eventsm
X
X
X
X
X
X
X
X
X
X
PA= Pseudomonas aeruginosa, OP= Oropharyngeal,
 AZLI=
Aztreonam for Inhalation Solution.
a
Hematology and serum chemistry only needed at screening if there are no labs available within the previous 12 months to assess eligibility
b
For subjects 3 months of age to <6 years of age and subjects 6 years of age and older who cannot reliably perform spirometry assessments - chest auscultation, respiratory 
rate, and oxygen saturation
c
All females of childbearing potential, if result is positive confirm with a serum pregnancy test
e
If ET visit occurs within 30 days of the last dose of study drug
g
These visits may be combined and performed on the same day
h
Fungal culture (for Aspergillus spp) analysis from respiratory sample only on Day 1 and Day 29
i
Anti-PA Antibodies (only needed at screening if there are no results available within the previous 24 months)
j
If ET visit occurs before Day 29
k
These visits (not including Week 112 or the ET visit) can be performed at home by specialist CF nurses if this is standard of care at the clinic and appropriate respiratory 
samples can be obtained and processed
l
Subjects should be contacted via telephone on Day 14 to assess whether they have had any adverse events or taken any concomitant medications and instruct subject/parent to 
switch to second carton of study drug treatment on Day 15
m
During Follow-up Culture phase, only those AE/SAEs related to protocol mandated procedures should be reported to Gilead PVE. Also, AEs/SAEs related to Cayston 
treatment in the re-treatment phase must be collected and reported to Gilead PVE.
n
If the subject is not able to expectorate sputum at a study visit, alternative methods of lower respiratory tract specimen collection may be performed as per local standard of 
care (eg induced sputum, cough swab, nasopharyngeal aspiration, laryngeal suction). If a lower respiratory specimen cannot be obtained, an oropharyngeal (throat) swab may 
be taken
CCI
CCI
CCI


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6.3. 
6.3.1. 
Pretreatment Assessments 
Screening Visit 
Final 
Arnendment3 
Subjects will be screened before randomization to detennine eligibility for pa1ticipation in the 
study. Invasive study procedures such as blood draws should be done at the end of the study 
visit. The following will be perfonned and documented at screening: 
• 
Obtain written Infonned Consent 
• 
Obtain demographics and medical histo1y 
• 
Ask subject and/or parent/caregiver about their concomitant medications 
• 
Obtain vital signs, including weight and height 
• 
Perfo1m a complete physical examination 
• 
Obtain urine sample for pregnancy test (female subjects of child bearing potential only). If 
result is positive confom with a sernm pregnancy test 
• 
Administer sho1t-acting ~2 agonist 
I 
• 
Obtain respirato1y sample for microbiology 
• 
Obtain blood samples for hematology, serum chemistiy if no results available in past 
12 months 
• 
Obtain blood sample for biomarkers if no PA antibody titer data are available in past 
24 months 
• 
Assess subject eligibility per Inclusion/Exclusion criteria 
• 
Assess subject for adverse events (all AEs/SAEs related to protocol mandated procedures to 
be repo1ted) 
6.3.2. 
Day 1 Assessments 
Subjects will have 14 days from the time of screening to complete Day 1. It is acceptable for the 
Screening visit and Day 1 to occur on the same day. In this case, the Study procedures perfo1med 
at Screening will not need to be repeated. 
At Day 1, after the subject's eligibility for the study has been confomed, the subject will be 
randomized into the study to receive one of two study dosing regimens. 
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Prior to Treatment with Study Drng 
The following will be perfonned and documented at Day 1 prior to dosing: 
• 
Assess subject eligibility per Inclusion/Exclusion criteria 
Final 
Arnendment3 
• 
Ask subject and/or parent/caregiver about any new or changes to existing concomitant 
medications 
• 
Perfo1m a modified physical exam 
• 
Obtain urine sample for pregnancy test (female subjects of child bearing potential only) 
• 
Obtain respirato1y sample for microbiology 
• 
Obtain nasal swab sample for microbiology 
• 
Randomize subject in IWRS 
Treatment with Study Drng 
• 
Dispense Study treatment kits, Altera® Nebulizer System (eBase and Altera® handset, mask 
if applicable), sterilizer and dosing log 
• 
Instrnct subject on study diug adininistration, dosing, and storage and on proper 
operation/cleaning of Altera® nebulizer 
• 
Perfo1m nebulizer functionality test 
• 
Adininister short-acting ~2 agonist 
I 
• 
Perfo1m clinical observation (for subjects 3 months of age to <6 years of age and subjects 
6 years of age and older who can't reliably perfonn spirometiy assessments, including: chest 
auscultation, respirato1y rate, and oxygen saturation) 
• 
Adininister study diug in the presence of the investigator, study nurse, or research 
coordinator; delive1y of this dose will be timed 
Post Study Drng Procedures 
• 
Assess and document any AEs occmTing since diug adininistration ( all AEs/SAEs regardless 
of cause or relationship to be repo1ied). 
• 
Adininister short-acting ~2 agonist 
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• 
Perfo1m clinical observation (for subjects 3 months of age to <6 years of age and subjects 
6 years of age and older who cannot reliably perfo1m spirometiy assessments, including: 
chest auscultation, respirato1y rate, and oxygen saturation) at least 30 minutes post-dose (or 
until investigator feels it is safe to discharge the subject) to asce1tain whether the subject 
experiencing acute bronchospasm, and/or allergic response 
I 
6.3.3. 
Randomization 
Subjects will be randomly allocated to a dosing group in a blinded fashion according to a 
pre-specified randoinization scheme prepared by an independent statistician. Upon qualification 
for the study, subjects will be randomized using a computerized IWRS system. 
The IWRS system will provide kit numbers so that Study Treatment Kits can be dispensed. 
6.4. 
6.4.1. 
Initial Eradication Phase 
Day14 
Subjects should be contacted via telephone on Day 14 to assess whether they have had any 
adverse events (All AEs/SAEs regardless of cause or relationship to be repo1ted) or taken any 
concomitant medications and instiuct subject/parent to switch to second ca1ton of study dmg 
ti·eatment on Day 15. A visit to the study center may be substituted for a telephone conta.ct, per 
the subjects and Investigator's discretion. 
6.4.2. 
Day 29/Week 4 
Following the completion of study ti·eatment subjects will return to the site for their Day 29 
visits. The following assessments will be completed (Invasive study procedures such as blood 
draws should be perfonned at the end of the study visit): 
• 
Collect used and unused diug vials, Altera® Nebulizer System ( eBase and Altera® 
handset/mask if applicable), sterilizer and dosing log from subject 
• 
Ask subject and/or parent/caregiver about any new or changes to existing conc01nitant 
medications 
• 
Perfo1m a modified physical exam 
• 
Obtain urine sample for pregnancy test (female subjects of child bearing potential only) 
• 
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Assess subject for adverse events ( only AE/SAEs related to protocol-mandated procedures 
must be collected and reported to Gilead PVE. Also, AEs/SAEs related to Cayston ti·eatment 
in the re-ti·eatment phase must be collected and reported to Gilead PVE) 
6.5.2. 
Week 112/End of Study 
The end of this u-ial is defined as the date of the last study visit of the last study subject. Subjects 
that continue through their Week 112 study visit will have the following end of study 
assessments completed. 
• 
Ask subject and/or parent/caregiver about any new or changes to existing concomitant 
medications 
• 
Perfo1m a complete physical exam 
• 
Administer sho1t-acting ~2 agonist 
I 
• 
Obtain respirato1y sample for inicrobiology 
• 
Assess subject for adverse events ( only AE/SAEs related to protocol-mandated procedures 
must be collected and repo1ted to Gilead PVE. Also, AEs related to Cayston ti·eatment in the 
re-ti·eatment phase must be collected and repo1ted to Gilead PVE) 
6.6. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study and continue to perfo1m the required study-related 
follow-up and procedures (see Section 6.8, Criteria for Discontinuation of Study Treatment). 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn 
from the study and an ET visit is to be scheduled immediately. In addition, an ET visit is 
required if subjects withdraw their consent from paiticipation. The following assessments will be 
completed at an ET visit. fuvasive study procedures such as blood draws should be perfo1med at 
the end of the visit. 
• 
Collect used and unused diug vials, Altera® Nebulizer System ( eBase and Altera® handset, 
mask if applicable), and dosing log from subject (if ET visit is prior to Day 29 visit) 
• 
Ask subject and/or pai·ent/cai·egiver about any new or changes to existing concomitant 
medications 
• 
Perfo1m a complete physical exam 
• 
Obtain urine sample for pregnancy test if ET visit is within 30 days of last dose of study diug 
(female subjects of child beai·ing potential only) 
• 
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6.7. 
Unscheduled Visits 
If subjects come to the study center outside of their study visit schedule for any reason related to 
their pait icipation in GS-US-205-1850 it will be considered an unscheduled study visit and the 
following assessments will be completed. 
• 
Ask subject and/or parent/cai·egiver about any new or changes to existing concomitant 
medications 
• 
Obtain vital signs, including weight and height 
• 
Perfo1m a modified physical exam 
• 
Obtain urine sample for pregnancy test (female subjects of child beai·ing potential only) 
• 
Administer short-acting ~2 agonist 
I 
• 
Obtain respirato1y sample for microbiology 
• 
Assess subject for adverse events (see Section 7.3 to identify which AEs are required to be 
repo1ted) 
6.8. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
• 
Use of a non-study antipseudomonal antibiotic during the 28-day treatment period. 
• 
Intercunent illness that would, in the judgment of the Investigator, affect assessments of 
clinical sta.tus to a significant degree. 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the Investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject's best 
interest 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance with visit schedule, study drng dosing or procedures 
• 
Pregnancy during the treatment period 
• 
Discontinuation of the study at the request of Gilead, a regulato1y agency or an IRB/IEC 
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6.9.
Details of Scheduled Assessments
Medical History
The subject’s medical history will be documented at Screening. The medical history should 
include significant diagnoses of acute and chronic medical conditions, including prior surgeries, 
co-morbid diseases, and allergies (β-lactams, in particular). The subject’s CF disease history, 
including any CF-related conditions (eg, CF lung disease, CF-related malabsorption, 
CF-related liver disease) and previously performed CF-related procedures, will be recorded.
The subject’s PA infection history, including the number of previous PA infections, number of 
cultures taken and sampling methods in the previous 2 years will also be recorded.
Physical Examination/Modified Physical Examination, Vital Signs, and 
Height and Weight Measurements
A complete physical examination will be conducted by an Investigator (a medical doctor listed 
on FDA Form 1572) at Screening and Week 112 or the ET visit. At all other visits, 
modified physical examinations will include head, ears, eyes, nose and throat (HEENT), 
respiratory, cardiovascular, and any other relevant organ systems based on AEs or clinical 
symptoms. Any changes since the previous visit will be assessed. Worsening of any pre-existing 
physical finding (since Screening) should be evaluated for significance and recorded as an AE in 
the AE eCRF, if appropriate.
Vital signs (heart rate, diastolic and systolic blood pressure, temperature, and respiratory rate) 
will be recorded at Screening. Heart rate and respiratory rate will be conducted for a full minute. 
Blood pressure will be assessed after the subject has been seated/reclined for 5 minutes.
Height (length for infants) will be measured to the nearest 0.1 cm (or in). Weight will be reported 
to the nearest 0.1 kg (or lb).
Clinical Observation
For all subjects < 6 years of age and subjects 6 years of age and older who cannot reliably 
perform spirometry assessments, clinical observation will be conducted by a qualified 
Investigator (either a licensed nurse practitioner or physician listed on FDA Form 1572) prior to 
drug administration on Day 1 and 30 minutes post drug administration to evaluate for evidence 
of drug-related bronchospasm. Clinical observation will include auscultation of the chest, and 
measurement of respiratory rate and oxygen saturation to ascertain whether the subject is 
experiencing acute bronchospasm, and/or allergic response. Worsening of any pre-study drug
administration finding should be evaluated for significance and recorded as an AE in the AE 
eCRF, if appropriate. Repeat evaluations should be performed until the Investigator considers it 
safe to discharge the subject.
 
 
 


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Samples for Laboratory Tests
Blood, respiratory samples, nasal swab, and urine samples will be collected during scheduled 
visits and at the Investigator’s discretion during unscheduled visits. Urine pregnancy tests will be 
performed for females of child bearing potential. All clinical laboratory tests will be sent to the 
central laboratory specified in the study manual. In addition, respiratory samples collected 
outside of the study as standard of care may be sent to a local laboratory.
6.9.4.1.
Hematology
The following hematological assessments will be performed if there are no labs available within 
the previous 12 months: hemoglobin (Hb), total red blood cell count (RBC), hematocrit (Hct), 
mean cell hemoglobin (MCH), mean cell volume (MCV), mean cell hemoglobin concentration 
(MCHC), white blood cell count (WBC) with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils), and platelets.
6.9.4.2.
Serum Chemistry
The following serum chemistry assessments will be performed if there are no labs available 
within the previous 12 months: blood urea nitrogen (BUN), AST, ALT, total protein, bilirubin, 
gamma glutamyl transferase (GGT), calcium, sodium, potassium, chloride, glucose, creatinine, 
and bicarbonate.
A blood draw will be taken at Screening for antipseudomonal antibody testing if there are no 
results available within the previous 24 months.
6.9.4.3.
Respiratory Sampling
Sputum or OP
Microbiological assessments will include qualitative and quantitative culture for PA, 
Burkholderia spp., S. aureus (methicillin-resistant S. aureus [MRSA] and methicillin-sensitive
S. aureus [MSSA]), S. maltophilia, Achromobacter spp., Haemophilus influenza, and Aspergillus
spp. At Day 1 and Day 29, a separate fungal culture will be performed to analyze the presence of 
Aspergillus spp.
Minimum inhibitory concentrations (MIC) of aztreonam and other antibiotics for PA will be 
determined at each visit. All phenotypically unique PA isolates from each subject at all visits will 
be genotyped when Day 1 isolates are available for comparison.
A minimum of 0.5 ml of sputum should be collected in a sterile specimen container.
If the subject is not able to spontaneously expectorate sputum at a study visit, alternative 
methods of lower respiratory tract specimen collection may be performed as per the site’s local 
standard of care (eg induced sputum, cough swab, nasopharyngeal aspiration, laryngeal suction). 
If a lower respiratory specimen cannot be obtained, an oropharyngeal (throat) swab may be
taken, although this will limit microbiology testing.
 


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Note: eve1y effo1i should be made to obtain an expectorated sputum sample. Detailed 
instructions on processing and shipment of microbiology sputum samples are provided in the 
Laborato1y Manual. 
Many pa1iicipating sites will also collect and analyze respirato1y PA samples outside of the study 
as standard of care. The local laborato1y culture data from these samples will be captured in the 
eCRF. Local laboratory culture data may be used for analysis purposes. 
At the conclusion of this study bacterial isolates collected from sputum may be retained in 
storage by the sponsor for an indefinite period for additional microbiology testing. 
Note: microbiology samples should be collected at least 4 hours after study drng or inhaled 
antibiotic dosing. 
Nasal Swab 
Upper respirato1y microbiological assessment will include qualitative molecular detection for 
bacteria and vims using the Biofire testing panel. A mid-turbinate (MT) swab will be used to 
sample the inferior mid-turbinate region of 1 nostr·il. The MT swab should be placed in storage 
media immediately and stored frozen. Detailed instructions on collecting, storing and shipping of 
upper respirato1y microbiology samples are provided in the Laborato1y Manual. 
6.9.5. 
Pregnancy Test 
A urine pregnancy test will be perfo1med on all female subjects of child bearing potential. If the 
urine pregnancy test is positive, the subject will be notified and a confinnato1y sernm pregnancy 
test will be perfo1med. If the confomato1y sernm pregnancy test is positive, the subject will be 
discontinued from the study drng. Pregnancies that occur after the end of tr·eatrnent visit but 
within 30 days of the last dose of study drng should be repo1ied as specified in Section 7. 7 .2.1. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, 
or occupational exposure.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
Preexisting events or conditions that increase in severity or change in nature after the consent 
form is signed or as a consequence of participation in the clinical study will also be considered 
AEs.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death
 
 


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
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The Investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
Assessment of Causality for Study drugs and Procedures
The Investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. 
For SAEs, an alternative causality must be provided (eg, pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.
 


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
Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture).
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events:
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug. AEs must be reported to the CRF/eCRF 
database as instructed.
During the Follow-up culture phase (Through Week 112), AEs related to protocol-mandated 
procedures must be collected and reported to Gilead PVE. Also, AEs related to Cayston 
treatment in the re-treatment phase must be collected and reported to Gilead PVE.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead may request that certain AEs be followed beyond the protocol defined follow up period.
Serious Adverse Events:
All SAEs and deaths, regardless of cause or relationship, that occurs after the subject first 
consents to participate in the study (i.e., signing the informed consent) until 4 weeks after study 
drug treatment must be reported to the CRF/eCRF database and Gilead PVE as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. During the follow-up culture phase (through week 112), SAEs related to 
protocol mandated procedures must be collected and reported to Gilead PVE.
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the Investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, he/she should promptly document and 
report the event to Gilead PVE.
During the Re-Treatment Phase if the subject is treated with Cayston and the investigator learns 
of any SAEs that are related to Cayston treatment a ‘Post Marketing Adverse Event Report 
Form’ must be completed. This report can be sent via email
 or fax 
 to PVE within 24 hours of becoming aware of such information.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
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Site personnel record all SAE data in the eCRF database and from there trnnsmit the SAE 
infonnation to Gilead PVE within 24 homs of the fuvestigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, i.e., the 
eCRF database is not functioning (i.e. cannot be accessed or is not available), record the SAE 
on the paper serious adverse event repo1ting fo1m and submit within 24 homs of the 
investigator's knowledge of the event to Gilead PVE: 
Fax: PD 
E-mail: PPD 
• 
As soon as it is possible to do so, any SAE repo1ted via paper must be h'anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, 
no fuither action is necessaiy. 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, and other 
documents ai·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensme the timely completion of accmate safety 
repo1ts. 
• 
Any medications necessaiy for tr·eatinent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fo1m. 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, 
and other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulato1y agencies repo1ts of SAEs, serious adverse dmg reactions {SADRs ), 
or suspected unexpected serious adverse reactions (SUSARs). fu accordance with the EU 
Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulato1y agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in cmTent regulations. 
Assessment of expectedness for SAEs will be dete1mined by Gilead using reference safety 
info1mation specified in the fuvestigator's brochme or relevant local label as applicable. 
All fuvestigators will receive a safety letter notifying them of relevant SUSAR repo1ts associated 
with any study dmg. The fuvestigator should notify the IRB or IEC of SUSAR repo1ts as soon as 
is practical, where this is required by local regulato1y agencies, and in accordance with the local 
institutional policy. 
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7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) 
that require medical or surgical intervention or lead to study drug interruption, modification, 
or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, x-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE or SAE 
as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, 
record the syndrome or diagnosis (eg, anemia), not the laboratory result (i.e. decreased 
hemoglobin).
For AEs or SAEs associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality, see Section 7.6.
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Severity should be recorded and graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found 
at: http://evs.nci.nih.gov/ftp1/CTCAE/ and listed under the following file name: 
“CTCAE 4.03 2010-0614 QuickReference 8.5x11.pdf.”
7.6.
Toxicity Management

All clinical and clinically significant laboratory toxicities will be managed according to
uniform guidelines detailed in Appendix 2.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat
testing within 3 calendar days of receipt of results and before investigational medicinal
product discontinuation, unless such a delay is not consistent with good medical practice.

When restarting investigational medicinal product following resolution of the adverse event,
the investigational medicinal product should be restarted at full dose or modified dose that is
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or
clinically significant laboratory adverse event following dose interruption mandates
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences
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7.7.
Special Situations Reports
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, product 
complaints for investigational medicinal product and/or medical device (as applicable) with 
associated adverse events, and pregnancy reports regardless of an associated AE, and AE in an 
infant after exposure from breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the Investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The Investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
 
 


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email:
 and Fax: 
.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE, fax number
 
or email 
.
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the Investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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8. 
8.1. 
8.1.1. 
STATISTICAL CONSIDERATIONS 
Analysis Objectives and Endpoints 
Analysis Objectives 
Final 
Arnendment3 
The prima1y objective of this study is to evaluate the safety and efficacy of a 14-day course vs a 
28-day course of AZLI 75 mg TID in subjects with new onset PA respirato1y tract 
colonization/infection as detennined by PA eradication over a 28-day post-treatment follow-up 
period. 
The secondaiy objectives of this study are as follows: 
• 
To evaluate the time from prima1y eradication to PA recmTence over a 108-week 
post-treatment follow-up period 
• 
To compare the efficacy of AZLI 75 mg TID for 14 days vs historical pooled TNS BID for 
28 days as determined by PA eradication over a 28-day post-treatment follow-up period 
• 
To evaluate the time to PA recmTence for a sub-group of subjects matching the population in 
the TNS ELITE Study {Ratjen 2009} over a 108-week post-treatment follow-up period 
8.1.2. 
Primary Endpoint 
The prima1y endpoint of this study is: 
• 
The propo1tion of subjects with PA-negative cultures through 28 days post-treatment in the 
14-day treatment group vs the 28-day treatment group. 
8.1.3. 
Secondary Endpoint 
Secondary endpoints are: 
• 
Time from prima1y eradication to PA recmTence over the 108-week post-treatment follow-up 
period. The primaiy eradication is achieved when all available cultures at 14 and 28 days 
post AZLI treatment ai·e PA negative 
• 
The propo1tion of subjects with PA-negative cultures through 28 days post-treatment in the 
14-day treatment group vs. historical pooled data for PA eradication at 28 days 
post-treatment in subjects treated with TNS 
• 
Time to PA recmTence over the 108-week post-treatment follow-up period for a sub-group of 
subjects matching the population in the TNS ELITE Study over a 108-week post-treatment 
follow-up period. 
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8.2. 
8.2.1. 
Planned Analyses 
Primary Analysis 
Final 
Arnendment 3 
The unblinded primaiy analysis of the primaiy endpoint will be conducted after all evaluable 
subjects have completed Study Week 8, or Study Week 16 if Week 8 culture data are missing, or 
ai·e early terminated, and the data have been cleaned and finalized for the analysis. 
The primai·y analysis will be tested with a -20% noninferiority mai·gin at a I-sided significance 
level of 0.025. This analysis of the primaiy endpoint will serve as the final analysis for this 
endpoint. 
Additional unblinded analyses on secondary endpoint Week 8 and safety data may also be 
conducted, depending on data availability. 
8.2.2. 
Final Analysis 
The unblinded final analysis will be perfonned after all subjects have completed the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data. have 
been cleaned and finalized. Final analysis will include analyses of data for seconda1y endpoints 
that depends on study completion and analysis on safety data collected during study follow-up 
phase. 
8.3. 
8.3.1. 
8.3.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
The prima1y analysis set for the efficacy analysis is the Evaluable Analysis Set that will include 
all randomized subjects who complete AZLI treatment with at least 75% compliance, and do not 
use any anti-PA antibiotics while on study treatment with AZLI. Missing PA culture data will be 
adjudicated before data unblinding based on available PA culture results. 
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The Intent-to-treat (ITT) Analysis Set will include all subjects who were randomized in the 
study. The ITT analysis set will be used in a sensitivity analysis of the primary endpoint to 
evaluate the impact of the treatment regimens on the treatment effect. The ELITE Study 
matching analysis set will consist of subjects from Evaluable Analysis Set who also satisfy the 
published criteria for efficacy analysis population in ELITE Study {Ratjen 2009}. The detailed 
criteria for subject’s inclusion in the ELITE study matching analysis set will be provided in the 
Statistical Analysis Plan (SAP).
8.3.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set that will include subjects 
randomized and who received at least one dose of study drug.
All data collected on or after the start of treatment and up to 4 weeks after the last dose of study 
drug will be included in the safety summaries.
8.3.1.3.
Biomarkers
The Biomarker Analysis Set includes all subjects who were randomized and have received at 
least 1 dose of the study drug and for whom biomarker data are available. Subjects will be 
analyzed according to the treatment they actually receive.
8.4.
Data Handling Conventions
No imputations will be made for missing baseline data unless otherwise specified.
8.5.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline characteristics will include a summary of body weight, height, BMI, anti-PA antibodies, 
MIC for PA isolates, and spirometry measurements (where applicable).
8.6.
Efficacy Analysis
Primary Analysis
Primary analysis of the primary endpoint is the test of noninferiority of the 14-day AZLI course
compared to the 28-day AZLI course based on the Evaluable Analysis Set.
The proportion of subjects PA-negative through 28 days post-treatment (Day 42 for subjects in 
the 14-day treatment group and Day 56 for subjects in the 28-day group) for each treatment 
group and the difference between treatment groups will be presented with 2-sided 95% 
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Noninferiority of the 14-day treatment regimen will be claimed if the lower bound of 1-sided 
97.5% confidence limit of the treatment difference (14-day course group vs 28-day course group) 
is above the noninferiority margin of -20%.
To evaluate the impact of the treatment regimens on the treatment effect, the primary efficacy 
analysis will be repeated using the ITT analysis set.
Descriptive summaries of PA eradication over 28 days post-treatment will be provided by age 
subgroups (3 months to < 2 years, 2 years to < 6 years, 6 to 17 years).
The effect of baseline characteristics that include clinical and laboratory parameters collected 
prior to start of study treatment on the success or failure of primary PA eradication will be 
explored using the appropriate statistical methodology.
The unblinded primary analysis of the primary endpoint will be conducted after all evaluable 
subjects have completed Study Week 8, or Study Week 16 if Week 8 culture data are missing, or 
are early terminated, and the data have been cleaned and finalized for the analysis.
Secondary Analyses
The median time to PA recurrence after the primary eradication over the 108-week 
post-treatment period will be assessed using Kaplan-Meier method. The median time and 
95% CIs will be presented based on the Evaluable Analysis Set. Additional summaries of time to
PA recurrence will be provided by age subgroups (3 months to < 2 years, 2 years to < 6 years, 
6 to 17 years).
The proportion of subjects with PA-negative cultures during 28 days post-treatment period in the 
14-day course group will be presented with 95% CI and compared descriptively with historical 
pooled data for proportion of subjects with PA eradication at 28 days post-treatment with TNS. 
The historical data for the proportion of subjects with PA-negative cultures during 28 days 
post-treatment period will be pooled from the published results from the studies conducted on the 
subjects with new onset of PA infection and similar TNS treatment duration and follow-up. 
{Gibson 2003b, Proesmans 2013}. The pooled proportion of subjects with successful PA
eradication at 28 days post-treatment with TNS is estimated to be 77%. Details of the estimation 
will be provided in the SAP.
The median time to PA recurrence and 95% CI will be presented for ELITE-matching analysis 
set and compared descriptively with the published result from ELITE Study.
8.7.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose of study drug plus 30 days will be summarized by treatment group (according to the 
study drug received). All data including the pretreatment and treatment-free follow-up period
will be presented in the data listings.
 


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Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug
administration record. Exposure and level of adherence will be summarized by treatment group.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
study drug up to the date of last dose of study drug plus 30 days or leading to premature 
discontinuation of study treatment.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group.
Laboratory Evaluations
Selected laboratory parameters will be summarized using only observed data, without imputation 
for missing data. Observed values and change from baseline at all scheduled time points will be 
summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 3.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of study drug plus 30 days, will be summarized by treatment group. If baseline data are 
missing, then any graded abnormality (i.e., at least a Grade 1) will be considered treatment 
emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in a data listing.
Other Safety Evaluations
Airway reactivity will be assessed by spirometry and clinical observation at 30 minutes 
post treatment.
Vital signs will be summarized using descriptive statistics (n, mean, standard deviation, median, 
Q1, Q3, minimum, and maximum).
 
 
 
 


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8.8.
Biomarker Analysis
PA-specific antibody titers will be obtained at Screening (if there is no historical data available 
within 24 months). Categorical results of anti-PA IgG antibody titer will be presented by the 
highest titer result and by individual antigen.
8.9.
Sample Size
A maximum feasible sample size of 130 evaluable subjects (65 subjects per arm) will provide
75% power to show that the treatment with AZLI for 14 days is not inferior to AZLI for 28 days 
with a -20% noninferiority margin at a 1-sided significance level of 0.025, assuming PA
eradication rates for both AZLI treatment groups is 75%. The -20% noninferiority margin 
preserves at least 65% of the comparator arm treatment effect, where treatment effect is 
calculated as the difference in PA eradication rates between AZLI for 28 days (from 
Study GS-US-205-0162) and the historical control placebo {Gibson 2003b, Wiesemann 1998}. 
With a nonevaluable rate of 5%-7%, up to 140 subjects will be enrolled to reach 130 evaluable. 
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data and provide recommendation to Gilead whether the 
nature, frequency, and severity of adverse effects associated with study treatment warrant the 
early termination of the study, whether the study should continue as planned, or whether the 
study should continue with modifications. The DMC may also provide recommendations as 
needed regarding study design.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, 
including possible early study termination, Gilead retains final decision-making authority on all 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with ICH E6(R2) addendum 
to its guideline for GCP and applicable laws and regulations.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their
financial interest or arrangements with Gilead, or proprietary interests in the investigational drug
during the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree to 
notify Gilead of any change in reportable interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date when the last subject completes the 
protocol-defined activities.
Institutional Review Board/Independent Ethics Committee Review and
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this protocol, 
informed consent form, and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) to an IRB/IEC. The investigator will not begin any study subject activities until approval 
from the IRB/IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from the 
IRB/IEC any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial IRB/IEC approval, with the exception of those necessary to reduce immediate risk 
to study subjects.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual
participating in this study after adequate explanation of the aims, methods, objectives, and
potential hazards of the study before undertaking any study-related procedures. The investigator
must use the most current IRB- or IEC-approved consent form for documenting written informed
consent. Each informed consent (or assent as applicable) will be appropriately signed and dated
by the subject or the subject’s legally authorized representative and the person conducting the
consent discussion, and also by an impartial witness if required by IRB or IEC or local
requirements. The consent form will inform subjects about genomic testing and/or planned 
sample retention. In addition to the study-specific informed consent to be signed by each subject
participating in the study, subjects will be required to document agreement to provide additional
samples or to allow the use of the remainder of their already collected specimens for optional
 
 
 
 


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future research, in accordance with applicable regulations. In addition to the study-specific
informed consent to be signed by each subject participating in the study, subjects will be required
to document agreement to provide additional samples for optional genomic research. The results
of the tests done on the samples will not be given to the subject or the investigator.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their
identities are protected from unauthorized parties. Only an identification code and any other
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form
or biological sample submitted to Gilead, or laboratory. Laboratory specimens must be labelled 
in such a way as to protect subject identity while allowing the results to be recorded to the proper
subject. Refer to specific laboratory instructions . NOTE: The investigator must keep a screening
log with details for all subjects screened and enrolled in the study, in accordance with the site
procedures and regulations. Subject data will be processed in accordance with all applicable
regulations.
The investigator agrees that all information received from Gilead, including but not limited to the
investigator’s brochure, this protocol, CRF/eCRF, the study drug, and any other study
information, remain the sole and exclusive property of Gilead during the conduct of the study
and thereafter. This information is not to be disclosed to any third party (except employees or
agents directly involved in the conduct of the study or as required by law) without prior written
consent from Gilead. The investigator further agrees to take all reasonable precautions to prevent
the disclosure by any employee or agent of the study site to any third party or otherwise into the
public domain.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study
to be fully documented and the study data to be subsequently verified. These documents should
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject
clinical source documents.
The investigator’s study file will contain the protocol/amendments, paper or electronic
completed subject CRFs, and governmental approval with correspondence, informed consent,
drug records, staff curriculum vitae and authorization forms, and other appropriate documents
and correspondence.
The required source data should include sequential notes containing at least the following
information for each subject:

Subject identification;

Documentation that subject meets eligibility criteria, ie, medical history, physical
examination, and confirmation of diagnosis (to support inclusion and exclusion criteria);
 
 


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol-specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end dates (including dose regimen) of study drug, including dates of dispensing and
return;

Record of all adverse events and other safety parameters (start and end dates, and including
causality and severity), and documentation that adequate medical care has been provided for
any adverse event

Concomitant medication (including start and end dates, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or according to 
local laws, whichever is longer, after the last approval of a marketing application in an ICH region 
(ie, United States, Europe, or Japan) and until there are no pending or planned marketing applications 
in an ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if specified by regulatory requirements, by 
local regulations, or by an agreement with Gilead. The investigator must notify Gilead before 
destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the investigator and Gilead to store these 
records securely away from the site so that they can be returned sealed to the investigator in case of 
an inspection. When source documents are required for the continued care of the subject, appropriate 
copies should be made for storage away from the site.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff
member whose training for this function is completed in the EDC system. The eCRF casebook
will only capture the data required per the protocol schedule of events and procedures.
The Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data
 


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related to eligibility have been received. Data entry should be performed in accordance with the
CRF Completion Guidelines (CCGs) provided by the Sponsor. Subsequent to data entry, a study
monitor will perform source data verification (SDV) within the EDC system. System-generated
or manual queries will be issued in the EDC system as data discrepancies are identified by the
monitor or Gilead staff, who routinely review the data for completeness, correctness, and
consistency. The site investigator or site coordinator or other designee is responsible for
responding to the queries in a timely manner, within the system, either by confirming the data as
correct or updating the original entry, and providing the reason for the update (e.g., data entry
error). Original entries as well as any changes to data fields will be stored in the audit trail of the
system. At a minimum, prior to any interim time points or database lock (as instructed by
Gilead), the investigator will use his/her log in credentials to confirm that the forms have been
reviewed, and that the entries accurately reflect the information in the source documents. At the
conclusion of the study, Gilead will provide the site investigator with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.6.
Investigator Inspections
The investigator will make available all source documents and other records for this study to
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority
inspectors.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in
accordance with local requirements and receive documented approval before modifications can
be implemented.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or
other scholarly media only after the following conditions have been met: The results of the study 
in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, 
manuscript, or presentation form or the study has been completed at all study sites for at least 
2 years.
 
 
 
 


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The investigator will submit to Gilead any proposed publication or presentation along with the
respective scientific journal or presentation forum at least 30 days before submission of the
publication or presentation. No such communication, presentation, or publication will include 
Gilead’s confidential information (see Section 9.1.5).
The investigator will comply with Gilead’s request to delete references to its confidential
information (other than the study results) in any paper or presentation and agrees to withhold
publication or presentation for an additional 60 days in order to obtain patent protection if
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this
protocol, eg, attendance at Investigator Meetings. If required under the applicable statutory and
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any
expenses paid or reimbursed for such services, including any clinical study payments, meal,
travel expenses or reimbursements, consulting fees, and any other transfer of value.
Access to Information for Monitoring
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of
the data being entered on them. The monitor should have access to any subject records needed to
verify the entries in the CRF/eCRF. The investigator agrees to cooperate with the monitor to
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the
clinical study. If the investigator is notified of an inspection by a regulatory authority the
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to
provide to representatives of a regulatory agency or Gilead access to records, facilities, and
personnel for the effective conduct of any inspection or audit.
Study Discontinuation
Both Gilead and the investigator reserve the right to terminate the study at any time. Should this
be necessary, both parties will arrange discontinuation procedures and notify the subjects,
appropriate regulatory authority, IRBs, and ECs . In terminating the study, Gilead and the
investigator will assure that adequate consideration is given to the protection of the subjects’
interests.
 
 
 
 


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10.
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aeruginosa colonisation in patients with cystic fibrosis. Lancet 2001;358 
(9286):983-4.
Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection 
in patients with cystic fibrosis: the ELITE trial. Thorax 2009;65 (4):286-91.
Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF, Jr. Lack of cross-reactivity between 
aztreonam , a monobactam antibiotic, and penicillin in penicillin-allergic subjects. 
J Infect Dis 1984;149 (1):16-22.
Saxon A, Swabb EA, Adkinson NF, Jr. Investigation into the immunologic cross-reactivity of 
aztreonam with other beta-lactam antibiotics. Am J Med 1985;78 (2A):19-26.
Schelstraete P, Haerynck F, Van daele S, Deseyne S, De Baets F. Eradication therapy for 
Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients not 
chronically colonized by P. aeruginosa. J Cyst Fibros 2013;12 (1):1-8.
Shawar RM, MacLeod DL, Garber RL, Burns JL, Stapp JR, Clausen CR, et al. Activities of 
tobramycin and six other antibiotics against Pseudomonas aeruginosa isolates 
from patients with cystic fibrosis. Antimicrob Agents Chemother 1999;43 
(12):2877-80.
Tiddens HA, De Boeck K, Clancy JP, Fayon M, H GMA, Bresnik M, et al. Open label study of 
inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: 
The ALPINE study. J Cyst Fibros 2015;14 (1):111-9.
Treggiari MM, Rosenfeld M, Retsch-Bogart G, Gibson R, Ramsey B. Approach to eradication of 
initial Pseudomonas aeruginosa infection in children with cystic fibrosis. Pediatr 
Pulmonol 2007;42 (9):751-6.
Vaincre la Mucoviscidose, Institut national d'études démographiques. The French National 
Cystic Fibrosis Observatory (ONM): Report on 2004 Data. ONM  2006.
Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in 
cystic fibrosis by early treatment. Lancet 1991;338 (8769):725-6.
Wiedemann B, Steinkamp G, Sens B, Stern M. The German cystic fibrosis quality assurance 
project: clinical features in children and adults. Eur Respir J 2001;17 (6):1187-94.


Aztreonam for Inhalation Solution
Protocol GS-US-205-1850
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
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Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Doring G, et al. Placebo-
controlled, double-blind, randomized study of aerosolized tobramycin for early 
treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Pediatr 
Pulmonol 1998;25 (2):88-92.
Zemanick ET, Harris JK, Conway S, Konstan MW, Marshall B, Quittner AL, et al. Measuring 
and improving respiratory outcomes in cystic fibrosis lung disease: opportunities 
and challenges to therapy. J Cyst Fibros 2010;9 (1):1-16.


Aztreonam for Inhalation Solution
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Gilead Sciences, Inc.
Amendment 3
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Management of Clinical and Laboratory Adverse Events
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


Aztreonam for Inhalation Solution 
Protocol GS-US-205-1850 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 Velocity Way 
Foster City, CA 
94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 3 
Randomized, Double-Blind, Phase 3B Trial to Evaluate the Safety and Efficacy of2 Treatment 
Regimens of Aztreonam 75 mg Powder and Solvent for Nebulizer Solution/ Aztreonam for 
Inhalation Solution (AZLI) in Pediatric Subjects with Cystic Fibrosis (CF) and New Onset 
Respiratory Tract Pseudomonas aeruginosa (PA) Infection/Colonization. 
AMENDMENT 3 PROTOCOL- 15 APRIL 2020 
This protocol has been approved by Gilead Sciences~ In...,.c..., . ...:::T.::h:.;:;.e.::;fo.;;;.;l;;;;lo;;;..wm
;.;.;;;;;· :,;;i.;;=;;;a;.:.;tur;;;;.;;.e .;;;d;.;;;.oc:.:i=.1m
::..:.e;.:n.:.:t;;;..s _ 
PPft 
PD 
Name (Printed) 
Author 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page73 
15 April 2020 


Aztreonam for Inhalation Solution
Protocol GS-US-205-1850
Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 74
15 April 2020
Appendix 2.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
If confirmed and possibly and/or probably related to 
investigational medicinal products:
1.
Withhold investigational medicinal products until Grade 2
2.
Restart all investigational medicinal products at full dose
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, discontinue 
all investigational medicinal products dosing permanently
If Grade 3 or 4 recurr
ce that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aztreonam for Inhalation Solution
Protocol GS-US-205-1850
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Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
Page 75
15 April 2020
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a
Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, 
unless permanently sterile or with medically documented ovarian failure.
b
Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or has medical documentation of 
permanent male infertility.
2) Contraception Requirements for Female Subjects
a
Study Drug Effects on Pregnancy and Hormonal Contraception
Non-clinical toxicity studies of aztreonam have demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of AZLI in pregnant women. 
Data from clinical pharmacokinetic interaction studies of aztreonam have demonstrated that 
there is no reduction in the clinical efficacy of hormonal contraception. Please refer to the latest 
version of the Investigator’s brochure for additional information and to the SmPC/PI.
b
Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. In the event of 
a delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy. This is true even for women of childbearing potential with 
infrequent or irregular periods. They must also agree to one of the following from Screening 
until after the last dose of study drug.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization


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Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
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Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers (diaphragm with spermicide, cervical cap with spermicide, sponge
with spermicide)
■
Male barriers (male condom, with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until after the last dose of study drug.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM). Female condom and male condom 
should not be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the Investigator if they become pregnant at any time during 
the study, or if they become pregnant within 4 weeks of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the Investigator and discontinue study drug immediately. Instructions for 
reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
Randomized, Double-Blind, Phase 3B Trial to Evaluate the 
Safety and Efficacy of 2 Treatment Regimens of Aztreonam 
75 mg Powder and Solvent for Nebulizer Solution / 
Aztreonam for Inhalation Solution (AZLI) in Pediatric 
Subjects with Cystic Fibrosis (CF) and New Onset 
Respiratory Tract Pseudomonas aeruginosa (PA) 
Infection/Colonization
Aztreonam Lysine for Pseudomonas INfection Eradication 2 
(ALPINE 2) Study 
Name of Test Drug:
Aztreonam 75 mg powder and solvent for nebulizer solution 
(European Union [EU]) or Aztreonam for Inhalation Solution 
(United States [US]) (AZLI) 
Study Number:
GS-US-205-1850
Protocol Version (Date):
Original: 11 November 2016
Amendment 1: 31 March 2017
Amendment 2: 06 November 2017
Amendment 3: 15 April 2020
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
01 December 2021
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


Aztreonam for Inhalation Solution (AZLI)
Statistical Analysis Plan
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Version 1.0
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................3
1.
INTRODUCTION..................................................................................................................................................6
1.1.
Study Objectives........................................................................................................................................6
1.2.
Study Design .............................................................................................................................................6
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Data Monitoring Committee Analyses......................................................................................................9
2.2.
Primary Analysis .......................................................................................................................................9
2.3.
Final Analysis............................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
Intent-to-treat (ITT) Analysis Set..........................................................................................10
3.1.2.
Evaluable Analysis Set..........................................................................................................10
3.1.3.
ELITE Study Matching Analysis Set ....................................................................................11
3.1.4.
Per-Protocol Analysis Set......................................................................................................11
3.1.5.
Safety Analysis Set................................................................................................................12
3.2.
Subject Grouping.....................................................................................................................................12
3.3.
Strata and Covariates...............................................................................................................................12
3.4.
Examination of Subject Subgroups .........................................................................................................12
3.5.
Multiple Comparisons .............................................................................................................................12
3.6.
Missing Data and Outliers.......................................................................................................................13
3.6.1.
Missing Data..........................................................................................................................13
3.6.2.
Outliers ..................................................................................................................................13
3.7.
Data Handling Conventions and Transformations ..................................................................................13
3.8.
Study Day and Analysis Visit Assignment .............................................................................................14
3.8.1.
Definition of Study Day ........................................................................................................14
3.8.2.
Analysis Visit Windows........................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................15
4.
SUBJECT DISPOSITION ...................................................................................................................................17
4.1.
Subject Enrollment and Disposition........................................................................................................17
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................18
4.2.1.
Duration of Exposure to Study Drug.....................................................................................18
4.2.2.
Adherence to Study Drug ......................................................................................................18
4.2.2.1.
Prescribed Adherence ......................................................................................19
4.3.
Protocol Deviations .................................................................................................................................20
4.4.
Assessment of COVID-19 Impact...........................................................................................................20
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................20
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................20
4.4.3.
Missed and Virtual Visits due to COVID-19 ........................................................................20
4.4.4.
COVID-19 Adverse Events...................................................................................................21
4.4.5.
Overall Assessment of COVID-19 Pandemic Impact...........................................................21
5.
BASELINE CHARACTERISTICS .....................................................................................................................22
5.1.
Demographics and Baseline Characteristics ...........................................................................................22
5.2.
Other Baseline Characteristics and CF Disease Characteristics..............................................................22
5.3.
Medical History.......................................................................................................................................23


Aztreonam for Inhalation Solution (AZLI) 
Statistical Analysis Plan 
GS-US-205-1850 
Version 1.0 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 25 
6.1. 
Pri1nruy Efficacy Endpoint ...................................................................................................................... 25 
6.1. 1. 
Definition of the Prima1y Efficacy Endpoint ........................................................................ 25 
6.1.2. 
Analysis of the Prima1y Efficacy Endpoint ........................................................................... 25 
6.2. 
Secondruy Efficacy Endpoints ................................................................................................................ 27 
6.2.1. 
Definition of Seconda1y Efficacy Endpoints ......................................................................... 27 
6.2.2. 
Anal sis Methods for Secondru Efficac End oints ........................................................... 27 
7. 
SAFETY ANALYSES ......................................................................................................................................... 30 
7.1. 
Adverse Events and Deaths ..................................................................................................................... 30 
7.1. 1. 
Adverse Event Dictiona1y ..................................................................................................... 30 
7.1.2. 
Adverse Event Severity ......................................................................................................... 30 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 30 
7.1.4. 
Serious Adverse Events ......................................................................................................... 30 
7.1.5. 
Treatinent-Emergent Adverse Events .................................................................................... 30 
7.1.5.1. 
Definition of Treatinent-Emergent Adverse Events ........................................ 30 
7 .1.5.2. 
Inco1nplete Dates ............................................................................................. 31 
7.1.6. 
SUllllllaries of Adverse Events and Deaths ............................................................................ 31 
7 .1.6. l. 
Summaries of AE incidence in Combined Severity Grade 
Subsets ............................................................................................................. 31 
7 .2. 
Laborato1y Evaluations ........................................................................................................................... 32 
7.2.1. 
SUllllllaries of Numeric Laborat01y Results .......................................................................... 32 
7.2.2. 
Graded Laborato1y Values .................................................................................................... 33 
7.2.2.l. 
Summaries ofLaborat01y Abnonnalities ........................................................ 33 
7 .3. 
Body Weight, Height, and Vital Signs .................................................................................................... 33 
7.4. 
Aiiway Reactivity .................................................................................................................................... 33 
7 .5. 
Prior and Concomitant Medications ........................................................................................................ 34 
7 .5. 1. 
Prior Medications .................................................................................................................. 34 
7.5.2. 
Conco1nitant Medications ...................................................................................................... 35 
7.6. 
Other Safety Measures ............................................................................................................................ 35 
7 .7. 
Changes from Protocol-Specified Safety Analyses ................................................................................. 35 
8. 
REFERENCES ..................................................................................................................................................... 36 
9. 
SOFTWARE ......................................................................................................................................................... 37 
10. SAP REVISION ................................................................................................................................................... 38 
11. APPENDIX 1 SCHEDULE OF ASSESSMENTS .............................................................................................. 39 
12. APPENDIX 2 DETERMINING MISSING AND VIRTUAL VISITS DUE TO COVID-19 ............................ .42 
12.1. 
Data Collection ....................................................................................................................................... .42 
12.2. 
Detennination of Missed and Viitual Visits ........................................................................................... .42 
Table 3-1. 
Table 12-1. 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Analysis Visit Windows .......................................................................................................... 15 
Example Search Tenns for "COVID-19" and "Viitual" Used to Identify 
Missed/Viitual Visits .............................................................................................................. .43 
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Aztreonam for Inhalation Solution (AZLI)
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LIST OF ABBREVIATIONS
AE
adverse event
ATC
anatomical therapeutic chemical
AZLI
Aztreonam 75 mg powder and solvent for nebulizer solution (European Union [EU]); aztreonam 
for inhalation solution (US)
BID
twice daily
BMI
body mass index
CF
cystic fibrosis
CFU
colony forming units
CI
confidence interval
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
eCRF
electronic case report form
ET
early termination
EU
European Union
FAS
full Analysis Set
FEF25-75
forced expiratory flow from 25% to 75% of the forced vital capacity
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
Identification
ITT
intent to treat
IWRS
Interactive Web Response System
IV
intravenous
KM
Kaplan-Meier
LLT
lower-level term
LOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mantel-Haenszel


Aztreonam for Inhalation Solution (AZLI)
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01 December 2021
MIC
minimum inhibitory concentration
MMRM
mixed-effect model for repeated measures
NLP
Natural Language Processing
PA
Pseudomonas aeruginosa
PP
Per-protocol
PT
preferred term
PTM
placebo to match
Q1, Q3
first quartile, third quartile
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI (units)
international system of units
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TNS
tobramycin nebulizer solution
ULN
upper limit of normal
TID
3 times daily
WHO
World Health Organization


Aztreonam for Inhalation Solution (AZLI) 
Statistical Analysis Plan 
GS-US-205-1850 
1. 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study repo1t (CSR) 
for Study GS-US-205-1850. This SAP is based on the study protocol amendment 3 dated 
15 April 2020 and the electronic case repo1t fo1m (eCRF). The SAP will be finalized before the 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
1.1. 
Study Objectives 
The primaiy objective of this study is as follows: 
To evaluate the safety and efficacy of a 14-day course vs a 28-day course of Aztreonam 75 mg 
powder and solvent for nebulizer solution (European Union [EU]); aztreonam for inhalation 
solution (US) (AZLI) 75 mg three times a day (TID) in subjects with new onsetPseudomonas 
aeruginosa (PA} respirato1y tract colonization/infection as detennined by PA eradication over a 
28-day post-treatment follow-up period. 
The secondaiy objectives of this study are as follows: 
• 
To evaluate the time from prima1y eradication to PA recmTence over a 108-week 
post-treatment follow-up period 
• 
To compai·e the efficacy of AZLI 75 mg TID for 14 days vs historical pooled tobramycin 
nebulizer solution (TNS) two times a day (BID) for 28 days as dete1mined by PA eradication 
over a 28-day post-treatment follow-up period 
• 
To evaluate the time to PA recmTence for a sub-group of subjects matching the population in 
the TNS ELITE Study {Ratjen 2010} over a 108-week post-treatment follow-up period 
I 
I 
1.2. 
Study Design 
This is a randomized, double-blind, multi-center study in pediatric subjects age 3 months to less 
than 18 yeai·s with CF and newly detected PA respirato1y tract colonization/infection. Subjects 
will be randomized in 1 : 1 ratio in AZLI 28-day or AZLI 14-day treatment aim. The 
randomization will be stratified by age group (3 months to < 2 yeai·s, 2 to < 6 years, and 6 to 
< 18 yeai·s). 
CONFIDENTIAL 
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The study schedule will consist of a minimum of 13 visits: Screening, Day 1 (Baseline and 
Randomization), Day 29, Weeks 6, 8, 16, and at 12-week intervals thereafter through Week 112. 
Subjects may be screened up to 14 days prior to the Baseline visit to determine eligibility for 
participation in the study. Screening and Baseline may occur on the same day for subjects.
Initial Eradication Phase (Primary Endpoint):
At the Baseline visit (Day 1), eligible subjects will be randomized to a 28-day course of AZLI 
75 mg TID or a 14-day course of AZLI 75 mg TID followed by a 14-day course of placebo to 
match (PTM) TID. Note: AZLI and PTM will both be considered “study drug treatment”.
After completing study drug treatment, subjects will be followed through Week 8 for safety and 
recurrence of PA (cultures obtained at Day 29, Week 6, and Week 8).
Follow-Up Culture Phase:
Following the end of the Initial Eradication Phase, subjects will continue in the Follow-Up 
Culture Phase, with study visits and PA cultures obtained at Week 16 and then every 12 weeks 
for 112 weeks total study duration.  
Re-Treatment Phase:
Subjects with PA recurrence after study drug treatment should be re-treated with a standard of 
care antipseudomonal antibiotic regimen at the discretion of the Investigator. A non-exclusive 
list of re-treatment regimen options include:

Inhaled AZLI (Cayston®) 75 mg TID x 28 days

Inhaled tobramycin 300 mg BID x 28 days

Inhaled colistin 2 million units BID x 28 days (with or without oral ciprofloxacin)

Any intravenous (IV) antibiotic regimen (with or without additional inhaled or oral 
antibiotics)

Other antipseudomonal antibiotic regimen at the discretion of the Investigator (to be 
documented)
For the first PA recurrence, subjects will be followed and re-cultured at the end of re-treatment, 
4 weeks post re-treatment, and every 12 weeks thereafter through Week 112. If subjects have 
subsequent PA recurrences post re-treatment, they will be treated at the Investigator’s discretion 
and have continued follow-up cultures collected every 12 weeks through Week 112.
The total study period will be 112 weeks (4 weeks study drug treatment + 4 weeks Initial 
Eradication Phase + 104 weeks Follow-Up Culture Phase).
A schedule of the study design is provided below.


Aztreonam for Inhalation Solution (AZLI)
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1.3.
Sample Size and Power
A maximum feasible sample size of 130 evaluable subjects (65 subjects per treatment arm) will 
provide 75% power to show that treatment with AZLI for 14 days is not inferior to treatment 
with AZLI for 28 days with a 20% noninferiority margin at a 1-sided significance level of 0.025, 
assuming PA eradication rates for both AZLI treatment groups is 75% {Tiddens 2015}. 
Assuming a non-evaluability rate of 5 to 7%, up to 140 subjects needed to be enrolled to obtain 
130 evaluable subjects for the efficacy analysis.
Study 
1 
Day 
Study 
Week 
Saeeti 
Randomile 
(ll<ivll 
Post 
treatment 
Week 
14 
29 
42 
56 
112 
196 
280 
364 
448 
532 
616 
700 
2 
4 
6 
8 
16 
28 
40 
52 
64 
76 
8B 
100 
SludvTreillmenl 
Initial Eradic.att0n 
Follow-Up Cu 
re Pl""5e 
Phase 
(Prl m.1:ry fndpolm) 
Pbo 
2 
4 
12 
24 
36 
4B 
60 
72 
84 
96 
For first+ PA culture after study drug treatment 
L 
Re-treatment 
f-ollow - Up Culture Phase 
tnvestlgator-
I 
Decis.ion 
Cn(J i>f rt-(1'e1Jb~-~ 
Po>t r-::· neatnw:n! ~k 
Then.tve'r 12weebw,ti1~udvW~ll2 
For tng flrn PA. rocurroncCJ, subJectswill b-0 foho~d Jnd re cull1Jree1 ;t tho ood ot re uo;nmont, 4 \WCJki post 
rfli•lle,urnem, and every 12 weeks thereafter thtO!Jih weel 112 
For SuU~ue-1ut PA tLJlturt-, re-,-l:rt!,.U .ind (olle-c.t folknv-1.11-1 tultuu!) evt!r ~ 12 'fl,'ell!'k.:!. through ~tudv Wt=!@k 112 
784 
112 
108 


Aztreonam for Inhalation Solution (AZLI)
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Version 1.0
CONFIDENTIAL
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01 December 2021
2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will make 
recommendations to the sponsor if the nature, frequency, and severity of adverse effects 
associated with the study treatment warrant the early termination of the study, the continuation of 
the study, or the continuation of the study with modifications.
DMC data review meetings are scheduled via teleconference format. The initial DMC data 
review meeting is based on data collected after approximately 25% of planned subjects either 
have provided PA cultures through Week 8 or have discontinued the study. Additional meetings 
will be scheduled every 3 to 6 months following the initial data review meeting. The timing of 
these meetings may be modified at the discretion of the DMC based on enrollment rates and 
availability of data.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
documented in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Primary Analysis
Primary analysis of the primary endpoint is the test of non-inferiority of the 14-day AZLI course 
compared to the 28-day AZLI course based on the Evaluable Analysis Set. Primary analysis was 
to be performed after all subjects have completed Week 8, or Week 16 if Week 8 culture data are 
missing, or are early terminated, and the data have been cleaned and finalized for the analysis. 
However, due to the challenges brought by COVID-19 pandemic resulting in inability to clean 
and finalize the data for the primary analysis as required by the study protocol, the primary 
analysis will be combined with the final analysis.
2.3.
Final Analysis
After all subjects have completed the study through Week 112 or are early terminated, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized, the final analysis of the data was to be performed.
However, during ongoing COVID-19 pandemic, the risk of continuing the trial in this vulnerable 
CF paediatric patient population considerably outweighed the benefits of trial continuation. 
Therefore, the study was terminated early on September 23rd, 2021. At the time of study 
termination, all evaluable subjects completed the initial eradication period and provided data for 
the primary analysis, more than 60% of subjects evaluable for the primary analysis also 
completed 108-weeks follow-up period, in line with the terms of the agreed Pediatric 
Investigational Plan (PIP) for Cayston issued by the Pediatric Committee (PDCO) of the 
European Medicines Agency (EMA). 


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-subject listings will be presented for all subjects in the Intent-to-treat (ITT) Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable). Data collected on log forms, 
such as AEs, will be presented in chronological order within the subject. The treatment group to 
which subjects were randomized will be used in the listings. Age, sex at birth, race, and ethnicity 
will be included in the listings.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets, and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before the 
study blind is broken for analysis. The analysis set will be identified and included as a subtitle of 
each TFL.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
Intent-to-treat (ITT) Analysis Set
Intent-to-treat (ITT) Analysis Set includes all subjects who were randomized in the study.  The 
ITT analysis set will be used in a sensitivity analysis of the primary endpoint to evaluate the 
impact of the treatment regimens on the treatment effect and in data listings.
3.1.2.
Evaluable Analysis Set
The evaluable analysis set for the primary efficacy analysis will include all randomized subjects 
who complete AZLI treatment with at least 75% compliance (prescribed adherence to AZLI, 
defined in Section 4.2.2.1) and do not use any anti-PA antibiotics while on study treatment with 
AZLI. Evaluability of subjects with missing PA culture result through last dose of AZLI + 
28 days is determined after applying missing data imputation rules described in Section 3.6.1. 
After imputation, subjects with missing data in both central and local lab will not be included in 
the evaluable analysis set unless those subjects have positive PA culture from Week 4 to Week 6 
for AZLI 14 Days group, or from Week 4 to Week 8 for AZLI 28 Days group. 


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3.1.3.
ELITE Study Matching Analysis Set
The ELITE Study matching analysis set will consist of subjects from Evaluable Analysis Set 
who also satisfy the published criteria for efficacy analysis population in ELITE Study 
{Ratjen 2010}. The criteria for subject’s inclusion in the ELITE study matching analysis set are: 

Subjects must be 6 months and older at randomization

No anti-PA IgG Antibody Interpretation at Screening/Baseline = positive, and no history of 
positive anti-PA antibody on record

Did not use anti-pseudomonal antibiotics through 28 days after completion of active 
treatment (Week 6 or Week 8 visit, depending on treatment assignment)

Non-missing PA culture result at 28 days after last dose of AZLI (Week 6 or Week 8 visit, 
depending on treatment assignment)

PA negative through 28 days after completion of active treatment (Week 6 or Week 8 visit, 
depending on treatment assignment)

No important protocol deviation related to compliance with study drug administration (IPD 
TA01 “Subject administered more/less medication than required”), no violation of inclusion 
criterion #3 and exclusion criterion #1 
Inclusion criterion #3: Documented new onset of positive respiratory tract culture for PA 
within 30 days of Screening defined as either first lifetime documented PA-positive 
culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures 
(at least 2 cultures per year)
Exclusion criterion #1: Use of IV or inhaled antipseudomonal antibiotics within 2 years 
of Screening
3.1.4.
Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set includes subjects in the Evaluable Analysis Set who did not 
have any important protocol deviations that impacted the primary outcome evaluation, including 
and not limited to violation of inclusion criterion #3 or exclusion criterion #1, non-compliance 
with study drug regimen specified in the protocol (IPD TA01 “Subject administered more/less 
medication than required”) or taking prohibited medication (IPD XM01 “Subject took a 
medication prohibited by the protocol”). 
The PP Analysis Set is the secondary analysis set for the efficacy analyses.


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3.1.5. 
Safety Analysis Set 
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The Safety Analysis Set includes subjects randomized and who received at least one dose of 
study diug. This is the primaiy analysis set for safety analyses. 
3.2. 
Subject Grouping 
For analyses based on the ITT Analysis Set, Evaluable Analysis Set, the ELITE Study Matching 
Analysis Set and the PP Analysis Set, subjects will be grouped according to the treatment to 
which they were randomized. For analyses based on the Safety Analysis Set, subjects will be 
grouped according to the actual treatment received. The actual treatment received will differ 
from the randomized ti·eatment only when subject's actual ti·eatment differs from randomized 
ti·eatment for the entire treatment duration. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) in a 1 : 1 ratio using a sti·atified randomization schedule. Sti·atification will be based on 
three age groups (3 months to < 2 years; 2 to < 6 years; and 6 to < 18 years). 
If there are discrepancies in su-atification factor values between the IWRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. 
Analyses perfo1med using mixed-effect model repeated measures (MMRM), such as pulmonaiy 
function test analyses, will include baseline value in the model. Although the randomization is 
sti·atified by age group, age group will not be used as a covariate in the analysis model because 
spirometiy assessment is done for subjects 6 yeai·s and older. 
3.4. 
Examination of Subject Subgroups 
The primaiy endpoint will be sUilllnai·ized for all subjects and by age group (3 months to 
< 2 years, 2 to < 6 yeai·s, 6 to < 18 yeai·s), gender, PA infection histo1y ( first PA infection, 
recunent PA infection). 
3.5. 
Multiple Comparisons 
The primaiy endpoint will be tested at the I-sided significance level of 0.025. 
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3.6. 
3.6.1. 
Missing Data and Outliers 
Missing Data 
Version 1.0 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
To determine Evaluable Analysis Set, for subjects with missing centrnl microbiology culture 
results at post-baseline visits during primaiy eradication period the local microbiology culture 
results will be used from the same analysis visit, if available. If both central and local 
microbiology results ai·e missing for any visit, the missing data will be imputed using the next 
immediate visit. If the result at the next immediate visit is negative, then the negative result will 
be assigned. If the result at the next immediate visit is positive or missing then no imputation will 
be done, and the result will remain as missing. 
If Screening and Day 1 visits ai·e perfonned on the same day and Day 1 pre-dose spirometiy 
assessment is not provided, then the pre-dose analysis time point will be assigned to the 
Screening visit measurement. 
Missing microbiology cultures colony forming units (CFU) data in which the pathogen is absent 
as detennined by culture samples will be set to 0. Othe1wise, missing CFU data will not be 
imputed. 
For missing last dosing date of study dmg, imputation mles ai·e described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.5. 
3.6.2. 
Outliers 
No data. will be excluded from the analyses, including any outliers. 
3.7. 
Data Handling Conventions and Transformations 
The following conventions will be used for the imputation of date of bi1i h when it is paiiially 
missing or not collected: 
• If only month and yeai· of bi1i h is collected, then "15" will be imputed as the day of bi1i h 
• If only year of bi1i h is collected, then "01 July" will be imputed as the day and month of bi1ih 
• If yeai· ofbiith is missing, then date ofbiith will not be imputed 
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In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a subject, then age derived based on date of birth and the Day 1 
visit date will be used instead.  If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the Day 1 visit date.  For screen failures, the date the 
first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (eg, estimates of creatinine clearance, age at 
date of AE) will be based on age derived from date of birth and the date of the measurement or 
event, unless otherwise specified. 
Data that are continuous in nature but are less than the lower limit of quantitation (LOQ) or 
above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “ x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
CFU data will be transformed using the base 10 logarithm before calculating changes.  To 
account for zero values, 1 will be added to each CFU measurement before being transformed.  
Any CFU data values where the pathogen (eg, PA) was not isolated from a valid culture will be 
set to zero (0).
3.8.
Study Day and Analysis Visit Assignment
Data obtained after the follow-up culture phase visits will be excluded from the summaries but 
will be included in the listings.
For subjects who prematurely withdraw from the study, the early termination (ET) data (except 
respiratory culture records) will be assigned to what would have been the next scheduled visit 
where the respective data were scheduled to be collected (eg, for subjects with early withdrawals 
between Visit 3 and 4, the data collected at the ET visit will be summarized at the Visit 4 
timepoint).
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:


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
For post-dose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date 
Therefore, study Day 1 is the day of first dose of study drug administration.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. In general, the values obtained at the 
nominal visit will be used for analysis, with exception to respiratory culture results. 
Any data obtained at unscheduled visits will not be assigned to a particular visit or time point. 
The following rules will be applied for respiratory culture results:

A visit prior to the first dosing of study drug may be included in the calculation of the 
baseline value, if applicable. If there are multiple PA culture results of central or local labs on 
or prior to the study drug first dose date, priority will go to the record with positive result, 
then central lab, if available, and then the result closest to first dosing of study drug. 

Respiratory culture records will be assigned to the analysis visit according to analysis visit 
windows presented in Table 3-1, regardless of whether visit is a regular scheduled visit, 
unscheduled or Early Termination visit. 
Table 3-1.
Analysis Visit Windows
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
-43
1
Week 4
29
Date of last dose of 
AZLI treatment-Date of 
treatment start date +1
32
Week 6
42
33
45
Week 8
56
46
59
Week 16
112
60
126
Week X (X= 28, 40, 
52, 64, 76, 88, 100, 
112
X*7
(X-12)*7 +15
X*7 +14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.


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If multiple valid, nonmissing, continuous measurements exist in an analysis window, records will 
be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the average of these measurements (for continuous data) will be 
considered the baseline value.

For non-microbiology (e.g. spirometry) assessments, the postbaseline values will be assigned 
using the following priority order:
Non-missing nominal visit
The record closest to the nominal day for that visit will be selected
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected
If there is more than 1 record on the selected day, the worst will be taken, unless 
otherwise specified.
If multiple valid, nonmissing, non-microbiology categorical measurements exist in an analysis 
window, records will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected.

For post-baseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected.
For the respiratory culture data, when multiple records of central or local labs are mapped to the 
same nominal visit, for visits through Week 8, local lab result will only be used when central lab 
result from the same visit is missing; for visits after Week 8, priority will go to the record with 
positive result, and then the earliest result. If multiple central laboratory records are mapped to 
the same nominal visit then the priority will go to the record with positive respiratory culture 
result, and next to the scheduled visit record. If there are the same PA culture results from central 
and local lab done on the same day, then the priority is given to the central lab result.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each country, 
investigator within a country, and overall. The summary will present the number and percentage 
of subjects enrolled. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column.
A similar enrollment table will be provided by stratification factor stratum. The denominator for 
the percentage of subjects in the stratum will be the total number of randomized subjects. If there 
are discrepancies in the value used for stratification assignment between the IWRS and the 
clinical database, the value collected in the clinical database will be used for the summary. A 
listing of subjects with discrepancies in the value used for stratification assignment between the 
IWRS and the clinical database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects who met all eligibility criteria 
but were not randomized with reasons subjects not randomized, the number of subjects 
randomized, and the number of subjects in each of the categories listed below:

Safety Analysis Set

Per-Protocol Analysis Set

ITT Analysis Set

Evaluable Analysis Set
Did not meet evaluability criteria due to < 75% compliance
Did not meet evaluability criteria due to use of anti-PA antibiotics while on AZLI 
treatment
Did not meet evaluability criteria due to missing PA culture result during initial 
eradication phase

The ELITE Study Matching Analysis Set

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study 

Did not complete the study with reasons for premature discontinuation of study


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For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation

Lot number and kit ID of assigned study drugs
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in days using up to 1 decimal place (eg, 10.5 days). If the last study drug dosing date is 
missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date that occurred during the on-treatment period will 
be used.
The total duration of exposure to active AZLI treatment will be summarized using descriptive 
statistics and using the number (ie, cumulative counts) and percentage of subjects exposed 
through the following time periods: ≥ 1 day, ≥ 8 days, ≥ 15 days, and ≥ 29 days. Summaries will 
be provided by treatment group for the Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total number of vials of AZLI administered will be summarized using descriptive statistics. 
The presumed total number of vials administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Vials Administered =
No. of Vials Dispensed ―
No. of Vials Returned
Total dose (mg) taken will be calculated as 75 times the number of vials taken. 
) 


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In general, unreturned missing vials will be assumed to have not been inhaled.  Subjects without 
a vial return record are assumed to have taken one dose at clinic (at day 1 visit) and their total 
number of inhaled vials equals one.
4.2.2.1.
Prescribed Adherence
The level of prescribed adherence to the AZLI treatment will be determined by the total amount 
of study drug administered relative to the total amount of study drug specified by the protocol for 
a subject who completes treatment in the study.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol






Specifically, the Prescribed Adherence (%) of AZLI 14 Days group will be calculated as:
Prescribed Adherence (%)14 = min[100, 100* (total number of inhaled vials)/(3*14)]
The Prescribed Adherence of AZLI 28 Days group will be calculated as:
Prescribed Adherence (%)28= min[100, 100* (total number of inhaled vials)/(3*28)]
The prescribed adherence to AZLI and overall prescribed adherence (regardless of treatment 
assignment) will be provided in the listing. 
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75, ≥ 75 to < 80%, ≥ 80 to < 85%, ≥ 85 to 
< 90%, ≥ 90 to < 95%, ≥ 95%) will be provided by treatment group for the Safety Analysis Set.
Total number of used vials will be summarized (mean, median, SD, minimum, maximum, and 
n).  
Subjects are defined as treatment compliant if they used at least 75% of the vials they were 
supposed to use based on Prescribed Adherence calculations above.  
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).


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4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria by treatment group based on the ITT 
Analysis Set. A by-subject listing will be provided for those subjects who did not meet at least 1 
eligibility (inclusion or exclusion) criterion. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the ITT Analysis Set. A by-subject listing will be 
provided for those subjects with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which had an 
impact on the study conduct. Some subjects were unable to attend onsite visits due to shelter in 
place guidelines, site closures, or other reasons. This section describes how special situations due 
to COVID-19 will be handled in the analysis.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-subject listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided, if applicable.
4.4.2.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviations related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviations related to COVID-19.
4.4.3.
Missed and Virtual Visits due to COVID-19
An overall summary of the number and percentage of subjects with missed or virtual visits (e.g., 
at least 1, with 1, 2, 3 or more visits) due to COVID-19 will be provided by treatment group and 
overall. The denominator for the percentage calculation will be the total number of subjects in 
the safety population for that column.
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order.
Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields.  A detailed 
explanation of the algorithm is given in Appendix 2.


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4.4.4.
COVID-19 Adverse Events 
AEs of COVID-19 will be included in analyses of AEs if applicable, which will be determined 
through COVID-19 SMQ broad search. A by-subject listing of AEs of COVID-19 will be 
provided, if applicable.
4.4.5.
Overall Assessment of COVID-19 Pandemic Impact
For subjects affected by COVID-19 infection and/or pandemic while participating in the study, a 
listing of the following individual COVID-19 related outcome categories will be provided:
o
Death due to COVID-19
o
Adverse event of COVID-19, as determined by COVID-19 SMQ broad search 
o
Hospitalization (using data from AE eCRF) due to adverse event of COVID-19 as defined 
above
o
Study drug discontinuation due to COVID-19
o
Study discontinuation due to COVID-19
o
Missed visits due to COVID-19  
o
Missed PA culture collection due to COVID-19 
In addition, composite broad COVID-19 impact indicator will be derived based on the following 
individual categories defined above: death, adverse event, hospitalization, study drug 
discontinuation, study discontinuation, missed visits, and missed key assessments. Composite 
specific COVID-19 impact indicator will be derived based on death and specific adverse event.


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Version 1.0 
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2], vital signs) will be 
summarized by ti·eatment group and overall using descriptive statistics for continuous variables 
and using number and percentage of subjects for categorical variables. The summa1y of 
demographic data will be provided for the Safety Analysis Set for the following: 
• 
Age ( on the first dose date of any study dmg) as a continuous variable 
• 
Age group (3 months to < 2 years; 2 to < 6 years; and 6 to < 18 years) 
• 
Sex (male, female) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, 
White or Other) 
• 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not pennitted) 
• 
body weight [ in kg] 
• 
height [in cm] 
• 
body mass index [BMI in kg/m2] 
• 
vital signs (blood pressmes in mmHg, pulse in beats/min, temperate in C
0
) 
A by-subject demogi-aphic listing, including the infonned consent date, will be provided by 
subject ID number in ascending order. 
5.2. 
Other Baseline Characteristics and CF Disease Characteristics 
Other baseline characteristics include: 
I 
I 
I 
I 
• 
Respiration Rate at baseline (breaths/min) 
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
O2 Saturation (%) at baseline

Chest Auscultation at baseline

Presence of PA at baseline (Present or Absent)

PA mucoid phenotype (mucoid PA, non-mucoid PA)

Log10 PA CFU for Patients with Positive PA

MIC of Aztreonam for All PA Isolates

Highest Aztreonam MIC for PA (ug/mL)

Infection history (first PA infection, recurrence)

Anti-PA IgG antibodies (interpretation categories: negative, borderline, positive) 

CF Disease characteristics:
Sweat Chloride Test (mEq/L) 
Sweat Sodium (mEq/L)
CF Genotype (Total, Homozygous, Heterozygous, Unidentified, Other, Missing)
1) Homozygous if both of the results are ‘Delta F508’
2) Heterozygous if one result is ‘Delta F508’ and one is ‘other’, ‘unidentified’, or 
missing
3) Unidentified if both of the two results are ‘unidentified’, or if one result is 
‘unidentified’ and one is ‘missing’
4) Other if one result is ‘other’ and one is ‘other’, ‘unidentified’, or missing
5) Missing if both results are missing 
These baseline and CF disease characteristics will be summarized by treatment group and overall 
using descriptive statistics for continuous variables and using number and percentage of subjects 
for categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. 
In addition, the number and percent of subjects with positive result for pathogens detected from 
nasal swabs obtained at baseline visit using Biofire assay will be summarized.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Disease-specific medical history will be collected on the CRFs and will be summarized using 
descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous data, by the number and percent of subjects for categorical data, and by total counts 
for multiple records data. 


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Summaries of previous PA infection history will be provided for the safety analysis set. 
Summaries of previous PA infection history will include number of subjects with first PA 
infection and recurrent PA infection. Subcategories of the number of subjects with 1, 2, 3, 4, and 
≥ 5 additional previous PA infections (ie, not including the infection to qualify for the study) will 
be included within the category of recurrent PA infection. The number of subjects with available 
data will be used as the denominator in the summaries.
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with PA-negative cultures through 
28 days post-treatment in the 14-day treatment group vs 28-day treatment group. Evaluable 
Analysis Set of the primary efficacy endpoint is defined in Section 3.1.2. Subjects with no 
PA-positive culture at Week 4 through Week 6 (for 14-day AZLI treatment group) or Week 8 
(for 28-day AZLI treatment group) analysis visit will be considered to be a responder for the 
primary endpoint (analysis visits are defined in Section 3.8.2, handling of missing PA culture 
results are described in Section 3.8.3).
6.1.2.
Analysis of the Primary Efficacy Endpoint
Primary analysis of the primary endpoint is the test of non-inferiority of the 14-day AZLI course 
compared to the 28-day AZLI course based on the Evaluable Analysis Set. The proportion of 
evaluable subjects with PA-negative cultures through 28 days post-treatment (Week 6 visit for 
subjects in the 14-day treatment group and Week 8 visit for subjects in the 28-day group) for 
each treatment group will be presented with 2-sided exact 95% confidence interval (CI). The 
difference in proportions between treatment groups, and the associated 95% CIs will be 
constructed based on stratum-adjusted Mantel-Haenszel (MH) proportions, using age group (as 
in IWRS) as stratification factor, as follows {Koch 1989}:
pA – pB  Z(1-α/2 )* SE(pA – pB),
where 

(pA – pB) = 

h
h
h
w
d
w
, is the stratum-adjusted MH proportion difference, where 
h
d  = 
Bh
Ah
p
p

is the difference in the proportion of subjects who met the endpoint between 
14-day AZLI and 28-day AZLI groups in age stratum h.

h
w =
Bh
Ah
Bh
Ah
n
n
n
n

, is the weight based on the harmonic mean of sample size per treatment group 
for each stratum where 
Ah
n
and 
Bh
n are the sample sizes of 14-day AZLI and 28-day AZLI in 
age stratum h.

SE (𝑝𝐴 –𝑝𝐵 ) = 
2
*
*
*
*
2
)
(
1
)
1(
1
)
1(













h
Bh
Bh
Bh
Ah
Ah
Ah
h
w
n
p
p
n
p
p
w
, where 


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
1
5.0
*



Ah
Ah
Ah
n
m
p
and 
1
5.0
*



Bh
Bh
Bh
n
m
p
, and 

𝑚𝐴ℎ and 𝑚𝐵ℎ are the number of subjects who met the endpoint in14-day AZLI and 28-day 
AZLI in age stratum h.

α = 0.05 for the calculation of 95% CI 

Z(1-α/2) = Z0.975 is the 97.5th percentile of the normal distribution

Z score = 
(𝑝𝐴― 𝑝𝐵)
𝑆𝐸(𝑝𝐴―𝑝𝐵)
Evaluable Analysis Set of primary efficacy endpoint is defined in Section 3.1.2. Non-inferiority 
of the 14-day treatment regimen will be claimed if the lower bound of 1-sided 97.5% confidence 
limit of the treatment difference (14-day course group vs 28-day course group) is above the non-
inferiority margin of -20%. 
The primary endpoint will be summarized for all subjects and by age group (3 months to 
< 2 years, 2 to < 6 years, 6 to < 18 years) and for gender, infection history (first PA infection, 
recurrent PA infection), and presence of PA at baseline (presence, absence) subgroups, In each 
subgroup analysis, the proportion of evaluable subjects with PA-negative cultures at all time 
points through Week 8 for each treatment group will be summarized (n and percentage) and an 
exact 95% CI will be provided based on this sensitivity analysis population of subjects. The 
difference in proportions between treatment groups, and the associated 95% CIs will be 
constructed based on stratum-adjusted MH method using age as stratification factor, except for 
the by-age subgroup analysis, where the difference in proportions between treatment groups, and 
the associated 95% CIs will be calculated without age stratum adjustment.  
To evaluate the robustness of the treatment effect, the following sensitivity analyses of the 
primary endpoint will be conducted:

Sensitivity analysis 1 will be based on the ITT analysis Set and will use the same 
definition of primary efficacy endpoint as in Section 6.1

Sensitivity analysis 2 will be based on PP Analysis Set and will use the same definition 
of primary efficacy endpoint as in Section 6.1.

In sensitivity analysis 3, subjects with any anti-pseudomonal antibiotic use through 
28 days after completion of AZLI treatment (Week 6 or Week 8 visit), or with a 
PA-positive culture at Week 4 through Week 6 or Week 8, depending on treatment 
assignment, will be defined as treatment failures. Analysis will be based on Evaluable 
Analysis Set.

In sensitivity analysis 4, subjects with a PA-positive culture from either central or local 
lab at Week 4 through Week 6 or Week 8, depending on treatment assignment, will be 
defined as treatment failures. Analysis will be based on Evaluable Analysis Set.


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The proportion of evaluable subjects with PA-negative cultures at all time points through Week 8 
for each treatment group will be summarized (n and percentage) and an exact 95% CI will be 
provided based on this sensitivity analysis population of subjects. The difference in proportions 
between treatment groups, and the associated 95% CIs will be constructed based on 
stratum-adjusted MH method using age as stratification factor, as well.
6.2.
Secondary Efficacy Endpoints
6.2.1.
 Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are:

Time from primary eradication to PA recurrence over a 108-week post-treatment 
follow-up period

The proportion of subjects with PA-negative cultures through 28 days post-treatment in 
the 14-day treatment group vs historical pooled data for PA eradication at 28 days 
post-treatment in subjects treated with TNS

Time to PA recurrence after primary eradication for a sub-group of subjects matching 
the population in the TNS ELITE Study over a 108-week post-treatment follow-up 
period
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For time to recurrence secondary endpoint, local lab PA presence will be considered and will 
override a central lab PA absence result, if they are mapped to the same clinical visit. The actual 
date of the lab, whether unscheduled or at scheduled clinic visit will be used as the event date of 
the recurrence of PA after the primary eradication. Recurrence after PA eradication is defined as 
first positive PA culture result in subject who met the primary endpoint and had no local lab 
PA-positive culture from Week 4 to Week 6 for AZLI 14 Days group, or from Week 4 to Week 8 
for AZLI 28 Days group. The end of the primary eradication period will be calculated as 
following: the date of last dose of AZLI + 28 days. The first day of follow-up period will be 
derived as the date of last AZLI administration + 29 days. 
Time (in days) to the event will be calculated as [earliest date of event – (last AZLI dose date 
+28 days) +1].
Subjects without PA recurrence will be censored at the last lab visit date with PA culture result.
Time (in days) to censoring will be calculated as [last lab visit date – (last AZLI dose date 
+28 days) +1].
The median time to PA recurrence after the primary eradication over the 108-week post-
treatment follow-up period will be assessed using un-stratified Kaplan-Meier (KM) method. In 
addition to median time, the KM estimates of recurrence probability and 95% CIs will be 


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presented for each 12-week interval post-primaiy eradication by ti·eatment group based on the 
Evaluable Analysis Set Additional sUilllnai·ies of time to PA recmTence will be provided in 
months and by age subgroups (3 months to < 2 yeai·s, 2 yeai·s to < 6 yeai·s, and 6 to < 18 years). 
The conesponding KM figures will be provided. 
The median time to PA recmTence and 95% CI will be presented for ELITE-matching analysis 
set as described in Section 3.1.3, and compai·ed descriptively with the published result from 
ELITE Study (median time to recmTence after 28-day ti·eatment with tobrainycin is 26.12 months 
with 95% CI [14.69 to NA]). 
The propo1t ion of subjects with PA-negative cultures during 28 days post-ti·eatment period in the 
14-day course group will be sUilllnarized at each visit (n and percent) and be presented with 
exact 95% CI and compai·ed descriptively with historical pooled data for propo1tion of subjects 
with PA eradication at 28 days post-ti·eatment with TNS. The historical data for the proportion of 
subjects with PA-negative cultures during 28 days post-ti·eatment period will be pooled from the 
published results from the studies conducted on the subjects with new onset of PA infection and 
similar TNS ti·eatment duration and follow-up. { Gibson 2003, Proesmans 2013}. The propo1tion 
of subjects with PA eradication at 28 days post-ti·eatment with TNS in Gibson 2003 is 6/8 (75%), 
while that based on estimates from KM curve in Proesmans 2013 is 18/23 (78%). The pooled 
propo1tion of subjects with successful PA eradication at 28 days post-ti·eatment with TNS is 
estimated to be ( 6+ 18)/(8+23)=77%. 
-
I 
I 
I 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the MedDRA v24.1. System 
organ class (SOC), high-level term (HLT), and preferred term (PT) will be provided in the AE 
dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4 or 5 according to toxicity 
criteria specified in the protocol (Amendment 3). The severity grade of events for which the 
investigator did not record severity will be categorized as “missing” for tabular summaries and 
data listings. The missing category will be listed last in summary presentation. 
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Global Patient Safety 
Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE incidence in Combined Severity Grade Subsets 
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. This summary will be provided for all 
subjects and by age (3 months to < 2 years, 2 to < 6 years, 6 to < 18 years).
For other AEs listed below, summaries will be provided by SOC, HLT, PT, and treatment group:

TEAEs of Grade 3 or higher

TE treatment-related AEs

TE treatment-related AEs with Grade 3 or higher 

TE SAEs

TE treatment-related SAEs 

TEAEs leading to premature discontinuation of study drug


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
TE SAEs leading to hospitalization 
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition to the above summary tables, all TEAEs, TE SAEs, TE treatment-related AEs, and 
TE treatment-related SAEs will be summarized by PT only, in descending order of total 
frequency.
The AZLI exposure adjusted TEAE incidence rates will be presented by PT in descending order 
of overall rate. 
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All SAEs

All Deaths

All AEs of Grade 3 or higher

All AEs leading to premature discontinuation of study drug 
Summaries (number and percentage of subjects) of follow-up SAEs (by SOC, HLT, and PT) will 
also be provided using the safety analysis set. Follow-up SAEs are defined as those that start 
30 days after the last dose of study drug and don’t meet the definition of a treatment-emergent 
AE.
7.2.
Laboratory Evaluations
Laboratory data collected at baseline will be analyzed and summarized. The analysis will be 
based on values reported in conventional units. When values are below the LOQ, they will be 
listed as such, and the closest imputed value will be used for the purpose of calculating summary 
statistics as specified in Section 3.7. 
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each baseline laboratory test 
specified in the study protocol
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. The mean, median, Q1, Q3, minimum, and maximum 


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values will be displayed to the reported number of digits; SD values will be displayed to the 
repo1i ed number of digits plus 1. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
7.2.2. 
Graded Laboratory Values 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used to 
assign toxicity grades (0 to 4) to laborato1y results for analysis. Grade O includes all values that 
do not meet the criteria for an abno1mality of at least Grade 1. 
7.2.2.1. 
Summaries of Laborato1y Abno1malities 
A by-subject listing for abno1mal laborato1y test results will be provided by subject ID number 
for hematology, sennn chemistry , and urinalysis. Values falling outside of the relevant reference 
range and/or having a severity grade of 1 or higher will be included in the data listing, as 
appropriate. 
7.3. 
Body Weight, Height, and Vital Signs 
Descriptive statistics (sample size, mean, SD, median, QI, Q3, minimum and maximum) will be 
provided by ti·eatinent group for body weight, height, BMI and vital signs (heaii rate, systolic 
and diastolic blood pressure, body temperature, and respirato1y rate) at baseline. 
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study diug. Body weight and vital signs measured at unscheduled visits will be 
included for the baseline value selection. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No fo1mal statistical testing is planned. 
A by-subject listing of vital signs will be provided by subject ID number at baseline and 
unscheduled visits in chronological order. Body weight, height, and BMI will be included in the 
vital signs listing. 
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7.5. 
Prior and Concomitant Medications 
Version 1.0 
Medications collected at screening and during the study will be coded using the cunent version 
of the World Health Organization (WHO) Dmg dictionaiy. 
7.5.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first study drng. 
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drng class 
Level 2 and prefen ed name using the number and percentage of subjects for each treatment 
group and overall. A subject reporting the same medication more than once will be counted only 
once when calculating the number and percentage of subjects who received that medication. The 
summa1y will be ordered alphabetically by A TC medical class and then by prefened te1m 
alphabetically within each ATC medical class. 
For the purposes of analysis, any medication with a staii date prior to the first dosing date of 
study dmg will be included in the prior medication smnmaiy regai·dless of when the stop date is. 
If a paitial staii date is entered the medication will be considered prior unless the month and yeai· 
(if day is missing) or year (if day and month are missing) of the staii date are after the first 
dosing date. Medications with a completely missing staii date will be included in the prior 
medication smnmaiy, unless othe1wise specified. 
Smnmai·ies will be based on the Safety Analysis Set. No fonnal statistical testing is planned. 
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7.5.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class Level 2 and preferred name 
using the number and percentage of subjects for each treatment group. A subject reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered 
alphabetically by ATC medical class and then by preferred term alphabetically within each ATC 
medical class. 
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year (if 
day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the Safety Analysis Set. No formal statistical testing is 
planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes from Protocol-Specified Safety Analyses 
Additional analyses describing impact of COVID-19 pandemic are described in the 
Section 4.4.4.


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8.
REFERENCES
Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, et al. Significant 
microbiological effect of inhaled tobramycin in young children with cystic 
fibrosis. Am J Respir Crit Care Med. 2003;167 (6):841-9.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21. 
Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two 
treatment regimens for eradication of Pseudomonas aeruginosa infection in 
children with cystic fibrosis. J Cyst Fibros 2013;12 (1):29-34.
Ratjen F, Munck A, Kho P, Angyalosi G, Elite Study Group. Treatment of early Pseudomonas 
aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 
2010;65 (4):286-91.
Tiddens HA, De Boeck K, Clancy JP, Fayon M, H GMA, Bresnik M, et al. Open label study of 
inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: 
The ALPINE study. J Cyst Fibros 2015;14 (1):111-9.


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9.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 6.0. Statistical Solutions, Cork, Ireland.


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10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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11.
APPENDIX 1 SCHEDULE OF ASSESSMENTS 
Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day/Week
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
ET
Unscheduled
Written Informed Consent
X
Inclusion/Exclusion Criteria 
X
Xf
Subject Demographics
X
Medical History
X
Complete Physical Examination
X
X
X
Modified Physical Examination
X
X
X
X
X
X
Body Weight, Height and Vital 
Signs
X
X
Hematology and Serum Chemistry
Xa
Blood for Biomarkersi
X
Respiratory Sample for 
Microbiologyn 
X
X 
(pre-dose)
X
X
X
X
X
X
X
Nasal Swab for Microbiology
X 
(pre-dose)
Urine Pregnancy Testc
X
X 
(pre-dose)
X
X
Xe
X
Randomization
X


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Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day/Week
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
ET
Unscheduled
Instruct Subject on Study Drug 
Administration, Dosing, and 
Storage and on Proper 
Operation/Cleaning of Altera®
X
Administer Study Treatment in 
Clinic
X
Administer Study Treatment at 
Home, 3 times per day
X
Xl
Administer short-acting β2 agonist
X
X
(pref and 
post-dose)
X
X
X
X
X
X
X
Clinical Observations for study 
drug-induced adverse eventsb
X 
(pre and 
post-dose)
Dispense Study Treatment Kits, 
Sterilizer, Altera® Nebulizer 
System (eBase & handset, mask if 
applicable), and Dosing Log
X
CCI
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Screeningg
Baseline
(Day 1)g
Initial Eradication Phase
Follow-up culture 
Phase k
Other Visits
Day/Week
Day-13 to 
Day 1
Day 1h
Day 14/
Week 2
Day 29/
Week 4h
Week 6
Week 8
Weeks 16, 
28, 40, 52, 
64, 76, 88, 
100
Week 112
Visit Windows
± 1 day
± 1 day
± 3 day
± 3 day
± 14 day
± 14 day
Visit
1
2
(Telephone 
contact)
3
4
5
6-13
14
ET
Unscheduled
Collect device system components 
(eBase Unit, Handset and Mask if 
applicable), Used and Unused 
Drug Vials, and Dosing Log
X
Xj
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Adverse Eventsm
X
X
X
X
X
X
X
X
X
X
PA= Pseudomonas aeruginosa, OP= Oropharyngeal, 
 
AZLI= Aztreonam for Inhalation Solution.
a
Hematology and serum chemistry only needed at screening if there are no labs available within the previous 12 months to assess eligibility
b
For subjects 3 months of age to <6 years of age and subjects 6 years of age and older who cannot reliably perform spirometry assessments - chest auscultation, respiratory 
rate, and oxygen saturation
c
All females of childbearing potential, if result is positive confirm with a serum pregnancy test
e
If ET visit occurs within 30 days of the last dose of study drug
g
These visits may be combined and performed on the same day
h
Fungal culture (for Aspergillus spp) analysis from respiratory sample only on Day 1 and Day 29
i
Anti-PA Antibodies (only needed at screening if there are no results available within the previous 24 months)
j
If ET visit occurs before Day 29
k
These visits (not including Week 112 or the ET visit) can be performed at home by specialist CF nurses if this is standard of care at the clinic and appropriate respiratory 
samples can be obtained and processed
l
Subjects should be contacted via telephone on Day 14 to assess whether they have had any adverse events or taken any concomitant medications and instruct subject/parent to 
switch to second carton of study drug treatment on Day 15
m
During Follow-up Culture phase, only those AE/SAEs related to protocol mandated procedures should be reported to Gilead PVE. Also, AEs/SAEs related to Cayston 
treatment in the re-treatment phase must be collected and reported to Gilead PVE.
n
If the subject is not able to expectorate sputum at a study visit, alternative methods of lower respiratory tract specimen collection may be performed as per local standard of 
care (eg induced sputum, cough swab, nasopharyngeal aspiration, laryngeal suction). If a lower respiratory specimen cannot be obtained, an oropharyngeal (throat) swab may 
be taken
CCI
CCI
CCII 
I 


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12.
APPENDIX 2 DETERMINING MISSING AND VIRTUAL 
VISITS DUE TO COVID-19
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
12.1.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by Clinical 
Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic.  If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
12.2.
Determination of Missed and Virtual Visits 
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 12-1). The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit will be assigned as follows:
i.
If COVID-19 terms are identified through NLP and the visit date is missing, then 
result is ”Missed Visit”
ii. If COVID-19 and Virtual terms are identified through NLP for a visit, then result is 
“Virtual Visit”. When there are multiple records for the same subject and the same 
visit, if one record could be categorized as “Virtual Visit”, all records associated with 
this subject and this visit will be categorized as “Virtual Visit”
iii. Otherwise result is missing


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Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits.
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE 
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-205-1850_SAP_v1
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
04-Dec-2021
18:06:24
Clinical Research eSigned 05-Dec-2021
04:40:54
PPD
PPD