Conditions: Cystic Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the effect of andecaliximab (GS-5745) on pre-bronchodilator forced expiratory volume in 1 second (FEV1) % predicted in adults with cystic fibrosis (CF) after 8 weeks of treatment.

There will be 2 parts to this study. In Part 1, andecaliximab 600 mg or placebo will be administered for 8 weeks. In Part 2, andecaliximab 300 mg, 150 mg, or placebo will be administered for 8 weeks. Part 2 will be initiated after completion of Part 1.

Detailed description:

Arms:
arm 1: Andecaliximab 600 mg weekly for 8 weeks arm 2: Placebo weekly for 8 weeks arm 3: Andecaliximab 300 mg weekly for 8 weeks arm 4: Andecaliximab 150 mg + placebo weekly for 8 weeks arm 5: Placebo weekly for 8 weeks arm 6: (Part 1) Andecaliximab 600 mg weekly for 16 weeks; (Part 2) Andecaliximab 300 mg weekly for 16 weeks

Interventions: intervention 1: Andecaliximab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered via subcutaneous injection intervention 2: Administered via subcutaneous injection

Protocol document:
SAP_002.pdf: 
 
 
STATISTICAL ANALYSIS PLAN   
 
 
Study Title: 
A Phase 2b, Dose-Ranging Study of the Effect of GS-5745 on 
FEV1 in Adult Subjects with Cystic Fibrosis  
 
 
Name of Test Drug: 
Andecaliximab (GS-5745)  
 
 
Study Number: 
GS-US-404-1808 
 
 
Protocol Version (Date): 
Amendment 2  (May 25, 2016) 
 
 
Analysis Type: 
Final Analysis 
 
 
Analysis Plan Version: 
Version 1.0 
 
 
Analysis Plan Date: 
05 September 2017 
 
 
Analysis Plan Author(s): 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
PPD


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION ................................................................................................................................................ 5 
1.1. 
Study Objectives ...................................................................................................................................... 5 
1.2. 
Study Design ............................................................................................................................................ 6 
1.3. 
Sample Size and Power ............................................................................................................................ 9 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 10 
2.1. 
Interim Analyses .................................................................................................................................... 10 
2.2. 
Final Analysis ........................................................................................................................................ 10 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 11 
3.1. 
Analysis Sets .......................................................................................................................................... 11 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 11 
3.1.2. 
Full Analysis Set .................................................................................................................. 11 
3.1.3. 
Safety Analysis Set ............................................................................................................... 11 
3.2. 
Subject Grouping ................................................................................................................................... 11 
3.3. 
Strata and Covariates .............................................................................................................................. 12 
3.4. 
Examination of Subject Subgroups ........................................................................................................ 12 
3.5. 
Multiple Comparisons ............................................................................................................................ 12 
3.6. 
Missing Data and Outliers ...................................................................................................................... 12 
3.6.1. 
Missing Data ........................................................................................................................ 12 
3.6.2. 
Outliers ................................................................................................................................. 12 
3.7. 
Data Handling Conventions and Transformations ................................................................................. 12 
3.8. 
Analysis Visit Windows ......................................................................................................................... 12 
3.8.1. 
Definition of Study Day ....................................................................................................... 12 
3.8.2. 
Analysis Visit Windows ....................................................................................................... 13 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 13 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 15 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 15 
4.2. 
Extent of Study Drug Exposure and Adherence ..................................................................................... 15 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 15 
4.2.2. 
Adherence to Study Drug ..................................................................................................... 16 
4.3. 
Deviations .............................................................................................................................................. 16 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 17 
5.1. 
Demographics ........................................................................................................................................ 17 
5.2. 
Other Baseline Characteristics ............................................................................................................... 17 
5.3. 
Medical History ...................................................................................................................................... 17 
6. 
EFFICACY ANALYSES ................................................................................................................................... 18 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 18 
6.1.1. 
Statistical Hypothesis for the Primary Efficacy Endpoint .................................................... 18 
6.1.2. 
Analysis of the Primary Efficacy Endpoint .......................................................................... 18 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 18 
6.2.1. 
Definitions of Key Secondary Efficacy Endpoints ............................................................... 18 


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6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints .......................................................... 18 
6.3. 
Other Efficacy Endpoints ....................................................................................................................... 18 
7. 
SAFETY ANALYSES ........................................................................................................................................ 19 
7.1. 
Adverse Events and Deaths .................................................................................................................... 19 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 19 
7.1.2. 
Adverse Event Severity ........................................................................................................ 19 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 19 
7.1.4. 
Serious Adverse Events ........................................................................................................ 19 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 19 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 20 
7.2. 
Laboratory Evaluations .......................................................................................................................... 21 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 21 
7.2.2. 
Graded Laboratory Values ................................................................................................... 21 
7.2.3. 
Liver-related Laboratory Evaluations ................................................................................... 22 
7.3. 
Body Weight and Vital Signs ................................................................................................................. 22 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 22 
7.5. 
Electrocardiogram Results ..................................................................................................................... 22 
7.6. 
Other Safety Measures ........................................................................................................................... 22 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 22 
8. 
REFERENCES ................................................................................................................................................... 23 
9. 
SOFTWARE ....................................................................................................................................................... 24 
10. SAP REVISION .................................................................................................................................................. 25 
11. APPENDIX ......................................................................................................................................................... 26 
 
Appendix 1. 
Schedule of Assessments ........................................................................................................ 26 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1. 
Study Design Schema ............................................................................................................... 6 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
cystic fibrosis questionnaire - revised 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DB 
double-blind  
DMC 
data monitoring committee 
ECG 
electrocardiogram 
ET 
early termination 
FAS 
Full Analysis Set 
FEV1  
forced expiratory volume in 1 second 
FRI 
functional respiratory imaging 
GS 
Gilead Sciences 
HLT 
high-level term 
ICH 
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use) 
IXRS 
interactive Voice/Web Response System 
LLT 
lower-level term 
LOQ 
limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP9 
matrix metalloproteinase 9 
OL 
Open-label  
PK 
pharmacokinetics 
PT 
preferred term 
Q1, Q3 
first quartile, third quartile 
RSS 
Respiratory Symptom Scale 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SE 
standard error 
SI (units) 
international system of units 
SOC 
system organ class 
SNOT-22 
Sino-Nasal Outcome Test 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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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 rep01t (CSR) 
for Study GS-US-404-1808. This SAP is based on the study protocol Amendment 2 dated 
25 May 2016 and the elecu·onic case rep01t f01ms (eCRF). The SAP will be fmalized before 
database fmalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
The study was te1minated early by the sponsor on 08 June 2017 due to business decision. This 
SAP describes the analyses to supp01t the synoptic CSR. 
1.1. 
Study Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the effect of andecaliximab on pre-bronchodilator forced expirat01y volume in 
1 second (FEVt)% predicted in subjects with cystic fibrosis (CF) after 8 weeks ofu·eatment 
The secondary objectives of this study are as follows: 
• 
To assess safety, tolerability, and phatm acokinetics (PK) of andecaliximab in subjects with 
CF 
• 
To evaluate the effect of andecaliximab on post-bronchodilator FEV1% predicted in subjects 
with CF after 8 weeks of u·eatment 
Explorat01y objectives of this study ru·e as follows: 
IT 
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1.2. 
Study Design 
This was a Phase 2b, randomized, double-blind, placebo-controlled, multiple-center, multiple 
dose study comprising of 2 parts.   
In Part 1, 60 subjects were to be enrolled in a 1:1 ratio to receive weekly subcutaneous (SC) 
injections of either 600 mg andecaliximab or placebo for 8 weeks.   
Upon successful completion of Part 1, 90 subjects were to be enrolled in Part 2 in a 1:1:1 ratio to 
receive weekly SC injections of either 300 mg of andecaliximab, 150 mg of andecaliximab, or 
placebo for 8 weeks.  
An Interactive Voice/Web Response System (IXRS) was employed to manage subject 
randomization and enrollment into Part 1 and Part 2 of the study, shipping of study drug, and 
dispensing of study drug. 
Safety and efficacy analyses were to be performed for Part 1 after all subjects complete the Week 
8 visit or discontinued from the study. There were 3 Data Monitoring Committee (DMC) 
meetings planned in Part 1 and 1 in Part 2.  
Subjects enrolled into either Part 1 or Part 2 had the option of participating in an open-label 
extension (OLE) starting from the Week 8 visit. The open-label extension would allow an 
additional 16 weeks of dosing with andecaliximab 600 mg SC weekly in Part 1 and 300 mg SC 
in Part 2. 
Figure 1-1. 
Study Design Schema 
 
 


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There was a FRI sub-study which required 2 FRI scans (at Baseline and at the Week 8 visit).   
Up to 150 subjects with CF ≥ 18 years of age were planned to be enrolled. 
Subjects randomized to placebo in Part 1 received 4 SC injections per dose. Subjects randomized 
to placebo in Part 2 would receive 2 SC injections per dose. 
The study was terminated after 6 subjects were enrolled in Part 1 of the study. Therefore, Part 2 
was not initiated. 
Main Inclusion Criteria 
• Male or female 18 years of age or older 
• Confirmed diagnosis of CF as determined by the 2008 Cystic Fibrosis Foundation Consensus 
Report {Farrell 2008} criteria 
• Subjects must be able to perform acceptable and reproducible spirometry as per the 
American Thoracic Society (ATS) guidelines 
• Must have a body weight of > 40 kg (88.2 lb) at study Screening 
• Pre-bronchodilator FEV1 ≥ 40% and ≤ 80% of predicted at Screening 
• Two pre-bronchodilator spirometry measures taken at least 4 days apart (one during 
Screening, one at Baseline) using the sponsor provided central spirometry equipment must 
meet the following 2 criteria: 
 The relative difference of FEV1(L), calculated as the absolute value of [(first 
FEV1 - second FEV1) / first FEV1] x 100 should be < 12% AND 
 The absolute difference in FEV1 should be < 200 ml 
• Negative Investigation/History of Important Bacteria Infections: 
Tuberculosis (TB): 
 A negative QuantiFERON-TB Gold test during Screening 
Non-Tuberculous Mycobacteria species (NTM): 
 All sputum cultures for ANY Mycobacterium spp. performed within 24 months prior to 
Screening must be negative. If only 1 NTM culture was performed within 24 months 
prior to Screening, that NTM culture and the most recent NTM culture obtained 
> 24 months prior to Screening both must be negative AND 


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 A negative sputum culture < 12 months prior to Screening for any Mycobacterium spp. 
AND 
 No current treatment for active NTM during Screening 
Burkholderia spp. 
 All sputum/throat cultures for ANY Burkholderia spp. performed 24 months prior to 
Screening must be negative. If only 1 Burkholderia culture was performed 24 months 
prior to Screening, that Burkholderia spp. culture and the most recent Burkholderia spp. 
culture obtained > 24 months prior to Screening must both be negative AND 
 A negative culture for Burkholderia spp. during Screening AND 
 No current treatment for Burkholderia spp. during Screening 
• Clinically stable with no evidence of significant respiratory symptoms that would require 
administration of IV antibiotics, oxygen supplementation, or hospitalization within 30 days 
of Baseline. 
• A chest radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) 
within 90 days of Baseline, interpreted as showing no acute findings such as infiltrates (lobar 
or diffuse interstitial), pleural effusion, or pneumothorax, and no significant intercurrent 
illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed. If not 
available then a chest radiograph at Screening will be obtained and should be interpreted as 
above. 
• On stable CF chronic medical regimen for at least 30 days prior to Baseline and expected to 
remain stable through the completion of the study. This includes but is not limited to: chronic 
azithromycin use, inhaled bronchodilators, inhaled corticosteroids, inhaled dornase alpha, 
inhaled hypertonic saline, inhaled mannitol, ivacaftor, and/or ivacaftor/lumacaftor. 
 Inhaled antibiotics (ie, tobramycin, aztreonam, colistin) should be stable for 2 “on-
treatment cycles” to be considered a stable CF medication (ie, approximately 2 months if 
they are taken as continuous inhaled antibiotics or approximately 4 months if they are 
taken as an alternating inhaled antibiotic). 
• Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures 
Main Exclusion Criteria 
• Concurrent use of oral antibiotics (excluding the use of chronic oral azithromycin) or IV 
antibiotics within 30 days of Baseline. Prophylactic and chronic doxycycline use is 
prohibited during the study. 
• Hospitalization for a respiratory event within 30 days of Baseline 


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• Current use of systemic immunosuppressive drugs including oral corticosteroids within 
30 days of Baseline 
• Current requirement for daily continuous oxygen supplementation or requirement (medically 
necessary) of more than 2 L/minute at night (subject would not meet this exclusion criterion 
if supplemental oxygen is used for comfort only) 
• History of solid organ (including lung) or hematologic transplant, or currently on a transplant 
waiting list 
• Laboratory parameters at screening: 
 Abnormal liver function tests defined as > 3 times the upper limit of normal (ULN) of 
any of the following: serum aspartate transaminase (AST), serum alanine transaminase 
(ALT), gamma-glutamyl transpeptidase (GGT), and serum alkaline phosphatase. 
 Total bilirubin > 2 times the ULN 
 Hemoglobin < 10 g/dL for females and < 11.5 g/dL for  males at Screening 
 Estimated glomerular filtration rate (eGFR) <40 mL/1.73 m2 based on the 4-variable 
Modification of Diet in Renal Disease (MDRD) formula:  
GFR = 175 × [SCr]−1.154 × [age]−0.203 × [1.212 if patient is African American] × [0.742 if 
patient is Female] {Levey 2007} 
The study procedures performed during the main study and the optional OLE phase are presented 
in the Appendix 1. Subjects who did not elect to roll over into the OLE completed Week 8 study 
procedures, followed by the 30-day follow up visit.  
1.3. 
Sample Size and Power 
A sample size of 25 evaluable subjects per arm for Part 1 and Part 2 would provide 80% power 
to detect a 5% difference between andecaliximab and placebo treatment in change from Baseline 
in FEV1 percent predicted with a 2-sided alpha level of 0.1 and a common standard deviation 
(SD) of 7% {Brouwer 2014, Ramsey 2011, Retsch-Bogart 2009}. Assuming an attrition rate of 
15%, 30 subjects per arm were to be enrolled.  
With respect to the FRI sub-study, a sample size of 15 subjects on andecaliximab and 15 subjects 
on placebo would provide more than 90% power to detect a 6% difference in FRI measurements 
(approximating an absolute change of 3% in FEV1) between the andecaliximab and the placebo 
arms in FRI change from Baseline, based on a 2-sample t-test and 2-sided alpha level of 0.1. The 
calculation assumes the SD of FRI change being 5% for the andecaliximab arm and 2% for 
placebo arm, as the FRI response is expected to be more heterogeneous in the treatment group. 
The study was terminated after 6 subjects had been enrolled. Therefore, no inferential analyses 
will be performed. 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Interim Analyses 
The first DMC safety review was planned when 10 subjects completed the Week 2 visit or 
discontinued early.  
Due to the early study closure, the required number of subjects for the first planned DMC was 
not reached. Therefore, no DMC interim analyses were performed.  
2.2. 
Final Analysis 
After all subjects have completed the study or discontinued early, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the 
study blind will be broken and the final analysis of the data will be performed. 


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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. 
By-subject listings will be presented for all subjects in the All Randomized 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, as space permits. 
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. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. 
For each analysis set, the number and percentage of subjects eligible for inclusion will be 
summarized by treatment group. 
3.1.1. 
All Randomized Analysis Set 
The All Randomized Analysis Set includes all subjects who were randomized in the study. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were randomized into the study and took 
at least 1 dose of study drug. This is the primary analysis set for efficacy analyses. 
3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses. 
3.2. 
Subject Grouping 
For analyses based on the FAS, 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 
randomized treatment except when their actual treatment differs from randomized treatment for 
the entire treatment duration. In this case, subjects will be grouped based on actual treatment 
received. 


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3.3. 
Strata and Covariates 
No stratification factors or covariates will be used in the analyses supporting synoptic CSR.  
3.4. 
Examination of Subject Subgroups 
There will be no subgroup analyses. 
3.5. 
Multiple Comparisons 
Adjustments for multiplicity will not be applied, as no inferential analyses will be performed.   
3.6. 
Missing Data and Outliers 
3.6.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.  
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2. 
3.6.2. 
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis. 
3.7. 
Data Handling Conventions and Transformations 
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. If only the birth 
year is collected on the CRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day. 
3.8. 
Analysis Visit Windows 
3.8.1. 
Definition of Study Day 
Study Day will be calculated from the first dosing date of study drug and derived as follows: 
• For postdose 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. 


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For the outputs based on the study period (double-blind and open-label), the following rule will 
be applied:  
 If subject continues into open-label (OL) period then the double-blind period reports will 
include the data collected until the date of the first dose of study drug in OL period 
(Week 8) – 1 day. The open-label period summaries will include the data from the date of 
the first dose of OL treatment, inclusive. 
 If subject does not continue into OL period then all data collected starting from Day 1 
will be included in the double-blind period summaries. 
3.8.2. 
Analysis Visit Windows 
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point. 
However, the following exceptions will be made: 
• An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable. 
• For subjects who prematurely discontinue from the study, early termination (ET) data will be 
assigned to what would have been the next scheduled visit where the respective data were 
scheduled to be collected.  
• Data collected on 30-day follow-up visit will be summarized as a separate visit, and labeled 
as “Follow-up Visit”. 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window 
Pre-bronchodilator FEV1 and post-bronchodilator FEV1 are considered as 2 separate 
measurements. 
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. 


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If multiple, valid nonmissing, 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 postbaseline 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.  


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
A summary of subject disposition will be provided by treatment group and overall. This 
summary will present the number of subjects screened, the number of subjects randomized, and 
the number of subjects in each of the categories listed below, for overall and each study phase 
(double-blind and open-label): 
• Safety Analysis Set  
• Completed study drug  
• Did not complete study drug with reasons for premature discontinuation of study drug 
• Completed study  
• Did not complete study with reasons for premature discontinuation  
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 All Randomized Analysis Set 
corresponding to that column.  
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. 
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 7, regardless of any temporary interruptions in study drug administration, and will be 
expressed in days.  If the last study drug dosing date is missing, the latest study drug end date, 
clinical visit date, laboratory sample collection date, or vital signs assessment date that occurred 
during the on-treatment period will be used. 
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: baseline (Day 1), Week 1 (Day 8), Week 4 (Day 29), Week 8 (Day 57), 
Week 12 (Day 85), Week 16 (Day 113), Week 20 (Day 141), and Week 24 (Day 169). 
Summaries will be provided by treatment group for the Safety Analysis Set. No formal statistical 
testing is planned. 


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4.2.2. 
Adherence to Study Drug 
A summary of adherence to study drug will not be provided. 
A by-subject listing of study drug administration will be provided by subject ID number 
(in ascending order) and visit (in chronological order). 
4.3. 
Deviations  
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. 


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment 
group and overall using descriptive statistics for age, and using number and percentage of 
subjects for sex, race, and ethnicity. The summary of demographic data will be provided for the 
All Randomized Analysis Set. 
A by-subject listing of demographics, including the informed consent date, will be provided by 
subject ID number in ascending order. 
5.2. 
Other Baseline Characteristics 
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), genotype, and pre-bronchodilator and post-bronchodilator spirometry 
measurements. These baseline 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 All 
Randomized Analysis Set. No formal statistical testing is planned. 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order. 
5.3. 
Medical History 
The summaries of medical history will not be provided. 


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6. 
EFFICACY ANALYSES 
6.1. 
Primary Efficacy Endpoint 
The primary endpoint is the absolute change in pre-bronchodilator FEV1 percent predicted from 
Baseline to Week 8.  
The NHANES III {Hankinson 1999} method will be used to calculate the FEV1 percent 
predicted value. 
6.1.1. 
Statistical Hypothesis for the Primary Efficacy Endpoint 
No statistical hypotheses will be tested. 
6.1.2. 
Analysis of the Primary Efficacy Endpoint 
The descriptive statistics (n, mean, standard deviation [SD], median, Q1, Q3, minimum, and 
maximum) for the absolute values and absolute change in pre-bronchodilator FEV1 percent 
predicted will be presented for each post-baseline time point including open-label period.  
6.2. 
Secondary Efficacy Endpoints 
6.2.1. 
Definitions of Key Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• The absolute change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8 
• The relative change in pre-bronchodilator FEV1 percent predicted from Baseline to Week 8 
• The relative change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8.  
The relative change of FEV1 % predicted from baseline to Week 8 is calculated as the [absolute 
change from baseline to Week 8 / baseline FEV1 % predicted value] x 100. 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints 
Descriptive statistics (n, mean, standard deviation [SD], median, Q1, Q3, minimum, and 
maximum) for absolute change and relative change in post-bronchodilator FEV1 percent 
predicted from baseline, as well as relative change in pre-bronchodilator FEV1 percent predicted 
from baseline, will be provided for each post-baseline time point including open-label period.  
6.3. 
Other Efficacy Endpoints 
Other efficacy endpoints will not be analyzed. 


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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 current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) 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, or 4 according to toxicity criteria 
specified in the protocol. 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 AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Drug Safety and Public 
Health 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 date 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 (TE) AEs will be summarized based on the Safety Analysis Set. 
The AEs will be reported by the treatment period. If subject does not continue into the open-label 
period then all TEAEs will be reported in the double-blind period summaries. For subjects who 
continue into the open-label phase, all TEAEs during the double-blind treatment phase are the 
AEs started prior to the first dose of open-label treatment. The AEs with the onset date on or 
after the first dose of the open-label treatment and no later than 30 days after permanent 
discontinuation of study drug will be reported in the open-label summaries. 
7.1.6.1. 
Summaries of AE incidence in Combined Severity Grade Subsets  
For TEAEs described below, summaries will be provided by SOC, PT, treatment group, and 
study phase: 
• All TE treatment-related AEs 
• All TE SAEs 
• All TEAEs leading to premature discontinuation of study drug 
• TEAEs of Interest:  
 injection site reactions (based on Gilead medical search terms provided by DSPH)  


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A brief, high-level summary of AEs described above will also be provided by treatment group 
and study phase.  
In addition to the above summary tables, all TEAEs will be summarized by PT only, in 
descending order of total frequency. Summaries of all TEAEs by SOC, PT and maximum 
severity will also be provided.  
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 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, data listings will be provided for the following: 
• All AEs, indicating whether the event is treatment emergent 
• SAEs 
• Deaths 
• AEs leading to premature discontinuation of study drug  
7.2. 
Laboratory Evaluations 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology and serum chemistry separately. Values falling outside of the 
relevant reference range and/or having a severity grade of 1 or higher on the Gilead Grading 
Scale for Severity of Adverse Events and Laboratory Abnormalities [CTCAE severity grade] 
will be flagged in the data listings, as appropriate 
No formal statistical testing is planned. 
7.2.1. 
Summaries of Numeric Laboratory Results 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
Descriptive statistics for laboratory tests will not be presented. 
7.2.2. 
Graded Laboratory Values 
The Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 will be used for 
assigning toxicity grades to laboratory results for analysis. Grade 0 includes all values that do not 
meet the criteria for an abnormality of at least Grade 1. For laboratory tests with criteria for both 
increased and decreased levels, analyses for each direction (ie, increased, decreased) will be 
presented separately.  


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7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values within the reference range at 
baseline, but which become lower or higher than the reference range or values had a directional 
change in abnormality from baseline (eg, the value low at baseline became high at postbaseline 
visit) at any postbaseline time point, up to and including the date of last dose of study drug plus 
30 days. If the relevant baseline laboratory value is missing, any postbaseline laboratory value 
that is lower or higher than the reference range will be considered treatment emergent.  
7.2.2.2. 
Summaries of Laboratory Abnormalities 
The summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test, treatment group and study phase; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test. 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values within study period. 
A by-subject listing of treatment-emergent laboratory abnormalities will be provided by subject 
ID number and visit in chronological order. This listing will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades 
displayed. 
7.2.3. 
Liver-related Laboratory Evaluations 
Liver-related laboratory evaluations will be presented as part of serum chemistry results.  
7.3. 
Body Weight and Vital Signs 
Body weight and vital signs will not be summarized or listed.  
7.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will not be summarized or listed.  
7.5. 
Electrocardiogram Results 
Electrocardiogram (ECG) data will not be summarized or listed.  
7.6. 
Other Safety Measures 
A data listing will be provided for subjects experiencing pregnancy during the study. 
7.7. 
Changes From Protocol-Specified Safety Analyses 
The limited efficacy and safety summaries are provided due to low number of subjects enrolled 
prior to the study termination. 


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8. 
REFERENCES 
Brouwer ES, Napravnik S, Eron JJ, Jr., Stalzer B, Floris-Moore M, Simpson RJ, Jr., et al. Effects 
of combination antiretroviral therapies on the risk of myocardial infarction among 
HIV patients. Epidemiology 2014;25 (3):406-17. 
Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines 
for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis 
Foundation consensus report. J Pediatr 2008;153 (2):S4-S14. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the 
general U.S. population. Am J Respir Crit Care Med 1999;159 (1):179-87. 
Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Expressing the 
Modification of Diet in Renal Disease Study equation for estimating glomerular 
filtration rate with standardized serum creatinine values. Clin Chem 2007;53 
(4):766-72. 
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator 
in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365 
(18):1663-72. 
Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, et al. 
Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas in cystic 
fibrosis. Chest 2009;135 (5):1223-32. 
 


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9. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 


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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 
Appendix 1. 
Schedule of Assessments 
 
Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Withhold all 
inhaled CF 
therapies morning 
of study visit 
Xq 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFQ-Ra 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
TSQM (if 
available)a  
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
SNOT-22  (if 
available)a 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pulmonary 
Exacerbation 
Evaluation 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Complete Physical 
Examb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Symptom Driven 
Physical Examb 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Blood for Safety 
Labsc 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
ESRr 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Urine Cotinine 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Urinalysis  
X 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Serum Pregnancy 
Testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Urine Pregnancy 
Test 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Oxygen Saturation 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Screening 
Spirometry 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre- and post-
bronchodilator 
Spirometrye 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
PEFR 
X 
Xp 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Chest X-rayf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Induced sputum 
for biomarkers 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Spontaneous 
sputum for 
microbiology g 
X, X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
FRI Scanh 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood for PKi 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
PK sub-study 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-drug 
Antibodies 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
Blood for 
Biomarkers 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Blood for RNA 
Biomarkers  
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Blood for CF 
genotypingj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional blood 
sample for 
genomic researchj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administrationk 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Xn 
X-weekly through week 23-X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
 
Xo Xo 
Xo 
X 
X 
X 


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Screening 
Baseline 
Randomization 
Optional PK 
Study Drug 
Administration 
Visits 
Optional PK 
Study Drug 
Administration 
Visit
Primary 
Endpoint 
Optional Open-
Label 
Extension 
30-Day 
Follow-Up Visit 
Early 
Termination 
Visit
Week 
 
Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 
13-
15, 
17-
19, 
21-23 12 
16 
20 
24 
 
 
Day 
-30 
to 
-1 
1l 
5 
8 
15 
22 
29 
36 
43 
48 
50 
57 
64 
71 
 
85 113 141 169 
 
 
Window in days 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±1 
±3 
-3 to 
 + 4 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Home Health 
Visit Option 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Musculoskeletal 
Symptom 
Assessment 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
a 
Questionnaires should be obtained prior to any other procedures. At visits where there are multiple questionnaires, the CFQR should be completed first, then SNOT-22 and 
then TSQM. If on a given visit SNOT-22 is not done then the CFQ-R is completed first and then the TSQM. 
b 
Includes height at screening visit and weight at all visits and to be conducted prior to dosing. A complete physical examination will be performed at screening and the 30-day 
Follow-up Visit. A symptom-driven physical examination will be performed at the Baseline, Week 4, 8, 12, 16, 20, and 24, and can be performed as needed at other study 
visits.  
c 
Safety labs include CBC with differential, chemistry panel.   
d 
For female subject post-menopausal for less than 2 years, if FSH < 40 mIU/ mL a serum pregnancy test will be required. 
e 
Subjects will withhold their standard of care inhaled CF therapies prior to study specific spirometry  
f 
Chest x-ray will be obtained during the screening period if subject does not have a CT scan, MRI or chest x-ray obtained in the 90 days prior to Baseline.   
g 
Spontaneous and induced sputum should be obtained AFTER spirometry and FRI (if applicable) have been completed. If spontaneous sputum cannot be obtained, a throat 
swab may be used for microbiology culture. A second spontaneous sputum microbiology for culture will be collected in the screening period.  
h 
For subjects enrolled in the FRI sub-study only. Subjects will withhold their standard of care inhaled CF therapies prior to FRI. 


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i 
At Baseline, PK should be obtained prior to and 2 hours after study drug administration. At all other visits with study drug dosing, PK should be performed prior to study drug 
administration. Subjects who consent to the optional PK sub-study will have one additional single PK sample collected at Day 5 (±1) and Day 48 (±1). Optional Day 5 PK 
and Day 8 should occur at least 1 day apart. 
j 
Blood for CF genotyping should be taken at baseline for subjects who do not have a historical genotype on file, but may be collected at any time during the study, 
if necessary. Blood for optional genomic research should only be taken from subjects who consented to this optional procedure. It should be taken at baseline, but may be 
collected at any time during the study, if necessary.    
k 
Observe subject for 2 hours after study drug administration on Day 1, and for 30 minutes after study drug administration at all other visits during the blinded phase of the 
study.  
l 
The baseline/randomization visit may be split over 2 days as needed. If the visit is split over 2 days, the following procedures should be done on the first day prior to standard 
of care inhaled CF therapies as indicated in protocol Section 5.5: questionnaires, urine pregnancy test (for women of childbearing potential only), oxygen saturation, pre- and 
post-bronchodilator spirometry, and FRI. Subjects must withhold their standard of care inhaled CF therapies again the next morning and perform spirometry prior to any 
remaining study procedures and study dosing. The day on which the first dose of study drug is administered is Baseline.  
m 
Two spirometry measures (pre-bronchodilator) taken at least 4 days apart (one during Screening, one at Baseline) must be taken to meet inclusion criterion 7.   
n 
Study drug dosing will occur at Week 8 only for subjects who elect to enroll in the open-label extension and only after all other procedures have been completed. 
o 
Subjects enrolled into the open-label extension may request assistance administering the SC injections either by returning to the clinic or utilizing a home health care service 
provided by the Sponsor to ensure proper dosing and adherence. If determined acceptable by the DMC, home self-administration may be conducted in the OLE. 
p 
PEFR will be performed at Baseline only if baseline procedures are conducted over 2 days and induced sputum was conducted on Day -1 to confirm subjects are stable 
enough to be dosed. 
q 
As screening will occur over at least two different days, subjects should only be asked to withhold these medications the morning of their screening spirometry assessment 
and only after they have been properly consented. 
r 
To be conducted at the site’s local lab.  

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Dose-Ranging Study of the Effect of GS-5745 on 
FEV 1 in Adult Subjects with Cystic Fibrosis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
120100 
2015-002192-23 
NCT02759562 
Cystic Fibrosis 
GS-US-404-1808 
Name: 
Telephone: 
Email: 
Name: 
Telephone: 
Mobile: 
Email: 
Original: 
VHP Amendment 1.1: 
Amendment 2: 
PD 
PPD 
t-'t-'U 
David Gossage 
PPD 
PPD 
t-'t-'U 
14 Janumy 2016 
06 April 2016 
25 May2016 
CONFIDENTIALITY STATEMENT 
I 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy 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, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 2
25 May 2016
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....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
GS-5745 .................................................................................................................................................19
1.2.1.
General Information .............................................................................................................19
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................19
1.2.3.
Clinical Trials of GS-5745 ...................................................................................................20
1.3.
Rationale for this Study..........................................................................................................................21
1.3.1.
Route of Administration.......................................................................................................22
1.3.2.
Dose Selection......................................................................................................................22
1.3.3.
Study Duration .....................................................................................................................23
1.4.
Risk/Benefit Assessment for the Study..................................................................................................24
1.5.
Compliance ............................................................................................................................................25
2.
OBJECTIVES.....................................................................................................................................................26
3.
STUDY DESIGN................................................................................................................................................27
3.1.
Endpoints ...............................................................................................................................................27
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatments ...................................................................................................................................29
3.3.1.
Part 1 ....................................................................................................................................29
3.3.2.
Part 2 ....................................................................................................................................30
3.3.3.
Open-Label Extension (OLE)...............................................................................................30
3.4.
Duration of Treatment............................................................................................................................30
3.5.
Protocol Discontinuation Criteria...........................................................................................................31
3.6.
Source Data............................................................................................................................................31
3.7.
Biomarker Testing..................................................................................................................................31
3.7.1.
Biomarker Samples to Address the Study Objectives ..........................................................31
3.7.2.
Biomarker Samples and Imaging for Optional Future Research..........................................32
3.7.3.
Biomarker Samples for Optional Genomic Research...........................................................32
4.
SUBJECT POPULATION..................................................................................................................................33
4.1.
Number of Subjects and Subject Selection ............................................................................................33
4.2.
Inclusion Criteria....................................................................................................................................33
4.3.
Exclusion Criteria...................................................................................................................................35
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................37
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................37
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................37
5.2.
Description and Handling of GS-5745 and Placebo...............................................................................37
5.2.1.
Formulation..........................................................................................................................37
5.2.2.
Packaging and Labeling .......................................................................................................37
5.2.3.
Storage and Handling...........................................................................................................38
5.3.
Dosage and Administration of GS-5745 and Placebo............................................................................38
5.4.
Prior and Concomitant Medications and Excluded Therapies ...............................................................39


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5.5.
Concomitant Medication Management ..................................................................................................40
5.6.
Accountability for Study drug................................................................................................................40
5.7.
Rescreening of Study Subjects...............................................................................................................41
6.
STUDY PROCEDURES ....................................................................................................................................42
6.1.
Details of Study Visits ...........................................................................................................................42
6.1.1.
Subject Enrollment and Treatment Assignment...................................................................42
6.1.2.
Screening Period (Day -30 to -1)..........................................................................................46
6.1.3.
Baseline/Randomization (Day 1) .........................................................................................47
6.1.4.
Blinded Treatment Period: Day 5 through Week 7 ..............................................................47
6.1.5.
Week 8 (-3 to + 4): Primary Endpoint and Open-Label Extension ......................................48
6.1.6.
Utilization of Home Health Services....................................................................................48
6.1.7.
Open-Label Extension: Week 9 through 24 .........................................................................49
6.1.8.
30-Day Follow-Up Visit.......................................................................................................49
6.1.9.
Assessments for Premature Discontinuation from Study .....................................................49
6.1.10.
Criteria for Discontinuation of Study Treatment..................................................................50
6.2.
End of Study...........................................................................................................................................50
6.3.
Details of Scheduled Assessments .........................................................................................................50
6.3.1.
Physical Exam......................................................................................................................50
6.3.2.
Vital Signs............................................................................................................................50
6.3.3.
CFQ-R, TSQM, and SNOT-22 Questionnaires....................................................................51
6.3.4.
Pulmonary Exacerbation Evaluation ....................................................................................51
6.3.5.
Oxygen Saturation................................................................................................................52
6.3.6.
Spirometry............................................................................................................................52
6.3.7.
Peak Expiratory Flow Rate (PEFR) .....................................................................................54
6.3.8.
Induced Sputum....................................................................................................................54
6.3.9.
Spontaneous Sputum Collection for Bacterial Microbiology...............................................54
6.3.10.
Functional Respiratory Imaging – Sub-study only...............................................................55
6.3.11.
12-Lead ECG........................................................................................................................56
6.3.12.
Laboratory Assessments.......................................................................................................56
6.3.13.
Pharmacokinetic Assessments..............................................................................................56
6.3.14.
Sample Storage.....................................................................................................................57
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................58
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................58
7.1.1.
Adverse Events.....................................................................................................................58
7.1.2.
Serious Adverse Events........................................................................................................58
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................59
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................59
7.2.1.
Assessment of Causality for Study drugs and Procedures....................................................59
7.2.2.
Assessment of Severity ........................................................................................................60
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................60
7.4.
Gilead Reporting Requirements.............................................................................................................61
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................62
7.6.
Toxicity Management ............................................................................................................................62
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................63
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................63
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................63
7.7.
Special Situations Reports......................................................................................................................64
7.7.1.
Definitions of Special Situations..........................................................................................64
7.7.2.
Instructions for Reporting Special Situations.......................................................................64


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 4
25 May 2016
8.
STATISTICAL CONSIDERATIONS................................................................................................................66
8.1.
Analysis Objectives and Endpoints........................................................................................................66
8.1.1.
Analysis Objectives..............................................................................................................66
8.1.2.
Primary Endpoint .................................................................................................................66
8.1.3.
Secondary Endpoints............................................................................................................67
8.1.4.
Other Endpoints of Interest ..................................................................................................67
8.2.
Analysis Conventions.............................................................................................................................68
8.2.1.
Analysis Sets ........................................................................................................................68
8.3.
Data Handling Conventions ...................................................................................................................68
8.4.
Demographic Data and Baseline Characteristics ...................................................................................69
8.5.
Efficacy Analysis ...................................................................................................................................69
8.6.
Safety Analysis.......................................................................................................................................69
8.6.1.
Extent of Exposure...............................................................................................................69
8.6.2.
Adverse Events.....................................................................................................................70
8.6.3.
Laboratory Evaluations ........................................................................................................70
8.6.4.
Other Safety Evaluations......................................................................................................70
8.7.
Pharmacokinetic Analysis......................................................................................................................70
8.8.
Immunogenicity Analysis ......................................................................................................................71
8.9.
Biomarker Analysis................................................................................................................................71
8.10.
Sample Size............................................................................................................................................71
8.11.
Data Monitoring Committee ..................................................................................................................71
8.12.
Interim Analyses ....................................................................................................................................72
9.
RESPONSIBILITIES..........................................................................................................................................73
9.1.
Investigator Responsibilities ..................................................................................................................73
9.1.1.
Good Clinical Practice..........................................................................................................73
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................73
9.1.3.
Informed Consent.................................................................................................................73
9.1.4.
Confidentiality......................................................................................................................74
9.1.5.
Study Files and Retention of Records ..................................................................................74
9.1.6.
Case Report Forms...............................................................................................................75
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................76
9.1.8.
Inspections............................................................................................................................76
9.1.9.
Protocol Compliance............................................................................................................76
9.2.
Sponsor Responsibilities ........................................................................................................................77
9.2.1.
Protocol Modifications.........................................................................................................77
9.2.2.
Study Report and Publications .............................................................................................77
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
9.3.1.
Payment Reporting...............................................................................................................77
9.3.2.
Access to Information for Monitoring..................................................................................78
9.3.3.
Access to Information for Auditing or Inspections ..............................................................78
9.3.4.
Study Discontinuation..........................................................................................................78
10.
REFERENCES ...................................................................................................................................................79
11.
APPENDICES ....................................................................................................................................................82
Appendix 1.
Investigator Signature Page....................................................................................................83
Appendix 2.
Management of Clinical and Laboratory Adverse Events......................................................84
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................85
Appendix 4.
Recommended General Process for Diagnosing CF {Farrell et al 2008}............................88
Appendix 5.
Medications Washouts............................................................................................................90


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 5
25 May 2016
LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments........................................................................................................43
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Design ..........................................................................................................................29
Figure 6-1.
Suggested Schedule for Key Screening and Baseline Procedures..........................................46


GS-5745 
Protocol GS-US-404-1808 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Amendment2 
A Phase 2b, Dose-Ranging Study of the Effect of GS-57 45 on FEV 1 in 
Adult Subjects with Cystic Fibrosis 
120100 
2015-002192-23 
NCT02759562 
Up to 75 sites globally 
The primruy objective of this study is as follows: 
• 
To evaluate the effect of GS-5745 on pre-bronchodilator forced 
expirat01y volume in 1 second (FEV 1)% predicted in subjects with 
cystic fibrosis (CF) after 8 weeks of treatment 
The secondruy objectives of this study ru·e as follows: 
• 
To assess safety, tolerability, and phrumacokinetics (PK) of 
GS-5745 in subjects with CF 
• 
To evaluate the effect of GS-5745 on post-bronchodilator forced 
expirat01y volume in 1 second (FEV 1)% predicted in subjects with 
CF after 8 weeks of treatment 
Explorat01y objectives of this study are as follows: 
I 
I 
Page6 
25 May 2016 


GS-5745 
Protocol GS-US-404-1808 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
I 
I 
I 
Final 
Amendment2 
This is a Phase 2b, randomized, double-blind, placebo-controlled, 
multiple-center, multiple dose study comprising of 2 pruis. 
Prui 1 will enroll 60 subjects in a 1: 1 ratio to receive weekly 
subcutaneous (SC) injections of either 600 mg GS-5745 or placebo for 
8 weeks. 
Upon successful completion of Prui 1, Part 2 will enroll 90 subjects in a 
1:1:1 ratio to receive weekly SC injections of either 300 mg of GS-5745, 
150 mg ofGS-5745, or placebo for 8 weeks. 
Safety and efficacy analyses will be perf01med for Prui 1 after all 
subjects have completed the Week 8 visit or discontinued from the 
study. Data monitoring committee (DMC) meetings will occm at 
multiple times in Part 1 and before completion of Prui 2 (see DMC 
Section 8.11). Visits and procedmes for both Prui 1 and Prut 2 will be 
the same. 
Subjects enrolled into either Prut 1 or Prui 2 will have the option of 
participating in an open-label extension (OLE) at the Week 8 visit. 
The open-label extension will allow an additional16 weeks of dosing 
with GS-5745 600 mg SC weekly in Prui 1 and 300 mg SC in Prui 2. 
Page7 
25 May 2016 


GS-5745 
Protocol GS-US-404-1808 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Study Design Schema 
Part 1: Proof of Concept 
Baseline 
1 
FRI Hl 
FRI #2 Week 8 
(15 600mg:15 placebo) 
(15 600mg:15 placebo) 
FRI = Functional Respiratory 
Imaging 
I+)Advance to Part 2 
Part 2: Dose-Ranging 
{Day 1· Week 8) 
1 1 
FRI n1 
FRI N2 Week 8 
Final 
Amendment2 
Optional O~o 
Label Extensioo 
t16 weei<s 
{15 each 300mg:150mg:placebo) (15 eacfl300mg:150mg:piacebo} 
There will be a FRI sub-study for both Part 1 and Pali 2 which will 
require 2 FRI scans (at Baseline and at the Week 8 visit). A subset of 
study sites will be tmined in FRI. All subjects emolling into the study at 
those sites will pruiicipate in the FRI sub-study up to 35 subjects in 
Prui 1 and up to 52 subjects in Prui 2 to account for an attrition rate of 
15%. 
There will be a sputum cytology sub-study for both Prui 1 and Prui 2. 
A subset of select sites will perfonn sputum cytology slide prepru·ation 
from induced sputum samples to investigate changes in total cell count 
and cell count differential in sputum. No additional procedmes will be 
required of subjects pruiicipating in the sputum cytology sub-study. 
PPD 
Page8 
25 May 2016 


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 9
25 May 2016
Number of 
Subjects Planned:
Up to 150 subjects 
Target 
Population:
Subjects with CF ≥18 years of age
Duration of 
Treatment:
Subjects will receive weekly SC injections for 8 weeks. Subjects
completing either Part 1 or Part 2 will be invited to participate in an 
OLE and will receive an additional 16 weeks of weekly SC injections of 
GS-5745.  All subjects will be followed for 30 days after the last dose of 
study drug. 
Diagnosis and 
Main Eligibility 
Criteria:
Main Inclusion Criteria

Male or female 18 years of age or older 

Confirmed diagnosis of CF as determined by the 2008 Cystic 
Fibrosis Foundation Consensus Report {Farrell et al 2008} criteria 

Subjects must be able to perform acceptable and reproducible 
spirometry as per the American Thoracic Society (ATS) guidelines

Must have a body weight of > 40 kg (88.2 lb) at study Screening

Pre-bronchodilator FEV1 ≥40% and ≤80% of predicted at 
Screening

Two pre-bronchodilator spirometry measures taken at least 4 days 
apart (one during Screening, one at Baseline) using the sponsor 
provided central spirometry equipment must meet the following 
2 criteria:
The relative difference of FEV1(L), calculated as the absolute 
value of [(first FEV1 – second FEV1) / first FEV1] x 100 should 
be < 12% AND
The absolute difference in FEV1 should be < 200 ml

Negative Investigation/History of Important Bacteria Infections:
Tuberculosis (TB):
A negative QuantiFERON-TB Gold test during Screening
Non-Tuberculous Mycobacteria species (NTM):
All sputum cultures for ANY Mycobacterium spp. performed 
within 24 months prior to Screening must be negative. If only 
1 NTM culture was performed within 24 months prior to 
Screening, that NTM culture and the most recent NTM culture 
obtained >24 months prior to Screening both must be negative 
AND


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 10
25 May 2016
A negative sputum culture < 12 months prior to Screening for 
any Mycobacterium spp. AND
No current treatment for active NTM during Screening
Burkholderia spp. 
All sputum/throat cultures for ANY Burkholderia spp.
performed 24 months prior to Screening must be negative. 
If only 1 Burkholderia culture was performed 24 months prior to 
Screening, that Burkholderia spp. culture and the most recent 
Burkholderia spp. culture obtained >24 months prior to 
Screening must both be negative AND
A negative culture for Burkholderia spp. during Screening AND
No current treatment for Burkholderia spp. during Screening

Clinically stable with no evidence of significant respiratory 
symptoms that would require administration of IV antibiotics, 
oxygen supplementation, or hospitalization within 30 days of 
Baseline.

A chest radiograph, computed tomography (CT), or magnetic 
resonance imaging (MRI) within 90 days of Baseline, interpreted as 
showing no acute findings such as infiltrates [lobar or diffuse 
interstitial], pleural effusion, or pneumothorax, and no significant 
intercurrent illness; chronic, stable findings (eg, chronic scarring or 
atelectasis) are allowed. If not available then a chest radiograph at 
Screening will be obtained and should be interpreted as above.

On stable CF chronic medical regimen for at least 30 days prior to 
Baseline and expected to remain stable through the completion of 
the study. This includes but is not limited to: chronic azithromycin 
use, inhaled bronchodilators, inhaled corticosteroids, inhaled 
dornase alpha, inhaled hypertonic saline, inhaled mannitol, ivacaftor, 
and/or ivacaftor/lumacaftor.
Inhaled antibiotics (ie, tobramycin, aztreonam, colistin) should 
be stable for 2 “on-treatment cycles” to be considered a stable 
CF medication (ie, approximately 2 months if they are taken as 
continuous inhaled antibiotics or approximately 4 months if they 
are taken as an alternating inhaled antibiotic).

Must have the ability to understand and sign a written informed
consent form, which must be obtained prior to initiation of study
procedures


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Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 11
25 May 2016
Main Exclusion Criteria

Concurrent use of oral antibiotics (excluding the use of chronic oral 
azithromycin) or IV antibiotics within 30 days of Baseline. 
Prophylactic and chronic doxycycline use is prohibited during the 
study.  

Hospitalization for a respiratory event within 30 days of Baseline 

Current use of systemic immunosuppressive drugs including oral 
corticosteroids within 30 days of Baseline 

Current requirement for daily continuous oxygen supplementation or 
requirement (medically necessary) of more than 2 L/minute at night 
(subject would not meet this exclusion criterion if supplemental 
oxygen is used for comfort only)

History of solid organ (including lung) or hematologic transplant, 
or currently on a transplant waiting list

Laboratory parameters at screening:
Abnormal liver function tests defined as > 3 times the upper 
limit of normal (ULN) of any of the following: serum aspartate 
transaminase (AST), serum alanine transaminase (ALT), 
gamma-glutamyl transpetidase (GGT), and serum alkaline 
phosphatase.
Total bilirubin > 2 times the ULN
Hemoglobin < 10 g/dL for females and < 11.5 g/dL for males at 
Screening
Estimated glomerular filtration rate (eGFR) <40 mL/1.73 m2 
based on the 4-variable Modification of Diet in Renal Disease 
(MDRD) formula: GFR = 175 × [SCr]−1.154 × [age]−0.203 × [1.212 
if patient is African American] × [0.742 if patient is Female] 
{Levey et al 2006}
Study Procedures/
Frequency:
The following procedures will be performed during the main study and
the optional OLE phase. For subjects who do not elect to roll over onto 
the OLE, they will complete Week 8 study procedures, followed by the 
30-day follow up visit. All post Week 8 study visits and assessments are 
only applicable to subjects participating in the OLE phase.
Vital Signs (VS): Blood pressure, pulse, respiratory rate, temperature, 
and weight will be captured at each visit with the exceptions of the PK 
visits (Day 5) and (Day 48). 
Height: Height will be measured at Screening.
Physical exam (PE): Complete PE will be performed at Screening and 
the 30-day Follow-up visit.


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 12
25 May 2016
Centralized Spirometry: In the screening period 1 pre-bronchodilator 
spirometry will be conducted. 
At all other visits, Baseline through Follow-up, where spirometry is 
indicated, spirometry will be collected both pre- and post-bronchodilator.  
Subjects will withhold their standard of care inhaled CF therapies 
including bronchodilators prior to study specific spirometry.
Peak Expiratory Flow (PEF) Stability: Peak expiratory flow rate 
(PEFR) measurements will be collected and recorded each morning 
(AM) by subjects before their AM bronchodilator during the screening 
period to calculate their PEF stability limit. Subjects will perform and 
recorded daily PEF values for at least 7 days to determine the mean AM 
pre bronchodilator PEF value. This value will be used to determine a 
> 30% drop in PEF prior to study drug administration.  
Oxygen Saturation: Oxygen saturation will be measured at Baseline, 
Week 8, and at the 30 Day Follow-up Visit. 
Spontaneous Sputum Collection: Spontaneous sputum will be collected 
from all subjects for analysis of microbiology (dominant species and 
CFU). Collection will occur at Screening and at Weeks 2, 6 in the 
blinded phase of the study, and Week 20 in the OLE of the study.  
Induced Sputum: The induced sputum will be processed for Biomarker 
analysis including, but not limited to, total and free MMP9, and MMP9 
activity.  Collection will occur at Baseline, Weeks 4, 8, 12, and 24, and 
at the 30-Day Follow-up Visit. A sub-set of select sites will perform
sputum cytology slide preparation from induced sputum samples. 
FRI Sub-study Only: Approximately 30 subjects (15 on 600 mg 
GS-5745 and 15 on placebo) enrolled into Part 1 of the study will have 
FRI performed once at Baseline and again at Week 8. Subjects will 
withhold their standard of care inhaled CF therapies the AM of the FRI 
and receive standardized doses of inhaled albuterol/salbutamol prior to 
FRI. If the study proceeds to Part 2, approximately 15 subjects in each 
treatment arm (300 mg GS-5745, 150 mg GS-5745, and placebo) will 
have FRI performed once at Baseline and again at Week 8.  
Cystic Fibrosis Questionnaire-Revised (CFQ-R): The CFQ-R will be 
performed prior to any other study related procedures at Baseline, 
Weeks 2, 4, 6, 8, 12, 16, 20, 24, early termination visit, and at the 
30-day Follow-Up visit.
Treatment Satisfaction Questionnaire for Medication (TSQM) 
(If available): The questionnaire will be performed prior to any other 
study related procedures at Baseline, and on Weeks 4, 8, 12, 16, 20, 24, 
and at the early termination visit.


GS-5745 
Protocol GS-US-404-1808 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment2 
Sino-Nasal Outcome Test (SNOT-22) (If available): The questiollllaire 
will be perfonned prior to any other study related procedures at Baseline 
and Weeks 8, 24, and at the early tennination visit. 
Pulmonmy Exacerbation Evaluation: A modified version of the Fuchs 
criteria {Ramsey et al2011, Wainwright et al2015} will be used for 
categorization ofpulmonruy exacerbations at Baseline, Weeks 1, 2, 4, 6, 
8, 9, 10, 12, 16, 20, 24, and at the eru·ly tennination visit. 
PK Blood Draws: Perf01med 2 hours after study dmg adminisu·ation at 
Baseline. Phrumacokinetic blood draws will be perf01med prior to study 
dmg administration on Weeks 1, 2, 4, 6, 8, and at the early tennination 
visit. 
PK Sub-stud: PPD 
Anti-drug Antibodies (ADA): Baseline, Weeks 4, 8, 16, and 24, and at 
the 30-day Follow-Up Visit. 
Safety Laboratory Tests: Complete blood count (CBC) with differential, 
chemistry panel will be collected at Screening, Baseline, Weeks 2, 4, 8, 
and 16, and at the Follow-up visit. Urinalysis will be collected at 
Screening, Baseline, Weeks 2, 8, and 16, and at the Follow-up visit. 
E1ythrocyte Sedimentation Rate (ESR): Collected at Screening, Week 8 
and Week 24, and will be analyzed at the local lab. 
Urine Cotinine: Screening and Weeks 4, 8, and 16. 
Serum jJ-HCG (females of childbearing potential only) : Screening and at 
the 30-Day Follow-Up Visit. 
Urine Pregnancy Tests (females of childbearing potential only) : U1ine 
pregnancy tests will be perf01med at Baseline and at Weeks 2, 4, 6, 8, 9, 
10, 12, 16, 20, and 24. 
12-Lead ECG: Screening, Baseline, Week 4, 8, 16, 24, and the 30-day 
Follow-up visit. 
Blood Biomarker Samples: Blood for biomarkers will be collected at 
Screening, Baseline, Weeks 2, 4, and 8, and at the 30-day Follow-up 
visit. Biomru·ker analysis will include but not limited to total and free 
MMP9, and MMP9 activity. A blood sample will be collected for RNA 
to study gene expression at Baseline, Weeks 4 and 8, Eru·ly Te1mination 
visit and at the 30-day Follow-up visit. Blood will also be collected 
from all subjects at Baseline for CF genotyping for subjects who do not 
have a historical genotyping available. 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
0 tiona! Genomic Testing: PPD 
Final 
Amendment2 
GS-5745 dmg product is a sterile, clear, aqueous buffered solution. 
GS-5745 will be supplied as 150 mg/mL solution in a single-use, 
pre-filled syringe intended to deliver a 1.0 mL SC injection. 
Subjects in Prui 1 randomized to GS-5745 will receive 600 mg 
(4 SC injections of GS-5745) per dose. Subjects randomized to 
GS-5745 in Prui 2 will receive either 300 mg (2 SC injections of 
GS-5745) or 150 mg (1 SC injection ofGS-5745 and 1 SC injection of 
placebo). 
Matched placebo administered by SC injection. 
Subjects randomized to placebo in Pati 1 will receive 4 SC injections 
per dose. Subjects randomized to placebo in Prui 2 will receive 2 SC 
injections per dose. 
Safety: 
Safety evaluation will be assessed by adverse events (AEs), concomitant 
medications, clinicallaborat01y tests, vital signs, ECG data, and ADA 
data. 
Efficacy: 
The primaty endpoint is absolute change in pre-bronchodilator FEV 1 
percent predicted fi:om Baseline to Week 8 of the study. 
Phannacokinetics: 
Plasma concentrations of GS-5745 will be detennined. 
Statistical Methods: 
Primary Endpoint: 
CONFIDENTIAL 
The primruy endpoint, the absolute change in pre-bronchodilator FEV1 
percent predicted fi:om Baseline to Week 8, will be analyzed using a 
mixed effect model for repeated measme (MMRM) for Prut 1 and Prui 2 
respectively. The model for each prut of the study will include treatment, 
Baseline FEV1 percent predicted level, visit and treatment-by-visit 
interaction as fixed effect, and subject as a random effect. Estimated 
least squru·e means of treatment effects and estimated differences in 
treatment effects between GS-5745 treatment group and placebo group 
at Week 8 will be presented with the 90% confidence intervals (Cis) and 
adjusted p-values. 
Safety evaluation will be assessed by AEs, concomitant medications, 
clinicallaborat01y tests, vital signs, ECGs and ADA data. 
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GS-5745 concentrations and PK parameters (as applicable) will be listed 
and summarized using descriptive statistics.
Sample Size Justification:
A sample size of 25 evaluable subjects per arm for Part 1 and Part 2 will 
provide 80% power to detect a difference of 5% change from Baseline 
in percent predicted FEV1 between GS-5745 active treatment and 
placebo with a 2-sided alpha level of 0.1 assuming a common standard 
deviation (SD) of 7% {Brouwer et al 2014, Ramsey et al 2011, Retsch-
Bogart et al 2009}. To compensate for early drop out, 30 subjects per 
arm will be enrolled assuming an attrition rate of 15%.
With respect to the sub-study in FRI, a sample size of 15 subjects on 
GS-5745 and 15 subjects on placebo provides more than 90% power to 
detect a 6% difference in FRI measurements (approximating an absolute 
change of 3% in FEV1) between the GS-5745 and the placebo arms in 
FRI change from Baseline based on a 2-sample t-test at a 2-sided alpha 
level of 0.1. The calculation assumes the SD of FRI change being 5% 
for the GS-5745 arm and 2% for placebo arm, as the FRI response is 
expected to be more heterogeneous in the treatment group. To 
compensate for early drop out, up to 35 subjects in Part 1 and up to 
52 subjects in Part 2 will be enrolled assuming an attrition rate of 15%.
DMC Meetings
A total of 4 scheduled DMC meetings will occur throughout Part 1 and 
prior to the end of Part 2 of the study.

Part 1: Safety Analysis #1 after 10 subjects have completed Week 2
Visit or early discontinued from the study

Part 1: Safety Analysis #2 after 30 subjects have completed Week 8
Visit or early discontinued from the study

Part 1: Safety Analysis #3 and Interim Efficacy Analysis after all 
randomized subjects have completed Week 8 Visit or early 
discontinued from the study

Part 2: Safety Analysis #4 after 45 subjects have completed Week 8
Visit or early discontinued from the study
The detail is outlined in Section 8.11 with the corresponding 
GO/NO GO decision criteria. 
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
ABPA
allergic bronchopulmonary aspergillosis
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine transaminase
AST
aspartate transaminase
ATS
American Thoracic Society
BAL
bronchoalveolar lavage
CBC
complete blood count
CF
cystic fibrosis
CFU
colony forming units
CFQ-R
Cystic Fibrosis Questionnaire – Revised 
CFR
Code of Federal Regulations
CFTR
CF transmembrane conductance regulator
CI
confidence interval
COPD
chronic obstructive pulmonary disease
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DSPH
Drug Safety and Public Health
DMC
data monitoring committee
EC
ethics committee
eCRF
electronic case report form
ECG
Electrocardiogram
ELISA
enzyme-linked immunosorbent assay
ESR
Erythrocyte Sedimentation Rate
FDA
US Food and Drug Administration
FEF25-75
forced expiratory flow at 25-75%
FEV1
forced expiratory volume in 1 second
FRC
functional residual capacity
FRI
functional respiratory imaging
FSH
follicle stimulating hormone
FVC
forced vital capacity
GCP
good clinical practice
GGT
gamma-glutamyl transpetidase
GMP
good manufacturing process
hCG
human chorionic gonadotropin


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HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HSP
Hysterosalpingogram
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
IWRS
interactive web response system
IXRS
interactive web/voice response system
kDa
kiloDalton
LABA
long acting beta agonist
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities 
MMP9
matrix metalloproteinase 9
MMRM
mixed effect model for repeated measure
MRI
magnetic resonance imaging
mSv
Millisievert
NPD
nasal transepithelial potential difference
NTM
nontuburculosis mycobacterium
PA
Pseudomonas aeruginosa
PE
physical exam
PEF
peak expiratory flow
PEFR
peak expiratory flow rate
PFS
pre-filled syringe
PGP
Proline-Glycine-Proline
PK
Pharmacokinetics
PT
Preferred term
RSS
Respiratory Symptom Scale
SAP
Statistical analysis plan
SABA
short-acting beta agonist
SADR
serious adverse drug reaction
SAE
serious adverse event
SAMA
short-acting muscarinic antagonist
SC
Subcutaneous
SD
standard deviation
SNOT-22
Sino-Nasal Outcome Test


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SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TLC
total lung capacity
TSQM
Treatment Satisfaction Questionnaire for Medication
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
VS
vital signs


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1.
INTRODUCTION
1.1.
Background
Cystic fibrosis (CF) affects approximately 100,000 people worldwide {Dmitrienko et al 2003}.
CF is the most common life-shortening genetic disorder in Caucasians, with a median age of 
death of 27.5 years in the US {Boyle 2007, Cystic Fibrosis Foundation 2013} and 28.0 years in 
the EU {European Cystic Fibrosis Society 2010}. CF is an autosomal recessive disorder 
characterized by progressive, obstructive pulmonary disease.  Patients with CF are particularly 
susceptible to chronic airway infections with opportunistic bacteria such as Staphylococcus 
aureus, Haemophilus influenzae, Pseudomonas aeruginosa (PA), Stenotrophomonas maltophilia, 
Achromobacter species, and Burkholderia species.
The majority (70%) of patients with CF die of cardiorespiratory failure{Foundation 2010}.
This is the end result of a continuous cycle of airway obstruction, inflammation, and infection 
leading to bronchiectasis, parenchymal destruction, and loss of pulmonary function {Gibson et al 
2003}.  Patients also experience episodes of acute pulmonary exacerbation, which is 
characterized by worsening respiratory symptoms and an acute decline in lung function.
The current standard of care in CF includes treatment with inhaled anti-pseudomonal antibiotics 
(eg, tobramycin and Cayston®) and mucolytics (eg, dornase) {Mogayzel et al 2013}. 
Recently 2 CF transmembrane conductance regulator (CFTR) modulator therapies have been 
approved for treatment of CF patients with select genetic mutations. Ivacaftor (Kalydeco®) 
{Davies et al 2013, Ramsey et al 2011}  has been approved for CF patients who carry one of the 
G551D CFTR gating mutations. The other is a combination product combining ivacaftor with 
lumacaftor for CF patients who are homozygous with the most common CF mutation, F508del. 
Both drugs improve lung function and reduced pulmonary exacerbations.  While current CTFR 
modulator therapies provide clinical benefit to almost 50% of the CF population, the therapy 
does not represent a complete clinical cure.
1.2.
GS-5745
1.2.1.
General Information
For further information on GS-5745, refer to the Investigator’s Brochure (IB) for GS-5745.
1.2.2.
Preclinical Pharmacology and Toxicology
GS-5745 is a humanized high-affinity monoclonal IgG4 antibody that is a selective and potent 
allosteric inhibitor of matrix metalloproteinase 9 (MMP9). In CF patients, sputum MMP9 levels 
are 13- to 14-fold higher in sputum to 100-fold higher in bronchoalveolar lavage (BAL) than that 
of healthy controls at Baseline and during CF exacerbations, respectively {Bergin et al 2013, 
Hahn et al 2012}. Murine surrogates of GS-5745, with similar epitope specificity and inhibitory 
activity, have demonstrated significant anti-inflammatory and tissue-protective activity in rodent 
models of ulcerative colitis (UC) and rheumatoid arthritis (RA). Unlike pan-MMP inhibitors, 


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specific inhibition of MMP9 with a murine surrogate of GS-5745 showed no evidence of 
inducing musculoskeletal symptoms or pathology in a rat model. In addition, there were no 
effects on safety pharmacology endpoints (clinical observations, electrocardiograms, respiratory 
rate) in the 4-week repeat-dose toxicity studies at doses of up to 100 mg/kg/dose. 
The toxicology program consists of completed 4-week and 26-week repeat-dose IV toxicity 
studies in both rats and monkeys and a human tissue cross-reactivity study. To support the 
transition to a SC formulation, a SC local tolerability study in rats was conducted and the 
26-week toxicity studies in rats and cynomolgus monkeys included both IV and SC routes. 
Rat and rabbit embryo fetal development studies and a rat fertility study have also been 
completed. As expected, there was no specific GS-5745 staining observed in normal human 
tissues. At doses of GS-5745 up to 100 mg/kg/dose IV, data indicate no test article-related 
maternal or fetal effects in rats and rabbits, and no test article-related effects on male or female 
fertility in rats. Findings associated with GS-5745 treatment in the 4-week repeat-dose toxicity 
studies have been limited to reversible physeal hypertrophy in rats, an expected response to 
MMP9 inhibition, and reversible increased adrenal gland weight in female monkeys at all doses, 
which was associated with slight hypertrophy of the zona fasciculata in a single 100-mg/kg/dose 
female monkey. In the 26-week studies, there were no findings of toxicological concern in rats or 
cynomolgus monkeys following weekly IV or SC administration at doses up to 100 mg/kg/dose 
and 150 mg/kg/dose, respectively. The lack of physeal hypertrophy observed in the rat 26-week 
study is presumably due to the reversible nature of this finding as longitudinal bone growth and 
growth plate closure slows/completes. There were no adverse injection site reactions observed in 
the 26-week studies, and no adverse findings in the local tolerability study. 
The NOAEL in the rat and monkey 26-week studies was 100 mg/kg/dose IV and 
150 mg/kg/dose SC, the highest doses evaluated by each route of administration in each study. 
The maximum proposed SC clinical dose of approximately 10 mg/kg [600 mg (4 x 150 mg/ml 
injections) to a 60 kg patient] is 15-fold lower than the high SC dose in the 26-week toxicity 
studies.
Therefore, the toxicology studies support the proposed SC dose, dose regimen, and the duration 
of the clinical study. Overall, the nonclinical program has demonstrated that GS-5745 has the 
potential to be a safe and effective therapy for controlling the inflammation and tissue damage 
associated with CF. A more detailed description of the nonclinical program is provided in the IB.
1.2.3.
Clinical Trials of GS-5745
In addition to the clinical development program in CF, GS-5745 is being developed for the 
treatment of solid tumors, UC, RA, and chronic obstructive pulmonary disease (COPD). At least 
221 subjects have been enrolled in clinical studies evaluating GS-5745.  Details of the clinical 
studies in these diseases can be found in the IB.   


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A Phase 1 study of GS-5745 administered IV (up to 5 mg/kg GS-5745 every 2 weeks) or SC
(150 mg GS-5745 weekly) in patients with moderately to severely active UC demonstrated 
clinical activity at Day 36 and low rates of AEs were observed. Additionally, 
immunohistochemistry and RNA sequencing provided supportive evidence of the biological 
activity of GS-5745{Bhandari et al 2015}.
In a Phase 1 study of GS-5745 (with doses up to 1800 mg IV every 2 weeks) alone and in 
combination with chemotherapy in patients with advanced solid tumors, preliminary safety data 
demonstrated a manageable safety profile.  There were no observed responses in the 
monotherapy escalation phase. However, when combined with chemotherapy in the expansion 
phase in subjects with measurable target lesions there were objective response rates of 
64% (7/11) and 41% (7/17) for esophagogastric and pancreatic cancers respectively {Bendell et 
al 2015}.
GS-5745 has also been studied in RA. A total of 18 subjects (15 active: 3 placebo) with active 
RA documented by a mean Screening CRP value of >=8.0 mg/L received 400 mg of GS-5745 or 
placebo every 2 weeks for a total of 3 infusions. Subjects continued their routine RA medical 
regimen during the study, but the use of biologics was prohibited. All subjects had baseline 
moderate to high disease activity assess by Disease Activity Score (DAS28-CRP) and completed 
the study. At Day 43 the proportion of subjects that achieved either low disease activity or 
remission in the GS-5745 and placebo groups were 4/15 (27%) and 0/3 (0%) respectively.
Highlighting FEV1 results of the Phase 1 COPD study (8 active: 3 placebo), of the 6 subjects that 
received 400 mg IV every 2 weeks for a total of 3 infusions, 2 of 6 subjects demonstrated mean 
absolute improvement in FEV1% of 8.6% and 6.6% respectively. Changes in FEV1 in the 
2 placebo subjects that also completed 3 doses over the same time course were <4.0%. 
Though the sample size is small and study duration brief, it suggests GS-5745 may be able to 
positively affect FEV1 in respiratory indications.
To date there has been no study drug-related adverse safety signal observed in any of the 
completed or active studies in any of the indications under clinical development with GS-5745
(oncology, UC, Crohn's disease, RA, COPD).
1.3.
Rationale for this Study
MMP9 is a zinc-dependent endopeptidase that cleaves collagen and gelatin and is involved in 
neutrophil migration and remodeling of the airway. Neutrophils are a major source of MMP9, 
but it is also produced by bronchial epithelial cells, endothelial cells, smooth muscle cells, 
fibroblasts, and other immune cells such as macrophages, lymphocytes, eosinophils, mast cells, 
NK cells, and dendritic cells {Atkinson et al 2003}. Dysregulated MMP9 in CF has been 
postulated to contribute to proteolytic damage to lung parenchyma, enhance IL-8 activity, and 
release chemotactic peptides such as Proline-Glycine-Proline (PGP) {Devereux et al 2014}. 
Excess airway MMP9 is associated with reduced lung function {Gaggar et al 2007, Sagel et al 
2005} and acute exacerbations {Roderfeld et al 2009} in CF patients. Confirmation of the 
clinical importance of MMP9 in CF has been demonstrated in a recent prospective interventional 
study in CF subjects hospitalized with a respiratory exacerbation who received an 8-day course 


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of doxycycline, a non-specific inhibitor of MMP9 or placebo for 8 consecutive days in addition 
to standard of care medical therapy. Subjects that received doxycycline had significant 
reductions in 1) sputum MMP9 levels and activity, 2) a clinically meaningful increase in FEV1,
and 3) a reduction in hospital stay compared to the placebo group (Amit Gaggar, supporting 
documentation on file). Gilead’s proposed study aims to build upon these positive findings by 
exploring the effects of a selective MMP9 inhibitor (GS-5745) dosed over a long course on lung 
function in a cohort of stable CF subjects.
1.3.1.
Route of Administration 
The highest safe and practical dose of GS-5745 will be administered in Part 1 of the study to 
maximize the likelihood of observing a clinical effect on the primary endpoint, FEV1. As of 
07 Dec 2015 GS-5745 has been administered to 221 subjects in several Phase 1 studies in 
oncology, UC, RA, and COPD and in Phase 2 studies in UC and Crohn’s disease. The majority 
of dosing with GS-5745 has been with an IV formulation with up to 1800 mg every 2 weeks as 
the highest dose safely administered to oncology subjects. While a short-term IV study with 
GS-5745 may be achievable in CF, feedback from CF experts suggests that long-term chronic IV 
treatment with GS-5745 would be difficult and the preferred route would be SC. Thus, this 
proof-of-concept study will use a SC formulation.
1.3.2.
Dose Selection
The GS-5745 SC formulation currently available for clinical studies is a pre-filled syringe at a 
concentration of 150 mg/mL. To investigate the highest, safe and practical SC dose of GS-5745 
for this study, single and multiple SC injection regimens were considered. Weekly SC dosing of 
600 mg GS-5745 is expected to be safe in CF patients. Taking into consideration that the 
bioavailability of the SC formulation of GS-5745 is approximately 44%, this CF dosing regimen 
would translate to a bimonthly dose of approximately 528 mg which is below the proposed Phase 
3 oncology study in gastric adenocarcinoma of 800 mg IV Q 2 weeks and similar to the fixed 
dose IV dosing of 400 mg every 2 weeks in the Phase 1 RA and COPD studies. As of 
25 September 2015 review of the safety data of GS-5745 in all current indications 
(oncology, UC, Crohn’s disease, RA, and COPD) no adverse safety signal has been observed. 
Moreover, no increased risk of infections or sepsis has been noted despite the use of 
chemotherapy or immunosuppressive agents in the oncology, UC, Crohn’s and RA studies. 
Thus, the body of GS-5745 safety data suggests that dosing 600 mg SC weekly in CF subjects 
should not pose an unreasonable risk for serious adverse events.
To determine potential range of MMP9 concentrations as well as binding to GS-5745 in sputum 
of CF subjects, in vitro mixing experiments were performed. Sputum samples from six distinct 
CF patients with stable disease were evaluated. The mean MMP9 concentration was 
~2600 ng/ml (~28.3 nM), spanning 570-3700 ng/ml (6--40 nM), across these six sputum 
samples. After mixing varying concentrations of GS-5745 into each sputum sample, free MMP9 
and GS-5745-bound-MMP9 were measured using an enzyme-linked immunosorbent assay 
(ELISA). On average, 1:1 binding was observed between MMP9 and GS-5745, establishing 
stoichiometric binding of GS-5745 to MMP9 in sputum. Stoichiometric binding is expected 
based on the KD of GS-5745 for MMP9 and the knowledge that MMP9 complex formation 
(with TIMP, NGAL, etc.) does not interfere with GS-5745 binding. 


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To best predict a dose that achieves a GS-5745 concentration in molar excess of sputum MMP9, 
we considered both the previously-observed GS-5745 pharmacokinetics and CF-specific factors 
that may influence pharmacokinetics.  Subcutaneous dosing of GS-5745 has been studied in UC 
using a 150 mg/ml formulation in a prefilled syringe. Weekly dosing of one 150 mg SC injection 
for 4 weeks has demonstrated clinical efficacy in a Phase 1 study, and Phase 2 studies are 
underway in UC and Crohn’s disease using the SC formulation. Baseline mean total plasma 
MMP9 concentrations in the Phase 1 UC studies were found to be 143.09 ng/ml with the 
maximum value being 1279.40 ng/ml (N=50 (Gilead, data on file). In contrast, total plasma 
MMP9 concentrations in CF appear to be much higher with a mean of approximately 670 ng/ml 
and a maximum value of > 1500 ng/ml (N=19) {Hahn et al 2012} using the same ELISA. 
These findings suggest that the total body MMP9 load is greater in CF than in UC. The relative 
increase of MMP9 in CF to UC may be 4 to 5-fold. Thus, to account for a potentially larger 
MMP9 antigen sink in CF, subjects will receive a 4.0-fold higher dose in CF, or 600 mg 
(4 SC injections [1 mL/injection] of GS-5745 [150 mg/ml] weekly) in Part 1 of this study. 
Pharmacokinetic modeling provides further rationale for weekly SC dosing of 600 mg GS-5745. 
Plasma PK of GS-5745 in CF subjects was predicted based on preliminary population PK 
modeling results in UC patients, assuming a 5-fold higher target-mediated drug clearance in CF 
than in UC subjects base on higher plasma MMP9. GS-5745 levels in sputum were assumed to 
be 10% of plasma concentrations in CF subjects, based upon an approximate 1 log reduction 
between serum and sputum IgG4 in patients with non-CF bronchiectatsis {Hill et al 1998}, a 
surrogate for CF. The projected Cmax and Cmin of GS-5745 in sputum are 2.4 g/mL (16.3 nM) 
and 0.02 g/mL (0.14 nM) after the 1st 600 mg injection, and 7.1 g/mL (48.4 nM) and 
3.1 g/mL (21.1 nM) after the last injection, respectively, in majority of CF subjects. Based on 
the approximately 1:1 binding observed in the in vitro sputum mixing studies, the 600 mg SC 
weekly dosing is expected to achieve consistent binding to MMP9 in the sputum in the >75% of 
CF patients. Correspondingly, 300 mg and 150 mg SC weekly dosing are expected to achieve 
lower fractional binding of MMP9 in sputum for shorter durations than the 600 mg SC weekly 
dosing.
1.3.3.
Study Duration
Clinical improvement has been observed within 5 weeks of weekly SC dosing of GS-5745 in 
Phase 1 UC studies. A possible mechanism for this rapid response is that GS-5745 is a high 
affinity antibody with picomolar potency that targets MMP9 directly at the site of 
inflammation/tissue damage. The rapid clinical improvement may be due to the inhibition of 
upregulated MMP9 in affected regions of the colon. It is hypothesized that an 8-week period of 
treatment with GS-5745 may lead to further clinical improvement than the 5-week endpoint in 
the Phase 1 UC studies. 
It is uncertain if the clinical response timeframe seen in the UC Phase 1 studies can be 
extrapolated to CF. A study employing the anti-inflammatory ibuprofen, known to improve 
FEV1 in CF with chronic therapy {Konstan et al 1995} failed to demonstrate a clinical 
improvement in FEV1 after only a 4 week treatment course {Chmiel et al 2015}. To increase the 
likelihood of observing an improvement in FEV1 in this study, an 8-week dosing period will be 


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used paralleling the 8-week induction regimen planned for the Phase 2 UC study. If the results of 
Part 1 of this study are positive, then 2 lower doses, 300 mg and 150 mg, will be studied in Part 2 
of the study.
1.4.
Risk/Benefit Assessment for the Study
GS-5745 is currently being evaluated in 5 ongoing clinical studies for the treatment of solid 
tumors, UC, Crohn’s Disease, RA, and COPD.  From the adverse events reported in these trials 
none have been identified as adverse drug reactions causally related to the drug. Also, no drug 
interactions or contraindications have been reported.
Potential risks may include local injection site reactions and the rare possibility of 
hypersensitivity or allergic reactions which have been reported with the use of biologics.
A single hypersensitivity reaction was observed after a second infusion in a UC subject. 
The subject was evaluated at the local emergency room and was discharged home in satisfactory 
condition. Despite this single hypersensitivity reaction after an IV infusion of GS-5745, 
it should be noted that GS-5745 is not considered to be a ‘high risk’ agonist as it acts by 
antagonism and targets MMP9. However, to mitigate the potential risk associated with SC
administration of GS-5745, subjects will be monitored for 120 minutes after first SC injection 
and for 30 minutes after all subsequent SC injections of each dose during the blinded phases of 
Part 1 and Part 2 of the study. To be prepared for a theoretical risk of a systemic injection site 
reaction, study sites will be required to have on site and readily available, injectable epinephrine. 
Home health provider’s administering the at home injections will also have readily available an 
auto-injectable form of epinephrine. Prior to administering drug, clinic staff and the home health 
provider will review the clinical manifestations of anaphylaxis and the proper use of the 
auto-injectable epinephrine. Unless there is an adverse event safety signal of concern observed 
with SC injections in the blinded phases of Part 1 and Part 2, within OLE study subjects will be 
monitored for 120 minutes after the first SC injection and for 30 minutes after the second SC 
injection. For subsequent SC injections in the OLE, subjects will be monitored for at least 
15 minutes after each injection.
Only patients who are on stable CF medication regimens from 30 days prior to Baseline and 
throughout the duration of the study will be eligible to enroll therefore the impact on the patients’ 
habitual standard of care should be negligible.
Despite many advances in CF therapies, the majority of CF patients experience progressive loss 
of lung function and recurrent exacerbations. Compared with healthy controls, patients with CF 
have MMP9 concentrations 13- to 14-fold higher in sputum and 100-fold higher in 
bronchoalveolar lavage (BAL) samples {Bergin et al 2013, Devereux et al 2014, Hahn et al 
2012}. Dysregulated MMP9 in CF has been postulated to augment proteolytic damage to lung 
parenchyma, enhance IL-8 activity, and release chemotactic peptides such as PGP {Gaggar et al 
2007}. Excess airway MMP9 is associated with reduced lung function {Sagel et al 2005} and 
acute exacerbations in CF patients {Roderfeld et al 2009}. Therefore, treatment with GS-5745 
may reduce airway MMP9 activity in patients with CF and result in reduced airway 
inflammation and stabilization and/or improvement in lung function. 


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This clinical study will provide information about the benefits GS-5745 may have in the CF 
population and potentially provide an additional therapy to improve the health and 
life-expectancy of patients living with this life-limiting condition. These benefits are believed to 
outweigh any potential risks, particularly in the context of this clinical trial.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The prima1y objective of this study is as follows: 
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• 
To evaluate the effect of GS-5745 on pre-bronchodilator FEV1% predicted in subjects with 
CF after 8 weeks of treatment 
The secondmy objectives of this study m·e as follows: 
• 
To assess safety, tolerability, and PK ofGS-5745 in subjects with CF 
• 
To evaluate the effect of GS-5745 on post-bronchodilator FEV1% predicted in subjects with 
CF after 8 weeks of treatment 
Explorat01y objectives ofthis study m·e as follows: 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The prima1y efficacy endpoint of this study is: 
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• 
The absolute change in pre-bronchodilator FEV1 percent predicted from Baseline to Week 8 
The secondmy efficacy endpoints of this study are: 
• 
The absolute change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8 
• 
The relative change in pre-bronchodilator FEV 1 percent predicted from Baseline to Week 8 
• 
The relative change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8 
The safety of GS-5845 will be assessed by AEs, concomitant medications, clinicallaborat01y 
test, vital signs, and ADA data. 
Primary PK parameters will include Cma.x, Tmax, Clast, Tlast, and AUC!ast (as applicable). 
Explorat01y endpoints of this study m·e: 
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3.2. 
Study Design 
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This is a phase 2b, randomized, double-blind, placebo-controlled, multiple-center, multiple dose 
study. 
The study is comprised of 2 pruis. Prui 1 will enroll 60 subjects in a 1: 1 ratio to receive either 
600 mg GS-5745 SC or placebo in a blinded manner for 8 weeks. Safety and efficacy analyses 
will be perfonned for Prui 1 after all subjects have completed the Week 8 visit or discontinued 
from the study. If the FEV 1 percent predicted change combined with other endpoints indicate 
positive signals and the DMC detennines there are no significant safety signals, 
then advancement to Prui 2 will occur. Refer to Section 8.11 for more inf01mation. 
Prui 2 will enroll 90 subjects in a 1: 1: 1 ratio to receive SC injections of either 300 mg GS-57 45, 
150 mg GS-5745, or placebo for 8 weeks in a blinded manner. Visits and procedures for both 
Prui 1 and Pati 2 will be the srune. 
The FRI sub-study will require 2 FRI scans, one at Baseline and 1 at the Week 8 visit. A sub-set 
of study sites will be trained in FRI. All subjects enrolling into the study at those sites will 
pruiicipate in the FRI sub-study until approximately 30 subjects in Part 1 and up to 52 subjects in 
Prui 2 have enrolled into the sub-study and completed Week 8. See Section 6. 3.1 0 for additional 
inf01mation on FRI. 
There will be a sputum cytology sub-study for both Prui 1 and Pati 2. A select sub-set of sites 
will perf01m sputum cytology from induced sputum samples to investigate changes in total cell 
count and cell cmmt differential in sputum. No additional procedures will be required of subjects 
pruiicipating in the sputum cytology sub-study. 
Blood sam}:)les for PK will be obtained at select scheduled study visits. PD 
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Figure 3-1.
Study Design
3.3.
Study Treatments
3.3.1.
Part 1
Subjects who meet the eligibility criteria at screening will be randomized in a blinded fashion in 
a 1:1 ratio as follows:

Treatment arm (n=30): 600 mg GS-5745 (4 SC injections of 150 mg as 1 dose given weekly 
for 8 doses).

Placebo arm (n=30): matching placebo (4 SC injections as 1 dose given weekly for 8 doses).  


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3.3.2.
Part 2
Subjects who meet eligibility criteria at screening will be randomized in a blinded fashion in a 
1:1:1 ratio as follows:

Treatment arm 300 mg (n=30): 300 mg GS-5745 (2 SC injections of 150 mg as 1 dose given 
weekly for 8 doses).

Treatment arm 150mg (n=30): 150 mg GS-5745 (1 SC injection of 150 mg and 1 SC 
injection of placebo as 1 dose given weekly for 8 doses).

Placebo arm (n=30): matching placebo (2 SC injections as 1 dose given weekly for 8 doses).  
3.3.3.
Open-Label Extension (OLE)
On the Week 8 visit (-3 to + 4 days) of both Part 1 and Part 2, subjects (active and placebo) will 
be invited to participate in an OLE treatment period.  

Subjects choosing to participate from Part 1 will receive open-label 600 mg of GS-5745 
weekly for 16 additional weeks.  

All subjects choosing to participate from Part 2 will receive open-label 300 mg of GS-5745 
weekly for 16 additional weeks.
3.3.3.1.
Home Administration of Study drug
Weekly clinic visits during the study may pose a significant burden to study subjects. 
This burden must be balanced against the need to closely monitor these potentially vulnerable 
subjects during the early doses of study drug. Therefore all subjects will receive at least the 
first 2 SC study drug injections at the study site. Thereafter, subjects who experienced no major 
AEs associated with the SC injections  will have the option of utilizing a home health provider
organization (where available) to complete select visit procedures and study drug dosing during 
the blinded and OLE portions of this study (see Section 6.1.6). 
3.4.
Duration of Treatment
Randomized subjects in both Part 1 and Part 2 will complete 8 weeks of weekly dosing. 
Subjects that choose to participate in the OLE will receive an additional 16 weeks of weekly 
dosing of GS-5745 for a total of 24 weeks of dosing.  Subjects will have their final visit 30 days 
after the last dose of study drug.


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3.5.
Protocol Discontinuation Criteria
Study drug administration will be suspended in all subjects if any one of the following criteria 
are met:
1) The Principal Investigator (or his/her deputy) and the Sponsor consider the number and/or 
severity of AEs justify discontinuation of the study
2) The Sponsor makes a unilateral request to do so
3) An SAE or a confirmed Grade 4 laboratory finding in the same system organ class and 
determined to be related to study drug occurs in 2 or more subjects in a cohort.
4) Laboratory results that meet Hy’s Law criteria {U.S. Department of Health & Human 
Services (DHHS) et al 2009}
Decisions to reinitiate dosing will be made by the DMC and Sponsor upon review of all available
safety and tolerability data generated by subjects dosed to date.
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. 
3.7.
Biomarker Testing
3.7.1.
Biomarker Samples to Address the Study Objectives
Blood and sputum will be collected in this study and will be used to evaluate the association of 
exploratory systemic and/or tissue specific biomarkers with study drug response, including 
efficacy and/or AEs and to increase knowledge and understanding of the biology of MMPs and
CF or related diseases such as bronchiectasis, asthma, COPD, idiopathic pulmonary fibrosis, and 
sarcoidosis and/or the validation of a companion diagnostic for GS-5745. The specific analyses 
will include, but will not be limited to, total and free MMP9 and MMP9 activity.  A blood 
sample will be collected for RNA to study gene expression changes from Baseline in response to 
GS-5745 with particular emphasis on MMP9 pathway related transcript changes. Blood samples 
will also be collected for CF genotyping at Baseline for subjects who do not have a historical 
genotype on file. Since biomarker science is a rapidly evolving area of investigation, and AEs 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 current 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 tests based upon the growing state of art knowledge. 


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3.7.2. 
Biomarker Samples and Imaging for Optional Future Research 
PD 
3.7.3. 
Biomarker Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 150 subjects who meet the eligibility criteria at screening will be randomized to receive 
GS-5745 or placebo in Part 1 (60 subjects) and Part 2 (90 subjects). The sub-study for FRI will 
enroll up to 35 subjects in Part 1 and up to 52 subjects in Part 2 to account for an attrition rate of 
15%.   
Subjects who fail to meet all the inclusion criteria or who meet any of the exclusion criteria will 
not be randomized in this study.  No waivers for any study entry criteria will be granted.  
In order to manage the total study enrollment, Gilead Sciences, Inc. (Gilead), at its sole 
discretion, may suspend screening and/or enrollment at any site or study-wide at any time.  
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 18 years of age or older
2) Confirmed diagnosis of CF as determined by the 2008 Cystic Fibrosis Foundation Consensus 
Report {Farrell et al 2008} criteria 
3) Subjects must be able to perform acceptable and reproducible spirometry as per the 
American Thoracic Society (ATS) Guidelines
4) Must have a body weight of > 40 kg (88.2 lbs) at study Screening
5) Subjects must be a never-smoker or an ex-smoker with < 5 pack-year history of smoking and 
be smoke-free (including marijuana or e-cigarettes/vaping) for 12 months prior to Screening
6) Pre-bronchodilator FEV1 ≥40% and ≤80% of predicted at Screening
7) Two pre-bronchodilator spirometry measures taken at least 4 days apart (one during 
Screening, one at Baseline) using the sponsor provided central spirometry equipment must 
meet the following 2 criteria:  
The relative difference of FEV1(L), calculated as the absolute value of [(first FEV1 –
second FEV1) / first FEV1 ] x 100  should be < 12% AND 
The absolute difference in FEV1 should be < 200 ml


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8) Negative Investigation/History of Important Bacteria Infections:
Tuberculosis (TB):
A negative QuantiFERON-TB Gold test during Screening
Non-Tuberculous Mycobacteria species (NTM):
All sputum cultures for ANY Mycobacterium spp. performed 24 months prior to 
Screening must be negative. If only 1 NTM culture was performed 24 months prior to 
Screening, that NTM culture and the most recent NTM culture obtained >24 months prior 
to Visit 1 must both be negative AND
A negative sputum culture < 12 months prior to Screening for any Mycobacterium 
spp. AND
No current treatment for active NTM during Screening
Burkholderia spp. 
All sputum/throat cultures for ANY Burkholderia spp. performed 24 months prior to 
Screening must be negative.  If only 1 Burkholderia culture was performed 24 months 
prior to Screening, that Burkholderia spp. culture and the most recent Burkholderia spp.
culture obtained >24 months prior to Screening were both negative AND
A negative culture for Burkholderia spp. during Screening AND
No current treatment for Burkholderia spp. during Screening
9) Clinically stable with no evidence of significant respiratory symptoms that would require 
administration of (IV) antibiotics, oxygen supplementation, or hospitalization within 30 days 
of Baseline.
10) A chest radiograph, computed tomography (CT) or magnetic resonance imaging (MRI) 
within 90 days of Baseline, interpreted as showing no acute findings such as infiltrates 
[lobar or diffuse interstitial], pleural effusion, or pneumothorax, and no significant 
intercurrent illness; chronic, stable findings (eg chronic scarring or atelectasis) are allowed. 
If not available then a chest radiograph at Screening will be obtained and should be 
interpreted as above.
11) On stable CF chronic medical regimen for at least 30 days prior to Baseline and expected to 
remain stable through the completion of the study. This includes but is not limited to: chronic 
azithromycin use, inhaled bronchodilators, inhaled corticosteroids, inhaled dornase alpha, 
inhaled hypertonic saline, inhaled mannitol, ivacaftor, and/or ivacaftor/lumacaftor.

Inhaled antibiotics (ie, tobramycin, aztreonam, colistin) should be stable for 
2 “on-treatment cycles” to be considered a stable CF medication (ie, approximately
2 months if they are taken as continuous inhaled antibiotics or about 4 months if they are 
taken as an alternating inhaled antibiotic).  


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12) A negative serum pregnancy test is required for women of childbearing potential (as defined 
in Appendix 3)
13) 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)
14) Lactating females must agree to discontinue nursing before administration of study drug and 
during the course of the study
15) Male subjects must agree to refrain from sperm donation for 90 days after the last dose of 
study drug is administered
16) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures
17) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Concurrent use of oral antibiotics (excluding the use of chronic azithromycin) or IV 
antibiotics within 30 days of Baseline. Prophylactic and chronic doxycycline use is 
prohibited during the study.
2) Hospitalization for a respiratory event within 30 days of Baseline 
3) Active allergic bronchopulmonary aspergillosis (ABPA) requiring treatment; previous 
history of ABPA without current ABPA anti-fungal prophylaxis is acceptable
4) Any acute “non-CF related” illness within 2 weeks prior to Baseline (eg, gastroenteritis)
5) Current use of systemic immunosuppressive drugs including oral corticosteroids within 
30 days of Baseline 
6) Current requirement for daily continuous oxygen supplementation or requirement
(medically necessary) of more than 2 L/minute at night (subject would not meet this 
exclusion criterion if supplemental oxygen is used for comfort only)
7) History of anaphylaxis requiring the use of epinephrine
8) History of solid organ (including lung) or hematologic transplant, or currently on a transplant 
waiting list
9) History of lung resection


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10) History of HIV, hepatitis B, or hepatitis C
11) History of malignancy in the last 5 years except for subjects who have been successfully 
treated for non-melanoma skin cancer or cervical cancer
12) History of alcohol or drug abuse in the past year, including but not limited to cannabis, 
cocaine, opiates, as determined by the investigator 
13) Laboratory parameters at screening:

Abnormal liver function tests defined as > 3 times the upper limit of normal (ULN) of 
any of the following: serum aspartate transaminase (AST), serum alanine transaminase 
(ALT), gamma-glutamyl transpetidase (GGT), serum alkaline phosphatase.

Total bilirubin > 2 times the ULN

Hemoglobin < 10 g/dL for females and < 11.5 g/dL for males at Screening

Estimated glomerular filtration rate (eGFR) <40 mL/1.73 m2 based on the 4-variable 
Modification of Diet in Renal Disease (MDRD) formula: GFR = 175 × [SCr]−1.154 × 
[age]−0.203 × [1.212 if patient is African American] × [0.742 if patient is Female] {Levey 
et al 2006}
14) Clinically significant abnormal ECG at Screening; abnormalities considered not clinically 
significant, per investigator, are not exclusionary
15) Known hypersensitivity to the investigational medicinal product or formulation excipient
16) Presence of any condition or abnormality that would compromise subject safety or the 
quality of data, or any serious or active medical or psychiatric illness, which in the opinion of 
the investigator, would interfere with subject treatment, assessment, or compliance with the 
protocol
17) Receipt of any investigational non-biological drug therapy within 30 days of enrollment OR
receipt of any marketed or investigational biologic within 4 months prior to enrollment
18) Females who are pregnant or breastfeeding 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An interactive Voice/Web Response System (IVRS + IWRS = IXRS) will be employed to 
manage subject randomization and enrollment into Part 1 and Part 2 of the study, shipping of 
study drug, and dispensing of study drug.
5.1.1.
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 IXRS system 
for that subject. Directions for obtaining treatment assignment can be found in the IXRS User 
Guide. 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.
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 during the blinded phase of the 
study, 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 Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of GS-5745 and Placebo
5.2.1.
Formulation
GS-5745 for SC injection is formulated as a sterile, aqueous buffered solution in a single-use 
pre-filled syringe (PFS) with a plunger stopper. The buffered solution contains acetate at pH 5.0, 
sucrose and polysorbate 20 added for stabilization. Each 1 mL PFS contains 150 mg GS-5745 at 
a concentration of 150 mg/mL.  
Placebo for SC injection is formulated as a sterile, aqueous buffered solution in a single-use PFS 
with plunger stopper.  Each 1 mL PFS contains acetate buffer at pH 5.0, sucrose and 
polysorbate 20. 
5.2.2.
Packaging and Labeling
GS-5745 SC injection and placebo will be supplied in 1 mL glass pre-filled syringes with gray 
butyl coated stoppers.


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Study drug(s) to be distributed to centers in the United States (US) and other participating 
countries shall be labeled to meet applicable requirements of the US Food and Drug 
Administration (FDA), EU Guideline to Good Manufacturing Practice – Annex 13 
(Investigational Medicinal Products), and/or other local regulations. 
Gilead or designated distribution depots will distribute study drug to centers as per 
Good Manufacturing Practice (GMP) requirements.  
5.2.3.
Storage and Handling
GS-5745 and placebo for SC injection will be shipped and stored under refrigeration between 
2 to 8 °C (36 to 46 °F). Storage conditions are specified on the label.
Upon arrival at the clinical center, the study drug products must be stored in a secure area, 
accessible only to authorized study site personnel. To ensure drug stability and proper product 
identification, the drug products should be stored in the kits in which they are supplied until 
needed.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body.
5.3.
Dosage and Administration of GS-5745 and Placebo
GS-5745 or placebo for SC injection will be administered to subjects on the thighs, the stomach 
area (abdomen), or the deltoid area of the upper arms in the blinded phase of the study. In the 
OLE if self-injection at home is determined to be safe, deltoid injections will not be allowed. 
If the abdomen area is chosen, the area 5 cm (2 inches) around the umbilicus should be avoided. 
GS-5745 or placebo will be administered SC at the research center at study visits during the 
blinded phase of the study. If the dose requires multiple SC injections, all injections should be 
delivered within 1 hour.  The investigator or a qualified designee must be present during the 
administration during the blinded phase of the study. 
In the blinded phase of the study, if the subject has a body temperature of > 38ºC (100.4ºF) , 
his/her FEV1 % predicted is less than 40% or his/her FEV1 % predicted decreases by > 30% from 
Baseline on study site visits requiring spirometry, AM pre-bronchodilator PEF decreases by 
>30% from the mean PEFR obtained during Screening during non-spirometry visits, or in the 
medical opinion of the investigator or home health provider the subject is unfit to receive study 
drug at a given visit, the subject should not be administered study drug. In consultation with the 
medical monitor, the Investigator may delay dosing until the parameters above are met. 
See Section 6.3.6 for additional information on the spirometry measures.
During the OLE portion of the study subjects will have the option to continue to receive study 
drug SC injections at their respective study clinic receive SC injections by a qualified home 
health provider (where available) at their residence in the short-term with the long-term plan to 
eventually self-administer the study drug without supervision at home after the DMC and Gilead 
have reviewed safety data and agree home administration appears safe. At the beginning of the 


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OLE subjects will be instructed by clinic staff how to self-administer the SC injections using the 
thigh and stomach areas only. After successful training and sign-off by the study clinic and/or 
home health provider (where available) that the subject can correctly self-administered study 
drug, subjects will self-administer doses at home weekly (±3 days) between study visits and 
record the doses when they are administered. Subjects who find it difficult to self-administer the 
study drug SC injections at home may receive assistance with the administration from the home 
health care service (where available) to ensure proper dosing and adherence or receive their SC 
injections at their local study sites. All injections should be delivered within 1 hour.  
Subjects will also be instructed in the safe storage and transport of the study drugs as well as safe 
disposal of used syringes. 
Similar to the blinded phase of the study, in OLE if the subject has a body temperature of > 38ºC 
(100.4ºF), PEF decreases by > 30 % from the mean obtained during Screening during 
non-spirometry visits, or in the medical opinion of the investigator or home health provider the 
subject is unfit to receive study drug at a given visit, the subject should not be administered study 
drug. In consultation with the medical monitor, the Investigator may delay dosing until the 
parameters above are met.
If a subject fails to come to their respective study site for a scheduled study visit that includes SC 
administration of study drug, the investigator should contact the Gilead medical monitor to 
discuss if a late dose is acceptable or if the dose should be skipped. 
If a subject misses 2 doses defined as the series of study drug SC injections associated with 
2 study visits (clinic or home visits), the Gilead medical monitor should be contacted to discuss 
if the study drug should be withdrawn for that subject.  
5.4.
Prior and Concomitant Medications and Excluded Therapies
At each study visit, the study center will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription medications, non-prescription medications, therapies, and dietary supplements.
The use of all inhaled and/or IV antibiotics for respiratory exacerbations during the 12 months 
prior to Screening will be recorded.
The following medications are excluded from use during the study:

Systemic immunosuppressive drugs including 

An oral corticosteroid burst of > 7 days duration

Any investigational drug therapy

Prophylactic and chronic doxycycline


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Effective current therapies should not be discontinued for the sole purpose of participating in this 
study. Subjects may receive medications as supportive care or to treat AEs as deemed necessary 
by the investigator or the subject’s physician. Should subjects have a need to initiate treatment 
with any excluded concomitant medication, the Medical Monitor must be consulted prior to 
initiation of the new medication. In instances where an excluded medication is initiated prior to 
discussion with the Sponsor, the investigator must notify Gilead Sciences as soon as he/she is 
aware of the use of the excluded medication. The allowed concomitant medication(s) for CF
must be maintained at a stable dose throughout the duration of the study.
5.5.
Concomitant Medication Management 
Subjects must remain on stable CF medication regimens from 30 days prior to Baseline, and it is 
recommended they remain on those medications through the Follow-up visit. If a change in CF 
medication regimen is required during the course of the study, please contact the medical 
monitor prior to initiation of therapy. 
Specific requirements apply to inhaled CF medications:

At the time of study entry, subjects who are on a stable regimen of inhaled antibiotics that are 
continuously administered should remain on those antibiotics throughout the study.
A stable regimen of continuous or continuous alternating antibiotics is at least 
2 “on-treatment” cycles (about 2 months) prior to Baseline.

At the time of study entry, subjects who are on a stable regimen of inhaled cycling antibiotics 
(e.g. aztreonam for inhalation [Cayston], inhaled tobramycin [TOBI and TIP], inhaled 
colistin) should remain on these antibiotics throughout the study.  Inhaled cycling antibiotics 
should be administered in 28-day-on/28-day-off cycles.
A stable regimen of cycling antibiotics is at least 2 “on/off” cycles (about 4 months) prior 
to Baseline.

Standard of care inhaled CF therapies (eg, bronchodilators, dornase alpha, inhaled 
antibiotics, hypertonic saline, inhaled mannitol, inhaled corticosteroids) will be withheld 
prior to study specified spirometry according to Section 6.3.6
5.6.
Accountability for Study drug
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). 
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug

Record the date, subject number, the study drug kit number dispensed

Record the date, quantity of used and unused study drug.
For additional information about study drug accountability and return, refer to Section 9.1.7.


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5.7.
Rescreening of Study Subjects
Subjects may be rescreened only once if they meet no more than 1 of the criteria below. 
A request for rescreening form must be completed and approved by the medical monitor prior to 
a subject rescreen.
If a subject is randomized but not dosed due to a safety concern after the FRI has occurred, the 
subject may be rescreened with Medical Monitor approval, and may opt to not participate in the 
FRI sub-study at that site. 
1) A subject is unable to produce adequate sputum during the first attempt during screening for 
any required inclusion/exclusion criteria related to sputum bacteriology.  
2) A subject that requires a new course of oral or IV antibiotics, systemic corticosteroids or is 
hospitalized during screening, may rescreen 30 days after hospital discharge or at least 
30 days after the last course of antibiotics/corticosteroids
3) Any acute “non-CF related” illness within 2 weeks prior to Baseline (eg, gastroenteritis). 
4) An investigator may petition the medical monitor for a rescreen of subject for a 
single criterion that is not mentioned above providing details and rationale for the rescreen 
and completing a request for rescreening form.


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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 in Table 6-1 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).
6.1.
Details of Study Visits
6.1.1.
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 or 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 released to initiate dosing until: 

The Institutional Review Board (IRB) or Ethics Committee (EC) 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 investigator 
responsibilities.  


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Table 6-1.
Schedule of Assessments
Screening
Baseline
Randomization
Optional 
PK
Study Drug
Administration Visits
Optional 
PK
Study Drug
Administration 
Visit
Primary 
Endpoint
Optional Open-Label
Extension
30-Day 
Follow-Up 
Visit
Early 
Termination 
Visit
Week
Baseline
1
2
3
4
5
6
7
8
9
10
11, 
13-15, 
17-19, 
21-23
12
16
20
24
Day
-30 to -1
1l
5
8
15
22
29
36
43
48
50
57
64
71
85
113
141
169
Window in days
±1
±3
±3
±3
±3
±3
±3
±1
±3
-3 to + 4
±3
±3
±3
±3
±3
±3
±3
±7
Home Health Visit Option
X
X
X
X
X
Withhold all inhaled CF 
therapies morning of study 
visit
Xq
X
X
X
X
X
X
X
X
X
Written Informed Consent
X
CFQ-Ra
X
X
X
X
X
X
X
X
X
X
X
TSQM (if available)a
X
X
X
X
X
X
X
SNOT-22  (if available)a
X
X
X
Medical History 
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary Exacerbation 
Evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examb
X
X
X
Symptom Driven Physical 
Examb
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for Safety Labsc
X
X
X
X
X
X
X
X
ESRr
X
X
X
Urine Cotinine
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
Serum Pregnancy Testd
X
X
X
Urine Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X
Oxygen Saturation
X
X
X
X
Screening Spirometry
Xm


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Screening
Baseline
Randomization
Optional 
PK
Study Drug
Administration Visits
Optional 
PK
Study Drug
Administration 
Visit
Primary 
Endpoint
Optional Open-Label
Extension
30-Day 
Follow-Up 
Visit
Early 
Termination 
Visit
Week
Baseline
1
2
3
4
5
6
7
8
9
10
11, 
13-15, 
17-19, 
21-23
12
16
20
24
Day
-30 to -1
1l
5
8
15
22
29
36
43
48
50
57
64
71
85
113
141
169
Window in days
±1
±3
±3
±3
±3
±3
±3
±1
±3
-3 to + 4
±3
±3
±3
±3
±3
±3
±3
±7
Home Health Visit Option
X
X
X
X
X
Pre- and post-bronchodilator 
Spirometrye
X
X
X
X
X
X
X
X
X
X
PEFR
X
Xp
X
X
X
X
X
X
X
Chest X-rayf
X
ECG
X
X
X
X
X
X
X
Induced sputum for 
biomarkers
X
X
X
X
X
X
X
Spontaneous sputum for 
microbiology g
X, X
X
X
X
FRI Scanh
X
X
Blood for PKi
X
X
X
X
X
X
X
PK sub-study
X
X
Anti-drug Antibodies
X
X
X
X
X
X
X
Blood for Biomarkers
X
X
X
X
X
X
X
Blood for RNA Biomarkers 
X
X
X
X
X
Blood for CF genotypingj
X
Optional blood sample for 
genomic researchj
X
Randomization
X
Study drug administrationk
X
X
X
X
X
X
X
X
Xn
X-weekly through week 23-X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Xo
Xo
Xo
X
X
X
Musculoskeletal Symptom 
Assessment
X
X
X
X
X
X
X
X
X
a
Questionnaires should be obtained prior to any other procedures. At visits where there are multiple questionnaires, the CFQR should be completed first, then SNOT-22 and 
then TSQM. If on a given visit SNOT-22 is not done then the CFQ-R is completed first and then the TSQM.


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b
Includes height at screening visit and weight at all visits and to be conducted prior to dosing. A complete physical examination will be performed at screening and the 30-day 
Follow-up Visit. A symptom-driven physical examination will be performed at the Baseline, Week 4, 8, 12, 16, 20 and 24, and can be performed as needed at other study 
visits.
c
Safety labs include CBC with differential, chemistry panel.  
d
For female subject post-menopausal for less than 2 years, if FSH 40 mIU/ mL a serum pregnancy test will be required.
e
Subjects will withhold their standard of care inhaled CF therapies prior to study specific spirometry
f
Chest x-ray will be obtained during the screening period if subject does not have a CT scan, MRI or chest x-ray obtained in the 90 days prior to Baseline.  
g
Spontaneous and induced sputum should be obtained AFTER spirometry and FRI (if applicable) have been completed. If spontaneous sputum cannot be obtained, a throat 
swab may be used for microbiology culture. A second spontaneous sputum microbiology for culture will be collected in the screening period. 
h
For subjects enrolled in the FRI sub-study only.  Subjects will withhold their standard of care inhaled CF therapies prior to FRI.
i
At Baseline, PK should be obtained prior to and 2 hours after study drug administration. At all other visits with study drug dosing, PK should be performed prior to study 
drug administration.  Subjects who consent to the optional PK sub-study will have one additional single PK sample collected at Day 5 (±1) and Day 48 (±1). Optional Day 5 
PK and Day 8 should occur at least 1 day apart.
j
Blood for CF genotyping should be taken at baseline for subjects who do not have a historical genotype on file, but may be collected at any time during the study, 
if necessary.  Blood for optional genomic research should only be taken from subjects who consented to this optional procedure. It should be taken at baseline, but may be 
collected at any time during the study, if necessary.   
k
Observe subject for 2 hours after study drug administration on Day 1, and for 30 minutes after study drug administration at all other visits during the blinded phase of the 
study. 
l
The baseline/randomization visit may be split over 2 days as needed.  If the visit is split over 2 days, the following procedures should be done on the first day prior to standard 
of care inhaled CF therapies as indicated in Section 5.5: questionnaires, urine pregnancy test (for women of childbearing potential only), oxygen saturation, pre- and 
post-bronchodilator spirometry, and FRI.  Subjects must withhold their standard of care inhaled CF therapies again the next morning and perform spirometry prior to any 
remaining study procedures and study dosing.  The day on which the first dose of study drug is administered is Baseline. 
m
Two spirometry measures (pre-bronchodilator) taken at least 4 days apart (one during Screening, one at Baseline) must be taken to meet inclusion criterion 7.  
n
Study drug dosing will occur at Week 8 only for subjects who elect to enroll in the open-label extension and only after all other procedures have been completed.
o
Subjects enrolled into the open-label extension may request assistance administering the SC injections either by returning to the clinic or utilizing a home health care service 
provided by the Sponsor to ensure proper dosing and adherence. If determined acceptable by the DMC, home self-administration may be conducted in the OLE.
p
PEFR will be performed at Baseline only if baseline procedures are conducted over 2 days and induced sputum was conducted on Day -1 to confirm subjects are stable 
enough to be dosed.
q
As screening will occur over at least two different days, subjects should only be asked to withhold these medications the morning of their screening spirometry assessment 
and only after they have been properly consented.
r
To be conducted at the site’s local lab. 


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Figure 6-1.
Suggested Schedule for Key Screening and Baseline Procedures
6.1.2.
Screening Period (Day -30 to -1)
Subjects will be screened up to 30 days prior to randomization/enrollment to determine 
eligibility for participation in the study. Written informed consent must be obtained from each 
subject before initiation of any Screening procedures. After informed consent is obtained,
screening procedures outlined in Table 6-1 and described in the following text will be initiated. 
The screening procedures may require multiple visits.  Medical history taken during 
Screening will also include a 1-year history of hospitalizations and IV, inhaled, and oral 
antibiotic therapy for pulmonary exacerbations.  


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Two pre-bronchodilator screening spirometry measures taken at least 4 days apart (one during 
Screening, one at Baseline) must be taken to meet Inclusion Criterion 7 (see Section 6.3.6).  
Subjects meeting all of the inclusion criteria and none of the exclusion criteria are eligible for 
Randomization (Baseline).  Subjects who do not meet the eligibility criteria will be excluded 
from randomization and may be considered for rescreening for the study in consultation with the 
medical monitor.  
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs, as well as any AEs related to protocol-mandated procedures on the AE case 
report form (CRF/eCRF).  All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history are to be captured on the 
medical history CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for 
additional details.
6.1.3.
Baseline/Randomization (Day 1)
All Baseline tests and procedures must be completed prior to randomization and dosing on Day 1
as indicated in Table 6-1. 
If subjects are unable to complete all Baseline assessments in a single day, the 
baseline/randomization visit may be split over 2 consecutive days as needed. If the visit is to be 
split over 2 days, the following procedures may be done on the first day and should be done prior 
to standard of care inhaled CF therapies as indicated in Section 5.5:

Refer to Figure 6-1 for recommended visit schedule and order of procedures for Screening 
and Baseline visits. 

Sputum induction and blood draws for safety and pre-dose PK can be performed on either 
day of the baseline/randomization visit, but must be performed prior to study drug dosing.  

At the Baseline/Randomization visit, subjects who meet the eligibility criteria will be 
randomized into the study. Study drug should be administered after randomization. Subjects 
will be observed for 2 hours after the last injection. Blood for PK will also be obtained 
2 hours after the last injection of study drug. Day 1 will be the day on which the subject 
receives the first dose of study drug.  
6.1.4.
Blinded Treatment Period: Day 5 through Week 7
At visits in the blinded treatment period, subjects should complete the CFQ-R, SNOT-22, and 
the TSQM prior to all other procedures when indicated in Table 6-1. At visits where study drug
dosing is indicated, the subject should be observed for 30 minutes after the last injection.  
Subjects who provide separate consent for the PK sub-study will provide a Day 5 plasma PK 
sample. At the Day 48 visit blood for PK will be obtained.  


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For sites and subjects utilizing home health services for at home dosing of study drug, site staff 
should instruct the subject on the packaging, storage, self-administration, and safe needle 
disposal for GS-5745. Following 2 successful doses in clinic within the blinded period, 
the subjects and the site may choose to utilize the home health service (See Section 6.1.6 for 
further information). If the home health option is utilized, subjects will be dispensed GS-5745 at 
the visit prior to the scheduled home health visit for Weeks 3, 5, and 7 within the blinded period.
Subjects will perform peak expiratory flow rate measurements prior to study drug administration
on days when study spirometry is not performed.  Doses should be administered at 1 week 
intervals (±3 days), all injections for a single dose should be delivered within 1 hour, and the 
date/time of administration will be recorded.  Please refer to the Pharmacy Manual for additional 
information.
6.1.5.
Week 8 (-3 to + 4): Primary Endpoint and Open-Label Extension
All Week 8 tests and procedures must be completed prior to participating in the OLE and dosing
as indicated in Table 6-1. 
Subjects who agree to participate in the OLE portion of the study will be entered into the IXRS 
to confirm enrollment into the open-label extension after all other procedures as indicated in 
Table 6-1. The first dose of open-label GS-5745 should be dispensed as directed by IXRS and 
administered to the subject at Week 8.  Sites should train the subject on administration of the 
study drug at this visit.  Subjects will be observed for 30 minutes after the last injection for the 
first 2 doses.  
If the home health option is utilized during OLE, subjects will be dispensed GS-5745 at the visit 
prior to the scheduled home health visit for Weeks 11, 13 to 15, 17 to 19 and 21 to 23.
Subjects who do not agree to participate in the OLE portion of the study will be discontinued 
from the study and will be asked to return to the clinic in 30 days for their 30-day Follow-up visit 
as indicated in Table 6-1.
6.1.6.
Utilization of Home Health Services
Weekly clinic visits during the study may pose a significant burden to study subjects. 
This burden must be balanced against the need to closely monitor these potentially vulnerable 
subjects during the early doses of study drug. Therefore, sites and subjects will have the option 
of utilizing a home health nursing organization provided by the Sponsor to complete visit 
procedures and study drug dosing during selected visits during the blinded and OLE portions of 
this study. Should the subject and site choose to utilize the home health service, blinded study 
visits at Weeks 3, 5, 7 and OLE visits at Weeks 11, 13 to 15, 17 to 19 and 21 to 23 may occur at 
the subject’s home. The DMC and Gilead will be closely monitoring SC injection safety 
throughout the study. If it is judged in the OLE phase of the study that home self-administration 
without a home health provider present does not pose an unacceptable safety risk, then subjects 
may be trained for SC self-injection. Once the subject has successfully completed the 
self-administration training and is judged as capable of home SC self-administration of study 
drug by the trainer, the subject may begin self-administration of study drug at home without 
supervision at any of the remaining OLE visits mentioned above.


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6.1.7.
Open-Label Extension: Week 9 through 24
All OLE tests and procedures should be completed as indicated in Table 6-1 for subjects 
participating in the OLE only. 
At Week 9 and 10 site staff should instruct the subject on the packaging, storage, 
self-administration, and safe needle disposal for GS-5745. Following 2 successful doses in clinic 
within the OLE, subjects will be dispensed GS-5745 to administer Weeks 11, 13 to 15, 17 to 19, 
and 21 to 23 doses at home by a qualified home health service selected by the Sponsor to ensure 
proper dosing and adherence.  In the OLE subjects will perform peak expiratory flow rate 
measurements prior to study drug administration on days when study spirometry is not 
performed.  Doses should be administered at one week intervals (±3 days), all injections for a 
single dose should be delivered within 1 hour, and the date/time of administration will be 
recorded. Please refer to the Pharmacy Manual for additional information.
6.1.8.
30-Day Follow-Up Visit 
Thirty days after the last dose of study drug, subjects will return to the clinic for a follow-up 
visit.  Procedures should be completed as indicated in Table 6-1.  
6.1.9.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.1.10, 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. If the subject is withdrawn from the study, the following Early Termination 
procedures should be performed if possible:

Administer CFQ-R (prior to any procedures), SNOT-22 and TSQM

Review of AEs and concomitant medications

Complete physical examination including body weight

Obtain vital signs

Obtain serum pregnancy test (for females of child-bearing potential only)

Obtain blood for PK, ADA analysis, and biomarkers 

Obtain blood and urine for safety lab

Obtain oxygen saturation 

Obtain pre- and post-bronchodilator spirometry

Obtain induced sputum


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6.1.10.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness and/or 
fever, and in collaboration with the medical monitor, the investigator may decide to allow the 
subject to resume study dosing.

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

Pregnancy during the study; refer to Appendix 3

Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB/IEC
6.2.
End of Study
The end of this study is defined as the date of the last study visit of the last study subject. 
6.3.
Details of Scheduled Assessments
6.3.1.
Physical Exam
A complete physical exam will be performed at Screening and the 30-day Follow-up Visit.
A symptom-driven physical exam will be performed at Baseline, Weeks 4, 8, 12, 16, 20, and 24,
and can be performed as needed at other study visits. 
All physical exams will include a body weight measurement.  Height will be captured at 
Screening only.  
A musculoskeletal symptom assessment will be conducted at Screening, Baseline, and at 
Weeks 4, 8, 12, 16, 20, 24, and 30-day follow-up visit.
6.3.2.
Vital Signs
Vital signs to be collected include resting blood pressure, pulse, respiratory rate and temperature.  


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6.3.3.
CFQ-R, TSQM, and SNOT-22 Questionnaires
The CFQ-R is a CF-specific quality of life measure encompassing both generic and CF-specific 
domains for a 2-week recall period. Because all study subjects will be 18 years of age or older, 
only the self-administered version of the questionnaire will be used in this study. 
The questionnaire takes approximately 15 minutes to complete and will be administered before 
any other study procedures at study visits indicated in Table 6-1. This questionnaire will be in 
electronic form and accessed on a secure website using a PC or laptop computer, 
where available. 
The TSQM questionnaire is a generic medication acceptance measure designed to assess 
effectiveness, side effects, convenience, and global satisfaction. It is self-administered 
questionnaire that takes approximately 15 minutes to complete and will be administered before 
any other study procedures at study visits indicated in Table 6-1. This questionnaire will be in 
electronic form and accessed on a secure website using a PC or laptop computer.  
The Sino-nasal Outcome Test (SNOT-22) is a symptom-based rhinosinusitis outcome measure. 
The questionnaire is self-administered with 22 questions that takes approximately 15 minutes to 
complete. It will be administered before any other study procedures at study visits as indicated in 
Table 6-1. This questionnaire will be in paper form.  
Questionnaires should be obtained prior to any other procedures. At visits where there are 
multiple questionnaires, the CFQR should be completed first, then SNOT-22 and then TSQM. 
If on a given visit SNOT-22 is not done then the CFQ-R is completed first and then the TSQM.
6.3.4.
Pulmonary Exacerbation Evaluation
A modified version of the Fuchs criteria {Ramsey et al 2011, Wainwright et al 2015} will be 
used for categorization of pulmonary exacerbations during the course of the study. A pulmonary 
exacerbation is defined as a change in antibiotic therapy (IV, inhaled, or oral) for any 4 or more 
of the following 12 signs/symptoms. New or changed antibiotic therapy from the previous visit 
for the following sinopulmonary signs/symptoms will be determined at all visits and documented 
in the source documents:

Change in sputum

New or increased hemoptysis

Increased cough

Increased dyspnea

Malaise, fatigue, or lethargy

Temperature above 38ºC


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
Anorexia or weight loss

Sinus pain or tenderness

Change in sinus discharge

Change in physical examination of the chest

Decrease in pulmonary function by 10 percent or more from a previously recorded value

Radiographic changes indicative of pulmonary infection
6.3.5.
Oxygen Saturation
Oxygen saturation by pulse oximetry will be performed as indicated in in Table 6-1. Sites should 
follow their institutional guidelines for pulse oximetry. If a subject is on oxygen this should be 
measured after they have been off oxygen for at least 5 minutes. 
6.3.6.
Spirometry
All sites will be provided with centralized spirometry equipment to be used for spirometry 
assessments throughout the study. Spirometry data will be transmitted to a centralized spirometry 
vendor for quality review. In the Screening period, spirometry will be collected pre and 
post-bronchodilator, subjects are required to withhold their inhaled CF therapies including all 
bronchodilators.  Two pre-bronchodilator spirometry measures are required using the study 
provided central spirometry equipment to meet the inclusion criteria. If a subject’s Screening 
pre-bronchodilator FEV1 % is 38-39.9% or 80.1-82% the upper limit FEV1 % inclusion, baseline 
spirometry may be repeated one time assuming all other inclusion/exclusion criteria have been 
met. If a subject’s relative change in FEV1 % at Baseline from Screening is 12.1-14% the upper 
limit FEV1 % inclusion, baseline spirometry may be repeated one time assuming all other 
inclusion/exclusion criteria have been met.
At all visits after Screening, including Baseline, spirometry should be performed at 
approximately the same time of the morning on designated study-specific days in Table 6-1.
ATS guidelines should be followed for all PFT maneuvers as well as for selecting specific PFT 
efforts to report {American Thoracic Society Committee on Diagnostic Standards for Non-
Tuberculous Respiratory Diseases 1995}. Spirometry collected at Baseline and Week 8 visits 
will be reviewed for quality by the central spirometry vendor in real time to ensure that 
acceptable measurements are selected and to reduce variabliltiy at the Baseline visit. 
Additional study-specific PFT guidelines are outlined below. 
Standard of care inhaled CF therapies (eg, bronchodilators, dornase alpha, inhaled antibiotics, 
hypertonic saline, inhaled corticosteroids) will be withheld prior to study specified spirometry in 
the treatment and follow-up period as follows:


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Pre-bronchodilator spirometry is defined as occurring after a subject has:

Withheld their short-acting beta-agonist (eg, albuterol/salbutamol) or anticholinergic 
(eg, ipratropium bromide) for more than 4 hours before the spirometry assessment; AND

Withheld their long-acting bronchodilator (eg, salmeterol) for more than 12 hours before the 
spirometry assessment; AND

Withheld their once-daily, long-acting bronchodilator for more than 24 hours before the 
spirometry assessment. 
See Appendix 5 for specific inhaled washout details.
Doses of bronchodilators taken within the previous 24 hours of spirometry will be recorded for 
each spirometry assessment.  
Post-bronchodilator is defined according to ATS guidelines, occurring approximately 15 minutes 
after 4 puffs of a bronchodilator (ie, albuterol, salbuterol, or levalbuterol).
With the exception of the screening period, at all visits at which spirometry is indicated, both a 
pre-bronchodilator and a post-bronchodilator spirometry will be performed. In the event that a 
subject forgets to withhold their inhaled CF medications at Baseline or Week 8, the visit should 
be rescheduled to another date within the screening window.  At all other visits, if a subject 
forgets to withhold their inhaled CF medications, spirometry should be performed 
post-bronchodilator only and recorded as such.
On days of study drug administration at the study site the post-bronchodilator FEV1% predicted 
will be utilized as a safety measurement. If an individual subjects post-bronchodilator FEV1% 
predicted is either 1) <40% predicted, 2) >30% below the Baseline FEV1% predicted, or 3) PEF 
decreases by >30% from the mean obtained during Screening during non-spirometry visits, 
study drug dosing should be postponed and rescheduled during the study visit window. 
Subjects should not be informed of their study-related spirometry results during the Blinded 
Treatment Period (Baseline through Week 8) regardless if the subject prematurely discontinues 
treatment.  In addition, subjects should not be informed of their study drug allocation 
(active:placebo) until after all subjects have completed Part 1 of the protocol.
Refer to the Central Spirometry Study Manual for additional information about spirometry.
6.3.6.1.
Real-Time Central Spirometry Over-Read
At Baseline and at Week 8, critical FEV1 data points for the primary endpoint of the study, 
spirometry may be reviewed in real-time by the central spirometry reader. This real-time review 
should eliminate randomizing subjects that have unacceptable spirometry, exceed the FEV1
reversibility inclusion criterion, or at Week 8 have unacceptable spirometry and may prevent 
unnecessary radiation exposure for subjects performing FRIs at these visits.


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In the event that a real-time central spirometry over-read is not available at a given Baseline or 
Week 8 visit, the preferred option is to reschedule the subject for repeat spirometry (and FRI if 
applicable) within the study visit window. If this is not possible, the alternative will be to allow 
the study investigator to review the spirometry and if judged to be acceptable and meets the 
FEV1 reversibility criterion for Baseline, the subject may proceed to Randomization or Week 8
Visit FRI (if applicable). 
6.3.7.
Peak Expiratory Flow Rate (PEFR)
PEFR measurements are a simple and useful objective measure to assess current lung function. 
At Screening subjects will be given a peak flow meter and be instructed in its proper use. 
Daily serial AM assessments prior to morning CF inhaled medications and inhaled 
bronchodilators will be captured during Screening to obtain a target of at least 7 days or more of 
data. A mean AM pre-bronchodilator PEFR will be calculated. PEFR should be taken around the 
same time each morning. The mean AM PEFR value calculated at Baseline will be utilized as an 
anchor to assess an individual subject’s current lung function throughout the study.
On days of study drug administration that do not require study site spirometry (at study site or at 
subject’s home) an AM pre-bronchodilator PEFR will be obtained. If the best of 3 PEFR 
measurements is >30% below the mean PEFR Baseline value, a subject may administer 2-4 puffs 
of a short-acting bronchodilator and repeat the PEFR 15-20 minutes later. If post-bronchodilator 
PEFR remains >30% below the mean PEFR value then dosing of study drug should be 
postponed and rescheduled within the study window. 
Investigators may request subjects to perform additional unscheduled PEFR measurements 
throughout the study as judged by local clinical practice. These values should also be recorded. 
6.3.8.
Induced Sputum 
Induced sputum will be collected from subjects for analysis of biomarkers including, but not 
limited to, total and free-MMP9 and MMP9 activity. Refer to the Sputum Induction manual for 
details on the induced sputum procedure. 
6.3.9.
Spontaneous Sputum Collection for Bacterial Microbiology
Spontaneous sputum will be collected for analysis of microbiology (dominant species and CFU) 
only.  In the event that the subject cannot spontaneously expectorate sputum, a throat swab will 
be acceptable. Spontaneous sputum collected for microbiology will be sent to a central lab for 
analysis.  
A minimum of 0.5 mL or 0.5 g of sputum should be collected. Every effort should be made to 
obtain an expectorated sputum sample. If spontaneous sputum in not able to be collected at a 
scheduled spontaneous sputum visit, a throat swab for microbiology should be collected.  
Refer to Laboratory Manual for collection and shipping instructions. 


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Obtaining spontaneous sputum for microbiology prior to microbiology lab holidays or days the 
lab is closed is discouraged. 
The first spontaneous sputum sample culture results will be used to satisfy the negative 
Burkholderia spp. inclusion criterion.
Sputum and throat swabs for microbiology should be collected 4 hours or more after any inhaled 
antibiotics.
6.3.10.
Functional Respiratory Imaging – Sub-study only
Approximately 30 subjects (15 on 600 mg GS-5745, 15 on placebo) in Part 1 of the study and 
approximately 45 (15 on 300 mg GS-5745, 15 on 150 mg GS-5745, and 15 on placebo) subjects 
in Part 2 of the study will have FRI performed at a sub set of study sites as indicated in Table 6-1.  
Standard of care inhaled CF therapies (eg, bronchodilators, dornase alpha, inhaled antibiotics, 
hypertonic saline, inhaled mannitol, inhaled corticosteroids) will be withheld prior to spirometry 
and FRI. FRI should be performed after the bronchodilator is administered for spirometry, 
but prior to the standard of care inhaled CF medications.  In the event that a subject forgets to 
withhold their inhaled CF medications at Baseline or Week 8, the visit should be rescheduled to 
another date within the screening window.  
Every effort should be made to perform each FRI scan in the AM to avoid known potential 
diurnal variation in FEV1 values. In addition, every effort should be made to have the Week 8
FRI scan performed at the same time of day as the Baseline FRI +/- 3 hours. If the timing of the 
Week 8 FRI is > 4 hours the time of the Baseline FRI, then the Week 8 spirometry and FRI 
should be rescheduled within the study visit window. If this is not possible and the Week 8
spirometry are acceptable the subject may continue in the study, the Week 8 FRI study will be 
lost, and that FRI subject will need to be replaced.  Refer to the Fluidda FRI imaging manual for 
more information.
FRI imaging will be performed as described previously {De Backer et al 2010}. Briefly, a low 
dose multislice CT scan of the chest is taken at total lung capacity (TLC) and functional residual 
capacity (FRC). The radiation dose per scan is estimated to be on the order of 1 to 2 millisievert 
(mSv). A 2015 estimate for annual radiation exposure from natural sources from the U.S. 
Nuclear Regulatory Commission is 3.1 millisieverts. (ref) http://www.nrc.gov/reading-rm/doc-
collections/fact-sheets/bio-effects-radiation.html {United States Nuclear Regulatory Commission 
(USNRC) 2016}. Segmentation principles allow for quantification and visualization of the lung, 
lobar and airway volumes. Computational fluid dynamics is used to calculate airway resistance. 
FRI outcome parameters include: image-based lobar volume at FRC (iLobes_FRC), image-based 
airway volume at TLC (iVaw) and image-based airway resistance at TLC (aRaw). See the 
Fluidda FRI imaging manual for more details.


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6.3.11.
12-Lead ECG
A standard 12-lead ECG will be performed at screening, baseline, Week 4, 8, 16, 24 and the
30-day follow-up visit as indicated in Table 6-1. Sites should follow their institutional guidelines 
when performing the 12-lead ECG.  
6.3.12.
Laboratory Assessments
6.3.12.1.
Safety Laboratory Tests
Blood and urine will be collected for safety laboratory tests at time points indicated in Table 6-1.  
The tests will include complete blood count (CBC) with differential, chemistry panel, and 
urinalysis.  
6.3.12.2.
Urine Cotinine
Urine will be collected for a urine cotinine test at time points indicated in Table 6-1.
6.3.12.3.
Serum and Urine Pregnancy Tests
For females of childbearing potential, serum pregnancy tests will be done at Screening and at the 
30-day Follow-up Visit. Urine pregnancy tests will be performed for females of childbearing 
potential as indicated in Table 6-1, prior to FRI scans or any study drug administration at those 
visits. For additional information about the definition of childbearing potential, see Appendix 3
Section 2.  
6.3.12.4.
Erythrocyte Sedimentation Rate
Erythrocyte Sedimentation Rate (ESR): Collected at Screening, Week 8 and Week 24, and will 
be analyzed at the local lab. 
6.3.13.
Pharmacokinetic Assessments
6.3.13.1.
PK Blood Draws
Blood for PK analysis will be collected at time points as indicated in Table 6-1.  See Section 8.7
for additional information.  
6.3.13.2.
Serum Anti-Drug Antibodies
Blood will be collected for anti-drug antibodies at time points indicated in Table 6-1.  
6.3.13.3.
Blood Biomarker Samples
Blood for biomarkers will be collected at time points as indicated in Table 6-1. The analysis 
includes but is not limited to total and free MMP9, MMP9 activity and breakdown neo-epitopes 
of MMPs. Blood will also be collected at Baseline for CF genotyping for subjects who do not 
have a historical genotype on file.


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6.3.13.4. 
Biomarker Samples for Optional Genomic Research 
PD 
6.3.14. 
Sample Storage 
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The stored blood and sputum samples may be used by the Sponsor or its research partner 
for future clinical laborat01y testing to provide additional clinical data. At the conclusion of this 
study, these samples may be retained in storage by Gilead at its research partner facility for a 
period of up to 15 years. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An 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, overdose, drug abuse/misuse reports, or occupational exposure. Preexisting 
events that increase in severity or change in nature during or as a consequence of participation in 
the clinical study will also be considered AEs.
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.
7.1.2.
Serious Adverse Events
A SAE is defined as an event that, at any dose, results in the following:

Death

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


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
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.
7.1.3.
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, electrocardiogram, 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 (ie, decreased hemoglobin). For specific information on handling of clinical 
laboratory abnormalities in this study, please refer to Section 7.5.
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.
7.2.1.
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.


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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.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03.  See Section 7.5.  
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
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 30 days after last administration of study drug.  These AEs must be reported to the 
CRF/eCRF database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow-up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported. 


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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 DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’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 information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead Sciences DSPH
Fax: +1 (650) 522-5477
Email: Safety_fc@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, 
no further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment 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 
form.
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 regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs),


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or suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU 
Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent DMC (as described in 
Section 8.11). The DMC may have access to partially blinded or unblinded data and will make 
recommendations regarding the study according to the DMC charter. 
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, electrocardiogram, 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 (ie, 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 7.1.3.
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/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 Section 7.5 and Appendix 3.

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.


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
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
Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to Baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.


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7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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.  
7.7.2.
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 DSPH 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.
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.


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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 DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
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 DSPH 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 DSPH, 
fax number +1 650 522-5477 or email Safety_FC@gilead.com. Refer to Appendix 3 for 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive 
Requirements.
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 DSPH 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. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objective of this study is as follows: 
Final 
Amendment2 
• 
To evaluate the effect of GS-5745 on pre-bronchodilator FEV1% predicted in subjects with 
CF after 8 weeks of treatment 
The secondmy objectives of this study m·e as follows: 
• 
To assess safety, tolerability, and PK ofGS-5745 in subjects with CF 
• 
To evaluate the effect of GS-5745 on post-bronchodilator FEV1% predicted in subjects with 
CF after 8 weeks of treatment 
Explorat01y objectives of this study m·e as follows: 
IT 
I 
I 
I 
I 
I 
I 
8.1.2. 
Primary Endpoint 
• 
The absolute change in pre-bronchodilator FEV 1 percent predicted from Baseline to Week 8 
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8.1.3.
Secondary Endpoints
8.1.3.1.
Efficacy Endpoints

The absolute change in post-bronchodilator FEV1 percent predicted from Baseline to Week 8

The relative change in pre-bronchodilator FEV1 percent predicted from Baseline to Week 8

The relative change in  post-bronchodilator FEV1 percent predicted from Baseline to Week 8
8.1.3.2.
Safety Endpoints
The safety evaluation will be assessed by AEs, concomitant medications, clinical laboratory 
tests, vital signs and ADA data.
8.1.3.3.
Pharmacokinetic Endpoints
Primary PK parameters will include Cmax, Tmax, Clast, Tlast, and AUClast (as applicable)
8.1.4.
Other Endpoints of Interest

Changes from Baseline in total and free MMP9 concentration and enzyme activity in sputum 
and/or blood

Change from Baseline in FRI

Change from Baseline in CFQ-R-RSS

Change from Baseline in TSQM

Change from Baseline in SNOT-22 score

Change from Baseline in body weight

Change from Baseline in sputum bacterial CFUs

Change from Baseline in other biomarkers related to MMP9 pathway

Change from Baseline in sputum cytology

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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is defined as the Full Analysis Set (FAS), 
which includes all subjects who were randomized into the study and received at least 1 dose of 
study drug.  
Subjects will be analyzed according to the treatment group to which they are randomized. 
8.2.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set. The Safety Analysis Set 
includes all subjects who received at least 1 dose of study drug.
Subjects will be analyzed according to the treatment they actually receive. 
8.2.1.3.
Pharmacokinetics
The PK Analysis Set includes all subjects who were randomized and have received at least 
1 dose of study drug and for whom concentration data of GS-5745 are available. 
Subjects will be analyzed according to the treatment they actually receive. 
8.2.1.4.
Biomarkers
The Biomarker Analysis Set includes all subjects who were randomized and have received 
at least 1 dose of study drug and for whom biomarker data are available.
Subjects will be analyzed according to the treatment they actually receive. 
8.3.
Data Handling Conventions
Values for missing safety laboratory data will not be imputed. However, a missing Baseline 
result will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the Baseline value will be assumed to be normal (ie, no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. If safety laboratory results for a subject are missing 
for any reason at a time point, the subject will be excluded from the calculation of summary 
statistics for that time point.
Values for missing vital signs data will not be imputed. However, a missing Baseline result will 
be replaced with a screening result, if available.


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8.4.
Demographic Data and Baseline Characteristics
Demographic and Baseline measurements will be summarized using standard descriptive 
methods for continuous variables and number and percentage of subjects for categorical 
variables. 
Demographic summaries will include sex, race/ethnicity, and age. Baseline data will include a 
summary of body weight, height, BMI, spirometry measurements, patient-reported outcome 
scores. Additional Baseline characteristic variables may be added if necessary.
8.5.
Efficacy Analysis
The primary endpoint, the absolute change in pre-bronchodilator FEV1 percent predicted from 
Baseline to Week 8, will be analyzed using a mixed effect model for repeated measure (MMRM) 
for Part 1 and Part 2 respectively. The model for each part of the study will include treatment, 
Baseline FEV1 percent predicted level, visit and treatment-by-visit interaction as fixed effect, and 
subject as a random effect. Estimated least square means of treatment effects and estimated 
differences in treatment effects between GS-5745 treatment group and placebo group at Week 8
will be presented with the 90% confidence intervals (CIs) and adjusted p-values.
Analyses of absolute change in post-bronchodilator percent predicted FEV1, relative change in 
pre and post -bronchodilator percent predicted FEV1 and other endpoints listed in Section 8.1.4
will be discussed in the statistical analysis plan (SAP). In general, continuous endpoints with 
repeated measures will be analyzed using the MMRM model. For change in FRI and SNOT-22, 
an ANCOVA model with corresponding baseline values as covariate will be used. Categorical 
endpoints will be analyzed using MMRM and non-parametric tests. All endpoints will be 
summarized using descriptive statistics (n, mean, standard deviation [SD], median, Q1, Q3, 
minimum, and maximum) for continuous data and by the number and percent of subjects for 
categorical data.
8.6.
Safety Analysis
Safety endpoints will be analyzed by the number and percentage of subjects for categorical 
variables or 8-number summary (n, mean, standard deviation, median, first quartile [Q1], 
third quartile [Q3], minimum, and maximum) for continuous variables.  
All data collected during the course of study will be included in data listings. Additional details 
will be provided in the SAP.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration and study drug accountability eCRF pages. The number of doses administered 
and the level of adherence will be summarized.


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8.6.2.
Adverse Events
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.
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.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. 
In addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from Baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Section 7.5.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from Baseline at any time post Baseline will be summarized. If Baseline data 
are missing, then any graded abnormality (ie, at least a Grade 1) will be considered treatment 
emergent.
8.6.4.
Other Safety Evaluations
Individual data for physical examination findings, prior and concomitant medications and 
medical history will be provided. Vital signs measurements will be listed by subject and 
summarized by incidence of events/abnormalities or descriptive statistics as appropriate.
8.7.
Pharmacokinetic Analysis
The plasma concentration data of GS-5745 will be summarized by nominal sampling time and 
treatment using descriptive statistics (ie, n, arithmetic mean, geometric mean, coefficient of 
variation (%) standard deviation, median, minimum, and maximum). For the PK substudy, 
PK parameters (Cmax, Tmax, Clast, Tlast, and AUClast, as applicable) may be listed and summarized 
using descriptive statistics. Plasma concentrations over time may also be plotted in 
semi-logarithmic and linear formats as mean ± standard deviation, and median (Q1, Q3) for PK 
sub-study. Exposure-response analysis may be performed.


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8.8.
Immunogenicity Analysis
Immunogenicity of GS-5745 will be evaluated based upon the incidence of anti-drug (GS-5745) 
antibody (ADA) formation. The number and percentage of subjects exhibiting positive ADA 
results at each specified time point will be summarized. ADA results with supporting data will be 
included in a listing as well. Impact of ADA on GS-5745 PK, safety, and efficacy will also be 
evaluated as applicable.
8.9.
Biomarker Analysis
The changes from Baseline at Week 8 in total and free MMP9 and MMP9 activity in sputum and 
blood will be analyzed using an analysis of variance model or a mixed effect model for repeated 
measure for comparing GS-5745 to placebo cohorts.  Estimated least square means and 90% 
confidence intervals (CI) of the changes from baseline will also be reported for each cohort as 
well as for difference between GS-5745 and placebo cohorts. 
Analysis for other biomarkers and additional exploratory analyses will be discussed in 
Biomarker Analysis Plan (BAP).
8.10.
Sample Size
A sample size of 25 evaluable subjects per arm for Part 1 and Part 2 will provide 80% power to 
detect a difference of 5% in percent predicted FEV1 absolute change from Baseline between 
GS-5745 active treatment and placebo with a 2-side alpha level of 0.1 assuming a common SD 
of 7% {Brouwer et al 2014, Ramsey et al 2011, Retsch-Bogart et al 2009}. To compensate for 
early drop out, 30 subjects per arm will be enrolled assuming an attrition rate of 15%.
With respect to the sub-study in FRI, a sample size of 15 subjects on GS-5745 and 15 subjects on 
placebo provides more than 90% power to detect a 6% difference between the GS-5745 and 
placebo arms in FRI change from Baseline based on a 2 sample t-test at a 2-sided alpha level of 
0.1. The calculation assumes SD of FRI change being 5% for the GS-5745 arm and 2% for the 
placebo arm as the FRI response is expected to be more heterogeneous in the treatment group.
8.11.
Data Monitoring Committee
An independent multidisciplinary DMC will review the progress of the study and perform
interim reviews of safety data. A total of 4 scheduled DMC meetings will occur throughout 
Part 1 and prior to the end of Part 2 of the study as outlined below. 
Part 1: Safety Analysis #1
Because GS-5745 has not been administered previously to CF subjects, the DMC will review the 
unblinded safety data after 10 subjects (~5 active and ~5 placebo) have completed the Week 2
Visit or have prematurely discontinued from the study. Enrollment will continue during the 
DMC review process.


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Part 1: Safety Analyses #2 
The DMC will review the unblinded safety data after 30 subjects (~15 active and ~15 placebo) 
have completed the Week 8 Visit or have prematurely discontinued from the study.
Enrollment will continue during the DMC review process.
Part 1: Safety Analyses #3 and Interim Efficacy Analysis
An interim efficacy and safety analysis will be performed when all 60 subjects (~30 active and 
~30 placebo) have completed the Week 8 Visit or have prematurely discontinued from the study. 
The DMC and a select number of Gilead employees not directly involved in the study conduct 
will review the unblinded data. 
With no safety concern, an estimated mean difference in absolute FEV1% predicted between 
GS-5745 and placebo being ≥ 5% may trigger the initiation of Part 2. If the mean difference is 
< 2%, Part 2 may not be initiated. A comprehensive review of safety, FEV1, FRI and other 
efficacy data including sputum MMP-9, CFQ-R, SNOT-22, TSQM, and CF exacerbation will be 
conducted before the decision is made to advance to Part 2 of the study. Enrollment of subjects 
into Part 2 of the study will be postponed until after the completion of the third DMC and 
unblinded Gilead review of the data.
Part 2: Safety Analysis #4 
The DMC will review the unblinded safety data after 45 subjects (~ 15 in each treatment group) 
have completed the Week 8 Visit or have prematurely discontinued from the study. 
Enrollment will continue during the DMC review process.
8.12.
Interim Analyses
To determine if Part 2 of the study should be initiated, an interim analysis will be conducted 
when all the randomized subjects from Part 1 have completed the Week 8 visit or discontinued 
from the study. Unblinded data from Part 1 will be used to evaluate drug safety and efficacy, 
which may result in a study amendment before the initiation of Part 2 of the study.
A Gilead internal unblinded team independent of the blinded study team will be assembled at the 
beginning of the study, which consists of medical monitor, statistical programmer, biostatistician 
and other personnel if necessary. The Gilead internal unblinded team will be granted the access 
to unblinded clinical data including treatment assignment to closely monitor study progress and 
drug safety. To mitigate the risks of inadvertently releasing the treatment information to the sites 
and subjects, the internal team will keep the unblinded information confidential and will not 
communicate the information to blinded study team, site staff or subjects. Data unblinding due 
to medical emergency will follow standard Gilead procedures.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under 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.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor 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.
9.1.3.
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 and before undertaking any study-related procedures. 


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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 sample 
retention, and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled 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 showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. 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 brochure, this protocol, CRF/eCRF, the IMP, 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.
9.1.5.
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 two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms,
IRB/IEC, 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 (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, 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 date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, 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.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  Subsequent to data entry, a study monitor will perform source data verification 


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within the EDC system. Original entries as well as any changes to data fields will be stored in 
the audit trail of the system.  Prior to database lock (or any interim time points as described in the 
clinical data management plan), 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. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator 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). At the conclusion of the trial, Gilead will provide the site 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 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. At the start of the study, the study 
monitor will evaluate each study center’s study drug disposal procedures and provide appropriate 
instruction for disposal or return of unused study drug supplies. If the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead Sciences, 
the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. This can occur only after the study monitor has 
performed drug accountability during an on-site monitoring visit. 
A copy of the site’s study drug disposal SOP or written procedure (signed and dated by the PI or 
designee) will be obtained for Gilead site files. If the site does not have acceptable procedures in 
place, arrangements will be made between the site and Gilead Sciences (or Gilead Sciences’ 
representative) for return of unused study drug supplies.
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
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 IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies.
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.
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 9.1.4).
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
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's 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 trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
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 on 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.
9.3.3.
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.
9.3.4.
Study Discontinuation
Both the sponsor 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 appropriate 
regulatory authority(ies), IRBs, and IECs. 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.
REFERENCES
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Efficacy of GS-5745 an Anti-Matrix Metalloproteinase 9 (MMP) Monoclonal 
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Boyle MP. Adult cystic fibrosis. JAMA 2007;298 (15):1787-93.
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Chmiel JF, Konstan MW, Accurso FJ, Lymp J, Mayer-Hamblett N, VanDevanter DR, et al. Use 
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Cystic Fibrosis Foundation. Patient Registry Annual Data Report to the Center Directors 2013.
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and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a 
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De Backer JW, Vos WG, Vinchurkar SC, Claes R, Drollmann A, Wulfrank D, et al. Validation 
of computational fluid dynamics in CT-based airway models with SPECT/CT. 
Radiology 2010;257 (3):854-62.


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Devereux G, Steele S, Jagelman T, Fielding S, Muirhead R, Brady J, et al. An observational 
study of matrix metalloproteinase (MMP)-9 in cystic fibrosis. J Cyst Fibros 
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Dmitrienko A, Offen WW, Westfall PH. Gatekeeping strategies for clinical trials that do not 
require all primary effects to be significant. Statist Med 2003;22 (15):2387-400.
European Cystic Fibrosis Society. ECFS Patient Registry: Annual Data Report (Version 
01.2014).  2010.
Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines 
for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis 
Foundation consensus report. J Pediatr 2008;153 (2):S4-S14.
Foundation CF. Patient Registry. Annual Data Report to the Center Directors, 2009. Cystic 
Fibrosis Foundation  2010.
Gaggar A, Li Y, Weathington N, Winkler M, Kong M, Jackson P, et al. Matrix metalloprotease-9 
dysregulation in lower airway secretions of cystic fibrosis patients. American 
journal of physiology. Lung cellular and molecular physiology 2007;293 (1):L96-
L104.
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections 
in cystic fibrosis. Am J Respir Crit Care Med 2003;168 (8):918-51.
Hahn C, Xu X, Gaggar A. Relationship Between Matrix Metalloprotease-9 Levels And Activity 
In Systemic And Pulmonary Compartments In Cystic Fibrosis Lung Disease. Am 
J Respir Crit Care Med. 2012;185 (2012):A2802.
Hill SL, Mitchell JL, Burnett D, Stockley RA. IgG subclasses in the serum and sputum from 
patients with bronchiectasis. Thorax 1998;53 (6):463-8.
Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with 
cystic fibrosis. N Engl J Med 1995;332 (13):848-54.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation 
for estimating glomerular filtration rate. Ann Intern Med 2006;145 (4):247-54.
Mogayzel PJ, Jr., Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, et al. Cystic 
fibrosis pulmonary guidelines. Chronic medications for maintenance of lung 
health. Am J Respir Crit Care Med 2013;187 (7):680-9.
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiator 
in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365 
(18):1663-72.


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Amendment 2
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Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, et al. 
Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas in cystic 
fibrosis. Chest 2009;135 (5):1223-32.
Roderfeld M, Rath T, Schulz R, Seeger W, Tschuschner A, Graf J, et al. Serum matrix 
metalloproteinases in adult CF patients: Relation to pulmonary exacerbation. J 
Cyst Fibros 2009;8 (5):338-47.
Sagel SD, Kapsner RK, Osberg I. Induced sputum matrix metalloproteinase-9 correlates with 
lung function and airway inflammation in children with cystic fibrosis. Pediatr 
Pulmonol 2005;39 (3):224-32.
U.S. Department of Health & Human Services (DHHS), Food & Drug Administration (FDA), 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER). Guidance for Industry: Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation.  July, 2009.
United States Nuclear Regulatory Commission (USNRC). Biological Effects of Radiation. 
Available at: http://www.nrc.gov/reading-rm/doc-collections/fact-sheets/bio-
effects-radiation.html. Accessed May.  2016.
Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor-
Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N 
Engl J Med 2015.


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Amendment 2
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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
Appendix 4.
Recommended General Process for Diagnosing CF {Farrell et al 2008}
Appendix 5.
Medications Washouts


GS-5745 
Protocol GS-US-404-1808 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404, USA 
STUDY ACKNOWLEDGEMENT 
A Phase 2b, Dose-Ranging Study of the Effect ofGS-5745 on FEV1 in Adult Subjects with 
Cystic Fibrosis 
GS-US-404-1808, Amendment 2, 25 May 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed) 
Author 
Date 
PPD 
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 infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 83 
25 May 2016 


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Amendment 2
CONFIDENTIAL
Page 84
25 May 2016
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 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator


GS-5745
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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 85
25 May 2016
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.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  
In addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
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 medical documentation.
2) Contraception Requirements for Female Subjects
a. Study drug Effects on Pregnancy and Hormonal Contraception
The risks of treatment with GS-5745 during pregnancy have not been evaluated in humans. 
The potential for genotoxicity is not expected given that GS-5745 is a monoclonal antibody and 
embryofetal toxicity is suspected based on nonclinical toxicological studies. Women of 
childbearing potential should be informed of the potential risk and use highly effective methods 
of birth control during treatment with GS-5745 from screening until 30 days after the end of 
relevant systemic exposure. Given that GS-5745 is a monoclonal antibody, a clinically relevant 
interaction between GS-5745 and contraceptive steroids is not suspected and therefore, hormonal 
contraception may be used as part of the birth control methods. Please refer to the latest version 
of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline visit prior to randomization.  At minimum, a pregnancy 
test will be performed at the end of relevant systemic exposure.  In the event of a delayed 
menstrual period (over one month between menstruations), a pregnancy test must be performed 


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 86
25 May 2016
to rule out pregnancy.  This is even true for women of childbearing potential with infrequent or 
irregular periods.  Female subjects must also agree to one of the following from Screening until 
30 days following the end of relevant systemic exposure.

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
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)
Or

Consistent and correct use of one hormonal method and one barrier method
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
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 at least 30 days after the end of relevant systemic exposure.


GS-5745
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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 87
25 May 2016
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment until at least 90 days after 
the end of relevant systemic exposure.
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 and discontinue study drug immediately if 
they become pregnant or if they suspect that they are pregnant at any time during the study or 
within 30 days of last study drug dose. Subjects whose partner has become pregnant or suspects 
she is pregnant during the study must report the information to the investigator.  Instructions for 
reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.7.2.


GS-5745
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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 88
25 May 2016
Appendix 4.
Recommended General Process for Diagnosing CF {Farrell et al 
2008}
In individuals presenting with symptoms of CF or a positive family history, the following 
diagnostic process is recommended: 
1) A diagnosis of CF can be made if the sweat chloride value is ≥60 mmol/L. A second, 
confirmatory sweat chloride test is recommended unless mutation analysis identifies the 
presence of 2 CF-causing mutations. These patients, who may present at any age, are likely 
to develop CF lung disease.
2) A sweat chloride value ≤39 mmol/L in individuals over age 6 months is not consistent with a 
diagnosis of CF. CF is unlikely in this group. However, 2 identified CF-causing mutations 
can occur in this group; these individuals have CF and should be followed in a CF care 
center.
3) Individuals with sweat chloride values in the intermediate range (30 to 59 mmol/L for infants 
under age 6 months; 40 to 59 mmol/L for older individuals) should undergo extensive CFTR 
mutation analysis (ie, expanded panel of CFTR mutations, evaluation for deletions, or gene 
sequencing):
a) In the presence of 2 CF-causing mutations, a diagnosis of CF can be made.
b) Individuals with no or 1 CF-causing mutation and clinical findings suggestive of CFTR 
dysfunction (ie, obstructive azoospermia, bronchiectasis, or acute, recurrent, or chronic 
pancreatitis) may be diagnosed with a CFTR-related disorder, depending on their clinical 
picture or family history, and are at risk for CF. Sweat chloride testing should be repeated 
in infants by age 2 to 6 months and immediately in older individuals. If sweat chloride 
values remain in the intermediate range on repeat testing, then further assessment should 
be performed at a CF care center that can provide basic and ancillary testing to clarify the 
diagnosis, including:

Clinical assessment

Expanded genetic testing

Exocrine pancreatic function tests

Respiratory tract culture for CF-associated pathogens, especially P aeruginosa.
Depending on clinical presentation, assessment also may include ancillary tests, such as: 

Genital evaluation in males (ie, genital examination, rectal ultrasound, semen analysis)

Pancreatic imaging

High-resolution chest CT


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 89
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
Bronchoalveolar lavage, including microbiology assessment

Pulmonary function testing (not routinely recommended in infants at this time)

NPD testing

Exclusionary testing for ciliary dyskinesia and immune deficiency.
Significant clinical signs or symptoms of CF, laboratory indication of PI, or a positive culture for 
a CF-associated pathogen (especially P aeruginosa), should be considered strongly suggestive of 
CF. Individuals who have sweat chloride values in the intermediate range and exhibit no 
significant signs of CF should be monitored periodically for the appearance of symptoms until 
the diagnosis can be ruled in or out.


GS-5745
Protocol GS-US-404-1808
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 90
25 May 2016
Appendix 5.
Medications Washouts
Inhaled Bronchodilators
Minimum Time Interval from Last Medication to 
Complete Lung Function Testing
Short-acting B2 agonists 
(salbutamol, albuterol, levalbuterol)
4 hours
Long-acting B2 agonists Q12hrs 
(salmeterol, fomoterol, arformoterol)
12 hours
Long-acting B2 agonists Q24hrs 
(indacaterol)
24 hours
Short-acting B2 anticholinergics  
(ipratropium  bromide)
4 hours
Long-acting anticholinergics  Q24 hrs 
(tiotropium bromide)
24 hours
Short-acting bronchodilator combos
(albuterol/ipratropium bromide)
4 hours
Long-acting bronchodilator  combos
(vilanterol and umeclidinium)
24 hours
Long-acting bronchodilator & corticosteroid 12 hrs 
(fomoterol/budesonide, salmeterol/fluticasone propionate)
12 hours
Long-acting bronchodilator & corticosteroid 24 hrs 
(vilanterol/fluticasone furoate)
24 hours
Oral Bronchodilators
Standard B2 agonist tablets
12 hours
Long-acting B2 agonist tablets
24 hours
Theophylline
24 hours
Roflumilast
24 hours

Prot_000.pdf: 


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