Clinical trial NCT02443688
Conditions: Cystic Fibrosis
Sponsor: Celtaxsys, Inc.
Start date: 2015-10-30; Completion date: 2018-05-16
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of CTX-4430 administered once-daily for 48 weeks for treatment of CF.

Detailed description:
This study is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of CTX-4430 administered once-daily for 48 weeks for treatment of CF. A total of 195 pulmonary CF patients that meet all the inclusion and no exclusion criteria and provide written informed consent will be randomized to receive 50 mg CTX-4430, 100 mg CTX-4430, or placebo in a 1:1:1 ratio. Follow-up visits will be conducted approximately every 4 weeks from Week 4 to Week 52 (4 weeks after completion of treatment).

Arms: arm 1: Once daily oral capsule for 48 weeks arm 2: Once daily oral capsule for 48 weeks arm 3: Once daily oral capsule for 48 weeks
Interventions: intervention 1: CTX-4430 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol 
 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy, Safety, and Tolerability 
of CTX-4430 Administered Orally Once-Daily for 48 Weeks in Adult 
Patients with Cystic Fibrosis 
Study Number: 
CTX-4430-CF-201 
Study Phase: 
2 
Test Product: 
CTX-4430 
 
 
 
 
Indication: 
Cystic Fibrosis 
Sponsor: 
Celtaxsys, Inc.  
201 17th Street, Suite 530 
Atlanta, GA  30363 
United States 
 
  
 
 
 
 
Version 
Date 
1.0 
26 MAY 2015 
2.0, Amendment 1 
17 JULY 2015 
3.0, Amendment 2 
05 SEPTEMBER 2015 
3.1, Amendment 2 
30 SEPTEMBER 2015 
4.0, Amendment 3 
19 November 2015 
5.0, Amendment 4 
04 May 2016 
 
Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Celtaxsys, except to the extent necessary to obtain informed 
consent from persons receiving the investigational product or their legal guardians, or for 
discussions with local Regulatory Authorities, Institutional Review Boards, Ethics 
Committees, or persons participating in the conduct of the study.  


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF TABLES .........................................................................................................................5 
SPONSOR SIGNATURE PAGE ..................................................................................................6 
INVESTIGATOR SIGNATURE PAGE......................................................................................7 
SYNOPSIS ......................................................................................................................................8 
LIST OF ABBREVIATIONS .....................................................................................................12 
1 
INTRODUCTION............................................................................................................14 
1.1 
Cystic Fibrosis ................................................................................................................14 
1.2 
CTX-4430 .......................................................................................................................15 
1.2.1 
Nonclinical Studies of CTX-4430 ...................................................................15 
1.2.2 
Clinical Trials of CTX-4430 ............................................................................16 
2 
OBJECTIVES ..................................................................................................................19 
2.1 
Primary Objectives..........................................................................................................19 
2.2 
Secondary Objectives......................................................................................................19 
2.3 
Exploratory Objectives ...................................................................................................19 
3 
STUDY DESIGN ..............................................................................................................20 
3.1 
Overall Study Design ......................................................................................................20 
3.2 
Rationale for Study Design .............................................................................................20 
3.2.1 
Study Population ..............................................................................................20 
3.2.2 
Study Treatments .............................................................................................21 
3.2.3 
Study Endpoints ...............................................................................................23 
3.3 
Independent Data Monitoring Committee ......................................................................23 
3.4 
Study Duration ................................................................................................................23 
4 
SUBJECT POPULATION ..............................................................................................24 
4.1 
Inclusion Criteria ............................................................................................................24 
4.2 
Exclusion Criteria ...........................................................................................................25 
5 
INVESTIGATIONAL PRODUCTS ..............................................................................27 
5.1 
CTX-4430 .......................................................................................................................27 
5.2 
Placebo ............................................................................................................................27 
5.3 
Packaging and Labeling ..................................................................................................27 
5.4 
Storage ............................................................................................................................27 
5.5 
Screening.........................................................................................................................27 
5.6 
Randomization ................................................................................................................28 
5.7 
Blinding and Unblinding.................................................................................................28 
5.8 
Administration of Investigational Products ....................................................................28 
5.9 
Concomitant Medications ...............................................................................................29 
5.10 Other Study Restrictions .................................................................................................29 
5.10.1 Subject Activity Restrictions ...........................................................................29 
5.10.2 Contraception ...................................................................................................29 
5.11 Compliance .....................................................................................................................30 


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6 
STUDY PROCEDURES .................................................................................................31 
6.1 
Blood Sample Volume ....................................................................................................31 
6.2 
Guidelines for Study Procedures ....................................................................................31 
6.2.1 
Administration of CFQ-R ................................................................................31 
6.2.2 
Adverse Events ................................................................................................31 
6.2.3 
Body Mass Index .............................................................................................31 
6.2.4 
Complete Physical Examination ......................................................................31 
6.2.5 
Focused Physical Examination ........................................................................31 
6.2.6 
Hematology ......................................................................................................32 
 
 
6.2.8 
Pulmonary Exacerbation Checklist ..................................................................32 
6.2.9 
Serum chemistry ..............................................................................................33 
6.2.10 Spirometry........................................................................................................33 
6.2.11 Sputum Induction and Sample Collection .......................................................33 
6.2.12 Urinalysis .........................................................................................................34 
6.2.13 Urine Alcohol and Drug Screen .......................................................................34 
6.2.14 Vital Signs ........................................................................................................34 
6.2.15 Women of Childbearing Potential ...................................................................34 
 
6.3 
Screening Period .............................................................................................................35 
6.3.1 
Visit 1:  Screening ............................................................................................35 
6.4 
Treatment Period .............................................................................................................36 
6.4.1 
Visit 2:  Baseline (Within 21 days of Screening) ............................................36 
6.4.2 
Visit 3:  Week 4 (28 Days ± 5 Days After Visit 2) ..........................................37 
6.4.3 
Visit 4:  Week 6 (42 Days ± 5 Days After Visit 2) ..........................................39 
6.4.4 
Visit 5:  Week 8 (56 Days ± 5 Days After Visit 2) ..........................................39 
6.4.5 
Visit 6:  Week 12 (84 Days ± 5 Days After Visit 2) ........................................40 
6.4.6 
Visit 7:  Week 16 (112 Days ± 5 Days After Visit 2) ......................................41 
6.4.7 
Visit 8:  Week 20 (140 Days ± 5 Days After Visit 2) ......................................42 
6.4.8 
Visit 9:  Week 24 (168 Days ± 5 Days After Visit 2) ......................................43 
6.4.9 
Visit 10:  Week 28 (196 Days ± 5 Days After Visit 2) ....................................44 
6.4.10 Visit 11:  Week 32 (224 Days ± 5 Days After Visit 2) ....................................44 
6.4.11 Visit 12:  Week 36 (252 Days ± 5 Days After Visit 2) ....................................45 
6.4.12 Visit 13:  Week 40 (280 Days ± 5 Days After Visit 2) ....................................46 
6.4.13 Visit 14:  Week 44 (308 Days ± 5 Days After Visit 2) ....................................46 
6.4.14 Visit 15:  Week 48 (336 Days ± 5 Days After Visit 2) ....................................47 
6.5 
Follow-Up Period............................................................................................................48 
6.5.1 
Visit 16:  Week 52 (364 Days ± 5 Days After Visit 2) ....................................48 
7 
SUBJECT AND STUDY DISCONTINUATION ..........................................................49 
7.1 
Screen Failures ................................................................................................................49 
7.2 
Premature Discontinuation..............................................................................................49 
7.3 
Study or Site Termination ...............................................................................................50 
8 
ADVERSE EVENTS .......................................................................................................51 
8.1 
Reporting Responsibilities ..............................................................................................51 
8.2 
Definitions.......................................................................................................................51 
8.2.1 
Adverse Event ..................................................................................................51 


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8.2.2 
Serious Adverse Event .....................................................................................51 
8.2.3 
Severity Assessment ........................................................................................52 
8.2.4 
Causality Assessment.......................................................................................52 
8.2.5 
Assessment of Expectedness............................................................................53 
8.3 
Clinical Laboratory Abnormalities .................................................................................53 
8.4 
Physical Exam Abnormalities .........................................................................................53 
8.5 
Pregnancy ........................................................................................................................53 
8.6 
Reporting of Serious Adverse Events .............................................................................54 
8.7 
Reporting to Regulatory Authorities and Institutional Review Boards/Ethics 
Committees .....................................................................................................................54 
9 
STATISTICAL CONSIDERATIONS ...........................................................................55 
9.1 
Sample Size .....................................................................................................................55 
9.2 
Analysis Conventions .....................................................................................................55 
9.3 
Subject Populations .........................................................................................................55 
9.4 
Demographics and Baseline Characteristics ...................................................................56 
9.5 
Subject Disposition .........................................................................................................56 
9.6 
Analysis...........................................................................................................................56 
9.6.1 
Primary Efficacy Endpoint ..............................................................................56 
9.6.2 
Secondary and Exploratory Endpoints.............................................................57 
9.6.3 
Safety and Tolerability Endpoints ...................................................................58 
9.7 
Interim Analysis by IDMC .............................................................................................59 
10 
ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES ....................................60 
10.1 Ethical Conduct of the Study ..........................................................................................60 
10.2 Institutional Review Board Approval .............................................................................60 
10.3 Informed Consent............................................................................................................60 
10.4 Confidentiality ................................................................................................................60 
10.5 Protocol Amendments .....................................................................................................60 
10.6 Case Report Forms ..........................................................................................................61 
10.7 Source Document Maintenance ......................................................................................61 
10.8 Retention of Records.......................................................................................................61 
10.9 Study Monitoring ............................................................................................................61 
10.10 Protocol Deviations .........................................................................................................61 
10.11 Financial Disclosure........................................................................................................62 
10.12 Publication and Disclosure Policy ..................................................................................62 
11 
REFERENCES .................................................................................................................63 
APPENDIX 1 
SCHEDULE OF EVENTS ............................................................................66 
APPENDIX 2 
PROTOCOL AMENDMENTS AND SUMMARY OF CHANGES .........67 
Amendment 2, Protocol Version 3.0, 05 September 2015 ........................................................67 
Amendment 2, Protocol Version 3.1, 30 September 2015 ........................................................67 
Amendment 3, Protocol Version 4.0, 19 November 2015 ........................................................67 
Amendment 4, Protocol Version 5.0, 20 April 2016 .................................................................68 
Amendment 2, Protocol Version 3.0, 05 September 2015 Summary of Changes Table ..........73 
Amendment 2, Protocol Version 3.1, 30 September 2015 Summary of Changes Table ..........74 
Amendment 4, Protocol Version 5.0, 20 April 2016 Summary of Changes Table ...................81 


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LIST OF TABLES 
Table 1 
Annual Change in FEV1 in CF Patients Aged 18 to 30 Years ...............................21 
Table 2 
Anti-inflammatory Treatments for CF ...................................................................22 
Table 3 
Total Blood Volume Collected from Subjects During the Study ..........................31 
 






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SYNOPSIS 
Sponsor:  Celtaxsys, Inc. 
Study Title:  A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel 
Group Study to Evaluate the Efficacy, Safety, and Tolerability of CTX-4430 Administered 
Orally Once-Daily for 48 Weeks in Adult Patients with Cystic Fibrosis 
Test Product:  CTX-4430 
Name of Active Ingredient:  CTX-4430 
Study Number: CTX-4430-CF-201 
Study Phase: 2 
Study Centers: up to 70 centers in the United States and Europe 
Primary Objective:  
 To evaluate the safety and tolerability of CTX-4430 administered orally once-daily to 
cystic fibrosis (CF) patients for 48 weeks  
 To evaluate the efficacy of CTX-4430 administered orally once-daily to CF patients for 
48 weeks as determined by the absolute change from Baseline in FEV1 (forced expiratory 
volume in 1 second) percent predicted  
Secondary Objectives: 
 To evaluate the efficacy of CTX-4430 administered orally once-daily to CF patients for 
48 weeks as determined by the relative change from Baseline in FEV1 percent predicted  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on FVC (forced vital capacity) percent predicted and FEF25-75% (forced 
expiratory flow during the middle half of the forced vital capacity) percent predicted 
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on time to first pulmonary exacerbation while in the study  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on the number of pulmonary exacerbations  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on specified biomarkers (sputum DNA and elastase and serum high-sensitivity 
C-reactive protein [hs-CRP])  
Exploratory Objectives: 
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on sputum bacterial density  
 
 
 To evaluate the change from Baseline in subject’s health-related quality of life (HRQOL) 
while on CTX-4430 administered orally once daily for 48 weeks as measured by the Cystic 
Fibrosis Questionnaire - Revised (CFQ-R) 


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Study Design: 
This study is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the 
safety and efficacy of CTX-4430 administered once-daily for 48 weeks for treatment of CF. A 
total of 195 pulmonary CF patients that meet all the inclusion and no exclusion criteria and 
provide written informed consent will be randomized to receive 50 mg CTX-4430, 100 mg 
CTX-4430, or placebo in a 1:1:1 ratio. Follow-up visits will be conducted approximately every 
4 weeks from Week 4 to Week 52 (4 weeks after completion of treatment). 
Spirometry will be performed at Screening, before the first dose and at Weeks 4, 8, 12, 16, 24, 
32, 40, 48, and 52. Sputum will be induced and a sample collected before the first dose and at 
Weeks 8, 24, and 48 for measurement of DNA concentration, elastase concentration, and 
bacterial density (as measured by colony-forming units [CFUs]). A blood sample will be 
collected before the first dose and at Weeks 4, 8, 12, 24, 32, 40, 48, and 52 for measurement of 
hs-CRP. A pulmonary exacerbation criteria checklist will be completed before the first dose 
and at all subsequent study visits to the clinic or on the phone. 
 
 The CFQ-R will be administered before the first dose and at 
Weeks 12, 24, and 48. 
 
 
 
Adverse events (AEs) and concomitant medications will be recorded from Screening to 
Week 52. Hematology, and urinalysis will be evaluated at Screening, before the first dose and 
at Weeks 4, 8, 12, 24, 32, 40, 48, and 52. Serum chemistry will be evaluated at Screening, 
before the first dose and at Weeks 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, and 52. Weight and vital 
signs will be measured and pulse oximetry performed at all clinic visits. A complete physical 
exam will be performed at Screening and at Week 48. A physical exam focused on any 
medical complaints will be performed as required at all other visits. A 12-lead 
electrocardiogram (ECG) will be performed at Screening, before the first dose and at Weeks 4, 
8, 12, 24, 32, 40, and 48. 
An Independent Data Monitoring Committee (IDMC) will periodically (approximately every 8 
weeks) review the accumulating study data. The primary responsibility of the IDMC will be to 
monitor subject safety (including pulmonary exacerbations) and study conduct. 
Number of Subjects Planned: 195 subjects 
Diagnosis and Main Eligibility Criteria:  patients aged 18 to 30 years (inclusive) with 
confirmed diagnosis of pulmonary CF and on a stable regimen of CF treatment with FEV1 ≥50 
percent predicted and at least 1 acute pulmonary exacerbation in the 12 months prior to 
Screening 
Duration of Treatment:  48 weeks 
Test Product; Dose; and Mode of Administration:  CTX-4430; 50 or 100 mg/day; oral 
capsule 
Reference Therapy; Dose; and Mode of Administration:  Placebo; oral capsule 


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Criteria for Evaluation: 
Safety and Tolerability:  AEs, concomitant medications, clinical laboratory evaluations 
(hematology, serum, chemistry, urinalysis), vital signs, weight, pulse oximetry, ECG 
parameters 
Spirometry:  FEV1 (absolute value and percent predicted), FVC (percent predicted), FEF25-
75% (percent predicted) 
Pulmonary Exacerbations:  number of pulmonary exacerbations and time to pulmonary 
exacerbations, as defined by Fuchs criteria 
Biomarkers:  sputum DNA concentration, sputum elastase concentration, and serum hs-CRP 
concentration 
Bacterial Density:  presence/absence and quantitative counts (CFUs) of bacteria in sputum: 
Pseudomonas aeruginosa, Burkholderia cepacia complex, Achromobacter xylosoxidans, 
Stenotrophomonas maltophilia, and Staphylococcus aureus (including methicillin–resistant 
S aureus and small colony variants of S aureus)  
 
HRQOL:  scores for respiratory and other domains of the CFQ-R 
Statistical Methods:  
Sample Size: A total of 195 subjects will be enrolled in trial to provide 52 evaluable subjects 
per treatment group in the Per-protocol Population (PP), assuming a drop-out rate of 20% in 
48 weeks. 
Primary Efficacy Analysis:  The primary efficacy analysis of change from Baseline to Week 
48 in FEV1 percent predicted will be performed on the Full Analysis Population (defined as all 
randomized subjects receiving at least 1 dose of assigned treatment). The primary efficacy 
evaluation will compare the combined, average absolute change from Baseline in FEV1 
percent predicted of the 50 mg and 100 mg CTX-4430 treatment groups versus the placebo 
group. 
The primary analysis will be based upon an analysis of variance (ANOVA) in which the 
average of the Week 48 change from Baseline in FEV1 for the 2 CTX-4430 doses is compared 
to that in the placebo group. The ANOVA model will contain a separate term for each dose 
group with the average over the 2 CTX-4430 doses created by averaging the parameters 
estimates from the ANOVA model. In addition to terms for treatment group, the ANOVA will 
include stratification for the factors used for randomization. For subjects missing their Week 
48 assessment, the average placebo change from Baseline to Week 48 will be imputed. 
Descriptive statistics will be presented by treatment group and averaged CTX-4430 dose. 
If the primary analysis (aggregate CTX-4430 effect) reaches the 0.05 level of significance 
(1-sided), the individual CTX-4430 doses will be compared to the placebo arm using Dunnett's 
procedure at the 0.05 (2-sided) alpha level. This procedure maintains the type I error at the 
usual 0.05 (2-sided) level for the individual dose comparisons with placebo while allowing a 
proof of concept test for the pooled comparison at the 0.05 (1-sided). This approach is 
consistent with the Fleming and Richardson approach to Phase 2 screening trials in which a 
screening trial, if positive at the more stringent 0.05 2-sided level after preliminary testing, can 


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be treated as providing a more definitive statistical test and may reduce the amount of 
additional confirmatory trial data that is needed. No other adjustments for multiplicity will be 
used and other statistical analyses will be viewed as supportive. 
Sensitivity analyses for the primary analysis will be conducted in which 1) the last available 
data is used (last observation carried forward), 2) the primary analysis is repeated using 
observed data only, and 3) using a rank based analysis where missing data are assigned the 
worst rank.  
In addition to the univariate ANOVA, a mixed model repeated measures analysis of change 
from Baseline in FEV1 percent predicted at each post-Baseline visit using all available data 
will be used to explore the consistency of the treatment effect over time. The model will 
include treatment (all 3 doses), visit, and treatment-by-visit interaction with additional factors 
for the randomization strata.   
The primary analysis will be repeated on the PP as a supportive analysis. 
Safety and Tolerability Analyses:  The Investigator’s verbatim term for each AE will be 
mapped to system organ class and preferred term using the latest version of the Medical 
Dictionary for Regulatory Activities. 
Treatment-emergent AEs will be summarized by system organ class and preferred term; a 
subject will only be counted once per system organ class and once per preferred term within a 
treatment.   
Concomitant medications will be coded using the most current WHO Drug Dictionary and 
summarized by drug class and medication term with results presented by treatment group. 
Clinical laboratory results at each time point and change from Baseline will be displayed using 
summary statistics (n, mean, standard deviation [SD], median, minimum and maximum 
values) by treatment group. Listings of laboratory data will also be presented. Within each 
listing, laboratory values outside the normal ranges will be flagged as either high or low. In 
addition, shift tables will be presented to display the shift in the normal range categories (low, 
normal, high) from Baseline to each specified time point. Baseline is defined as the latest 
result obtained prior to first investigational product (IP) administration.   
Values at each time point and change from Baseline for weight, pulse oximetry, vital sign 
measurements (systolic and diastolic blood pressure, pulse, respiration rate, and temperature), 
and ECG parameters will be summarized with descriptive statistics (n, mean, SD, median, 
minimum, and maximum) at each time point by treatment group. Baseline is defined as the 
latest result obtained prior to first IP administration. In addition, shift tables will be presented 
to display the shift in the normal range categories (abnormal/normal) from Baseline to each 
specified time point.  Listings of these data will also be presented. 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
ATS 
aspartate aminotransferase 
American Thoracic Society 
AUC 
area under the time-concentration curve 
BMI 
body mass index 
CF 
cystic fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire - Revised  
CFTR 
cystic fibrosis transmembrane regulator 
CFU 
colony forming unit 
Cmax 
maximum observed plasma concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
ERS 
electronic case report form 
European Respiratory Society 
FAP 
Full Analysis Population 
FEF25-75% 
forced expiratory flow during the middle portion of the forced vital 
capacity 
FEV1 
forced expiratory volume in 1 second 
5-LO 
5-lipoxygenase  
FVC 
forced vital capacity 
GCP 
GGT 
Good Clinical Practice 
Gamma-glutamyltransferase 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
Hr 
human recombinant 
HRQOL 
health-related quality of life 
hs-CRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IC50 
50% inhibition concentration 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
interactive Web randomization system 
LTA4H 
leukotriene A4 hydrolase 
LTB4 
leukotriene B4 
NSAID 
nonsteroidal anti-inflammatory drug 
PK 
pharmacokinetic 
PP 
Per-protocol Population 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse events 
Tmax 
time at which maximum plasma concentration was observed 
UGT 
uridine glucuronosyltransferase triphosphate 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 


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1 INTRODUCTION 
1.1 
Cystic Fibrosis 
Cystic fibrosis (CF) is one of the most important causes of chronic pulmonary disease. About 
70,000 individuals are affected by CF worldwide.1 The disease occurs in equal proportions in 
males and females.2 CF is caused by mutation of the CF transmembrane regulator (CFTR) gene; 
the most common CFTR mutations are ΔF508, G542X, and G551D.3 One in 29 Caucasian 
Americans and 1 in 25 people in the United Kingdom (UK) are carriers of a CFTR mutation.1,4 
Although mostly found in those of Caucasian descent, CFTR mutations do occur in other races 
but with lower frequency.1 In the United States (US), 1 in 3400 children is born with CF,1 and an 
estimated 30,000 individuals have CF (75% diagnosed by the age of 2 years).1 In Europe, 1 in 
2000 to 3000 children is born with CF,5 and about 30,000 individuals have CF.6 The median 
survival of someone with CF in the US is 37.4 years and in the UK 41 years.1,2  
CF pathology is characterized by a cycle of infection, inflammation, and airway obstruction. 
Despite intensive treatment efforts to combat airway obstruction and infection, airway disease is 
the major cause of hospitalizations and death in the adult CF population. It is estimated that 
deaths from pulmonary complications of CF occur in over 80% of CF patients.7 A study in 
France reported that the 1-year mortality rate for patients admitted to hospital for severe 
pulmonary exacerbations was 22%, and, for those admitted to the intensive care unit, the 1-year 
mortality rate was 48%.7 Another recent study reported that 48% of CF patients were 
hospitalized for pulmonary exacerbations over a 26-month period.8 
Leukotriene A4 hydrolase (LTA4H) is strongly implicated in the etiology of airway diseases, 
including CF 9,10. LTA4H is a bifunctional enzyme with both epoxide hydrolase and 
aminopeptidase activities, catalyzing the formation of the ultimate pro-inflammatory mediator 
leukotriene B4 (LTB4) from LTA4. LTB4 is a powerful attractant and activator of inflammatory 
immune cells, particularly neutrophils. CF lung disease is characterized by significant 
neutrophilic infiltrates in the small airways and elevation of LTB4 in the airways.11,12 In 
destructive pulmonary diseases such as CF, inhibition of LTB4 production has the potential to 
reduce both neutrophil influx and release of damaging neutrophil-derived enzymes such as 
elastase.13,14 
Therapies aimed at decreasing the inflammatory response represent a relatively new strategy in 
the treatment of CF lung disease. Attention has focused primarily upon the therapeutic potential 
of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Although often 
beneficial, the use of systemic corticosteroids is limited by their unacceptable adverse effects. 
Although inhaled corticosteroids are used in CF, it is unclear if they are effective. High-dose 
ibuprofen has been shown to target CF lung inflammation, resulting in increased forced 
expiratory volume in 1 second (FEV1) and decreased neutrophilic lung infiltrates in adults and a 
slower rate of FEV1 decline in children.15,16 However, because of gastrointestinal effects 
including bleeding, its use has not been widely adopted. 
The most recent advance in the treatment of CF is modulation of the abnormal CFTR protein. 
Currently, ivacaftor is the only CFTR therapy approved for the treatment of CF.17 It is indicated 
only for the small percentage of CF patients (approximately 6%) who have the G551D and 


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functionally similar gating mutations. Trials with correctors and potentiators for other classes of 
CFTR genetic mutations (such as ataluren) and with combinations of correctors and potentiators 
(such as the ivacaftor/lumacaftor combination 18) are ongoing. However, even these targeted 
therapies may not address the dysregulated inflammatory response, as exemplified by the GOAL 
study.19  
Thus, there is a clear unmet need for additional treatment options for CF lung disease, 
particularly those that address the underlying inflammation in a safe and effective manner, and 
can be used concomitantly with other medications for CF. The involvement of neutrophils and 
critical role of LTB4 suggests that inhibition of LTA4H is a reasonable potential target for 
further clinical evaluation. 
1.2 
CTX-4430 
CTX-4430 is a novel synthetic, small-molecule, LTA4H inhibitor being developed to address the 
underlying pulmonary inflammation in CF. CTX-4430 inhibits both the epoxide hydrolase and 
the aminopeptidase activities of LTA4H in vitro. CTX-4430 has also shown inhibition of LTB4 
production after oral administration in both animal and human studies. 
1.2.1 
Nonclinical Studies of CTX-4430 
A full battery of pharmacology, pharmacokinetic (PK), and toxicology studies has been 
conducted, including studies of genetic, juvenile, and reproductive toxicology. Key findings are 
summarized below. Additional details of the nonclinical studies can be found in the current 
Investigator Brochure (IB). 
The pharmacologic effect of CTX-4430 correlates directly with plasma drug levels, suggesting 
no significant lag or persistence of effect. Trough plasma levels sufficient to achieve 50% or 
greater inhibition of LTB4 production have been associated with therapeutic effects in a number 
of inflammatory disease models. Nonclinical pharmacokinetic and metabolism studies indicated 
that CTX-4430 is rapidly absorbed in the upper intestine by passive transit across the gut tissue 
and then distributed throughout the water compartment of the body. CTX-4430 is eliminated 
predominantly intact as parent drug (>90%) via the liver to bile to feces route with only a small 
amount of parent drug (<3%) and metabolites appearing in urine. CTX-4430 was also evaluated 
for inhibition of human recombinant (hr) uridine glucuronosyltransferase triphosphate (UGT) 
enzymes UGT1A1 and UGT2B7. The values for the 50% inhibition concentration (IC50) for 
hrUGT2B7 and hrUGT1A1 were >125 µM, suggesting that at these concentrations the risk of 
inhibition by CTX-4430 is low. CTX-4430 is not a significant substrate or inhibitor of 
cytochrome P450 (CYP) enzymes or other transporters. In vitro studies suggest CTX-4430 may 
be a weak substrate of P-glycoprotein, a weak inhibitor of transporters OAT3, OCT2, and 
OATP1B1, or a weak inducer of CYP2B6. 
Pharmacological safety studies showed a low potential for acute adverse effects of CTX-4430 at 
human-equivalent oral doses below 649 mg/day. Signs of acute overdose may include non-life-
threatening, self-resolving changes in heart rate and blood pressure with concomitant 
electrocardiogram (ECG) changes that may be associated with nonlethal, self-resolving 
convulsion. Long-term toxicity studies in animals suggested safe chronic administration of oral 


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doses up to 200 mg/day in adult humans. On the basis of the nonclinical toxicity studies, signs of 
chronic toxicity in humans may include reduced food consumption, lack of body weight gain, or 
body weight loss. The toxicity of CTX-4430 in juvenile animals was similar to that observed in 
adult animals. 
No evidence of mutagenicity or clastogenicity was observed in genotoxicity assays, suggesting 
that CTX-4430 has low potential for these effects in humans. In nonclinical reproductive toxicity 
studies, CTX-4430 did not exhibit adverse effects on fertility, implantation, or embryofetal 
development at any dose level tested.  Therefore, on the basis of the nonclinical studies 
conducted to date, chronic doses up to 200 mg/day are reasonably expected to be safe in humans 
aged 2 years and older.  
1.2.2 
Clinical Trials of CTX-4430 
Three studies have been conducted in humans: 
 CTX-4430-HV-001:  A Phase I, Randomised, Double-Blind, Placebo-Controlled, Ascending 
Single- and Repeat-Dose Study of the Safety, Tolerability and Pharmacokinetics of 
CTX-4430 when Administered Orally to Healthy Adult Subjects with Two Single-Dose 
Groups Crossing over to Assess Food Effect 
 CTX-4430-CF-001:  A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending 
Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of CTX 4430 when Administered Orally to Cystic Fibrosis Patients for 
Fifteen Days 
 CTX-4430-DI-001:  A Phase 1, Open-Label, Two-Period, Fixed-Sequence, Drug-Drug 
Interaction Study to Evaluate the Pharmacokinetics and Safety of CTX-4430 and Midazolam 
in Healthy Adult Subjects 
The results of these clinical trials are summarized below, and additional details can be found in 
the current IB. 
In the clinical development program to date, 68 subjects (including 12 CF patients) have 
received multiple doses of CTX-4430 for 14 or 15 days. PK results from these multiple-dose 
studies in healthy volunteers and in CF patients showed that the PK parameters were largely 
similar between these 2 populations. CTX-4430 is relatively rapidly absorbed, achieving 
maximum observed plasma concentration (Cmax) within 1 to 2 hours after oral dosing in the 
fasted state. The estimated elimination half-life ranged from approximately 9 hours in CF 
patients to approximately 16 hours in healthy volunteers. The reason for this difference is not 
known; however, it had no effect on Cmax and only a small effect (20% difference) on the area 
under the time-concentration curve (AUC).  
Food delayed the median time at which maximum plasma concentration was observed (Tmax) but 
had only a slight effect on Cmax or AUC. After single 50 or 100 mg doses, mean Tmax increased 
approximately 3-fold (to 5.7 and 4.4 hours, respectively) while the mean Cmax decreased by 22% 
for 50 mg and by 36% for 100 mg. The mean AUC increased by 28% after the 50 mg dose and 
decreased by 21% following the 100 mg dose. These results suggest that food affects the rate but 
not the extent of absorption. 


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Steady state was reached by Day 7 in all 3 Phase 1 studies conducted to date. At steady state, 
mean AUC, Cmax, and Cmin (minimum observed plasma concentration) increased approximately 
1.5- to 2-fold over the values observed after the first 100 mg dose in both healthy volunteers and 
CF patients. 
The increase in systemic exposure (Cmax, concentration at steady state, and AUC) with dosage 
was nonlinear in the healthy volunteers, increasing in a slightly greater than proportional manner. 
In contrast, exposures after doses of 50 and 100 mg/day in CF patients were largely dose-
proportional.  
A drug-drug interaction study to assess the potential for CTX-4430 to induce CYP3A4/5 showed 
that CTX-4430 does not induce CYP3A4/5 activity in vivo and can thus be administered before 
CYP3A4- and CYP3A5-metabolized drugs (such as midazolam) without perpetrating a 
significant drug-drug interaction. 
Blood pharmacodynamics were studied in both healthy volunteers and CF patients. Plasma levels 
of CTX-4430 at peak and trough showed large multiples over the whole-blood IC50 for LTB4 
inhibition and concomitantly suppressed LTB4 production to a significant degree at doses of 
50 mg/day and higher. In healthy volunteers, the 100 mg dose yielded near maximal suppression 
of LTB4 production in blood. For reasons that are not yet known, similar plasma levels of 
CTX-4430 at the 100 mg dose level in CF patients yielded suppression of LTB4 production in 
blood (approximately 70% maximum inhibition) that was lower than that observed for healthy 
volunteers (greater than 80 maximum inhibition).  
Encouraging trends in blood and sputum biomarkers of inflammation were observed in CF 
patients in the Phase 1 study. Correlated reductions in sputum LTB4 (a marker for the CTX-4430 
mechanism), sputum DNA (a marker for neutrophil infiltration in CF lung), sputum elastase (a 
marker for neutrophil activity and tissue degradation in CF lung), and serum C-reactive protein 
(a marker for systemic inflammation) were observed in the subjects who received active 
CTX-4430 as compared both to values in subjects in the placebo group and to their own Baseline 
values. Most notable among these effects were reductions in sputum white blood cells (WBCs) 
and neutrophils for the entire CTX-4430 treated group. For sputum WBC, there was a 31% 
reduction from Baseline in the treated group as a whole and a 60% reduction from Baseline in 
the 100 mg CTX-4430 group. For sputum neutrophils, there was a 34% reduction from Baseline 
in the treated group and a 65% reduction from Baseline in the 100 mg CTX-4430 group. 
To date, CTX-4430 has been well tolerated by healthy volunteers at doses up to 200 mg once-
daily for 14 days. It has also been well tolerated at doses of 50 and 100 mg for 15 days in CF 
patients. There were no clinically relevant trends in vital signs, clinical laboratory values 
(including hematology and clinical chemistry), and the ECG results. The most common 
treatment-emergent adverse events (TEAEs) on multiple dosing with 50 mg or 100 mg of 
CTX-4430 were headache, abdominal pain or discomfort, oropharyngeal pain, cough, increased 
sputum, and hemoptysis. None of the TEAEs in these multiple-dose studies were considered 
definitely related to CTX-4430 by the Investigators. The highest degree of relatedness to 
CTX-4430 assessed for TEAEs in these studies was an assessment of probably related for a 
headache in a subject taking 50 mg CTX-4430. Headache was the most common adverse event 
considered by the investigators to be related to the use of CTX-4430 (13%). There was no dose 


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relationship in incidence or severity of TEAEs, and most of the events were mild or moderate in 
severity. There were no deaths in the Phase 1 studies. One subject with CF who received CTX-
4430 experienced a serious adverse event (SAE) of pulmonary exacerbation requiring 
hospitalization that was unlikely related to CTX-4430 and occurred 35 days after the last dose. 
No subjects who received CTX-4430 withdrew from the study because of a TEAE. 
 
 
 Based on the clinical data in healthy volunteers and 
CF patients, once-daily oral doses of 50 and 100 mg are suitable for study in subsequent clinical 
trials of CF. These doses exhibit good safety and tolerability as well as a range of pharmacologic 
effects in humans relevant to patients with CF and thus provide a basis for the initial assessment 
of longer-term safety and potential efficacy of CTX-4430 for treatment of CF. 
 


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2 OBJECTIVES 
2.1 
Primary Objectives 
 To evaluate the safety and tolerability of CTX-4430 administered orally once-daily to CF 
patients for 48 weeks  
 To evaluate the efficacy of CTX-4430 administered orally once-daily to CF patients for 
48 weeks as determined by the absolute change from Baseline in FEV1 (forced expiratory 
volume in 1 second) percent predicted 
2.2 
Secondary Objectives 
 To evaluate the efficacy of CTX-4430 administered orally once-daily to CF patients for 
48 weeks as determined by the relative change from Baseline in FEV1 percent predicted  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on FVC (forced vital capacity) percent predicted and FEF25-75% (forced 
expiratory flow during the middle portion of the forced vital capacity) percent predicted 
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on time to first pulmonary exacerbation while in the study  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on the number of pulmonary exacerbations  
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on specified biomarkers (sputum DNA and elastase and serum high-sensitivity 
C-reactive protein [hs-CRP])  
2.3 
Exploratory Objectives 
 To evaluate the effect of CTX-4430 administered orally once-daily to CF patients for 
48 weeks on sputum bacterial density  
 
 
 
 
 To evaluate the change from Baseline in subject’s health-related quality of life (HRQOL) 
while on CTX-4430 administered orally once daily for 48 weeks as measured by the 
Cystic Fibrosis Questionnaire - Revised (CFQ-R) 


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3 STUDY DESIGN 
3.1 
Overall Study Design 
This study is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the 
safety and efficacy of CTX-4430 administered once-daily for 48 weeks for treatment of CF. A 
total of 195 pulmonary CF patients that meet all the inclusion and no exclusion criteria and 
provide written informed consent will be randomized to receive 50 mg CTX-4430, 100 mg CTX-
4430, or placebo in a 1:1:1 ratio. Follow-up visits will be conducted approximately every 
4 weeks from Week 4 to Week 52 (4 weeks after completion of treatment). 
Spirometry will be performed at Screening, before the first dose and at Weeks 4, 8, 12, 16, 24, 
32, 40, 48, and 52. Sputum will be induced and a sample collected before the first dose and at 
Weeks 8, 24, and 48 for measurement of DNA concentration, elastase concentration, and 
bacterial density (as measured by colony-forming units [CFUs]). A blood sample will be 
collected, before the first dose and at Weeks 4, 8, 12, 24, 32, 40, 48, and 52 for measurement of 
hs-CRP. A pulmonary exacerbation criteria checklist will be completed before the first dose and 
at all subsequent study visits to the clinic or on the phone.
 
 The CFQ-
R will be administered before the first dose and at Weeks 12, 24, and 48.   
 
 There 
will be no genetic tests done on any samples taken in this study. 
Adverse events (AEs) and concomitant medications will be recorded from Screening to 
Week 52. Hematology, and urinalysis will be evaluated at Screening, before the first dose and at 
Weeks 4, 8, 12, 24, 32, 40, 48, and 52. Serum chemistry will be evaluated at Screening, before 
the first dose and at Weeks 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, and 52. Weight and vital signs will 
be measured and pulse oximetry performed at all clinic visits. A complete physical exam will be 
performed at Screening and at Week 48. A physical exam focused on any medical complaints 
will be performed as required at all other visits. A 12-lead ECG will be performed at Screening, 
before the first dose and at Weeks 4, 8, 12, 24, 32, 40, and 48. 
An Independent Data Monitoring Committee (IDMC) will periodically (approximately every 8 
weeks) review the accumulating study data. The primary responsibility of the IDMC will be to 
monitor subject safety (including pulmonary exacerbations) and study conduct.    
3.2 
Rationale for Study Design  
3.2.1 
Study Population 
The study population consists of patients with documented pulmonary CF, a planned target 
population for CTX-4430. The population included in this study (CF patients with ≥50% FEV1 at 
Baseline and at least 1 pulmonary exacerbation in the prior year) was chosen for its high rate of 


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annual decline in FEV1, with an expected mean annual decline in FEV1 percent predicted of 
3.3% to 5.1% as shown in Table 1. 
 Table 1 
Annual Change in FEV1 in CF Patients Aged 18 to 30 Years 
Baseline FEV1 Range  
(Percent Predicted) 
N 
Mean 
25% 
Percentile 
50% 
Percentile 
75% 
Percentile 
50 to 59 
531 
-3.3 
-6.8 
-3.0 
0.7 
60 to 79 
965 
-3.3 
-7.5 
-2.9 
1.2 
80 to 99 
598 
-3.8 
-7.0 
-3.2 
0.5 
≥100 
94 
-5.1 
-8.0 
-3.0 
0.1 
Source:  Cystic Fibrosis Foundation registry data. 
According to Konstan et al, high-dose ibuprofen significantly stems the annual rate of decline of 
FEV1, showing approximately 1.5% improvement in annual decline of FEV1 percent predicted vs 
placebo (P = 0.02). 20 While seemingly small in magnitude, this improvement represents a 40% 
reduction in rate of decline or effectively sparing of nearly 5 months of lung function year over 
year. The effect of high-dose ibuprofen on rate of FEV1 decline was attributed to its anti-
inflammatory activity via the inhibitory effect on neutrophil activation and migration via the 
LTB4 pathway. 15,21 Inhibition of LTA4H by CTX-4430 can have a similar effect on neutrophils 
and over the course of 48 weeks could have a positive effect on decline in FEV1 percent 
predicted as compared to placebo. 
3.2.2 
Study Treatments 
The 50 mg and 100 mg doses of CTX-4430 were selected for this study because these doses 
showed consistent reduction of LTB4 levels in CF patients in study CTX-4430-CF-001. 
Repeated dosing of 50 mg and 100 mg for 14 days in healthy volunteers and in CF patients for 
15 days produced an acceptable safety profile and was well tolerated. CTX-4430 has been 
administered to rats in doses up to 100 mg/kg/day for 6 months and to dogs in doses up to 
6 mg/kg/day for 9 months. The no-observed-adverse-effect level in the most sensitive species 
(dog) was 6 mg/kg day, corresponding to a human equivalent dose of 195 mg/day. CTX-4430 
exposure at this dose in the dog study was greater than or equivalent to the exposure at 200 mg in 
the healthy volunteer human study CTX-4430-HV-001. Thus, the 50 and 100 mg once-daily oral 
doses chosen for this study are well-supported by the chronic nonclinical toxicology studies, 
exhibit adequate safety and tolerability in human studies conducted to date, and demonstrate 
pharmacological effects in humans relevant to CF disease. 
Matching placebo was selected as the control for optimal assessment of the safety and efficacy of 
CTX-4430.  
A trial of 48 weeks is warranted for study of anti-inflammatory treatments in CF, even at the 
Phase 2 stage, since the expected major impact of this class of treatment will be to reduce the 
rate decline in FEV1. Current Cystic Fibrosis Foundation registry data (Table 1) indicate that the 
expected rate of FEV1 decline is in the range of 3.3 to 5.1 % per year. Variability (as coefficient 
of variation, CV) of FEV1 percent predicted in CF trials typically ranges from 7 to 10%, meaning 
that CV will be on the order of twice the size of the anticipated FEV1 change over the course of a 
year. Thus, 48 weeks is the optimum duration for discerning an effect on rate of FEV1 decline 


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that enables projection of anticipated effect size and powering for Phase 3 studies while 
minimizing total patient enrollment in Phase 2. This duration is consistent with precedent for CF 
treatments considered to be anti-inflammatory, as described in Table 2. 
Table 2 
Anti-inflammatory Treatments for CF 
Drug 
Mechanism 
N 
Duration 
(Weeks) 
Outcomes 
Biomarker 
FEV1  
Acute 
Pulmonary 
Exacerbations  
AZD9668 
Elastase 
inhibition 
56 
4 
No reduction in 
sputum elastase or 
PMNs but reduction 
in IL-6 and RANTES 
No effect 
Not reported 
SB-656933 
IL-8 
antagonism 146 
4 
Trend to reduction of 
sputum elastase, 
DNA, PMNs 
No effect 
Not reported 
Azithromycin a 
Unknown 
260 
24 
Not reported 
73% reduction in 
rate of decline 
(-0.5% vs -1.9%) 
50% reduction 
NAC 
Glutathione 
enhancement 70 
24 
No reduction in 
sputum elastase 
6% increase mostly 
driven by reduction 
in decline compared 
to placebo 
(+1.1% vs -5.6%) 
Not reported 
High-dose 
ibuprofen 
LTB4 
inhibition 
85 
192 
Not reported 
40% reduction in 
rate of decline 
(-2.17% vs -3.6%); 
58% reduction in 
rate in compliant 
subjects  
(-1.48% vs -3.57%) 
No change in 
number of 
hospitalizations 
DNA = deoxyribonucleic acid; IL-6 = interleukin 6; IL-8 = interleukin 8; LTB4 = leukotriene B4;  
NAC = N-acetylcysteine; PMN = polymorphonuclear leukocytes; RANTES = regulated upon activation, normal T-cell 
expressed and secreted. 
a  No subjects with Pseudomonas aeruginosa 
Sources:  References 20,22,23,24,25. 
Short (4 weeks) studies have been attempted for evaluation of anti-inflammatory treatments in 
CF but have resulted in an inability to observe changes in FEV1 sufficient to guide Phase 3 
design. Longer (≥24 weeks) studies have been more informative but have either been excessively 
long (as with high-dose ibuprofen) or reliant on an unusually high rate of decline (as with 
N-acetylcysteine). The most relevant example is that of azithromycin tested in patients not 
infected with Pseudomonas aeruginosa, which showed a rate of FEV1 decline in the placebo 
group (1.94% in 6 months) consistent with current annual rates of decline. In this case, 
azithromycin reduced FEV1 decline compared to placebo by 1.4% in 24 weeks. This decline 
projects to a 73% reduction in rate of decline compared to placebo and a 2.8% improvement in 
annual rate of FEV1 decline, which would be clearly significant outcomes for CF patients. 
However, because of the small effect size (1.4%) even with a large patient sample (125 per 
cohort), the change in FEV1 did not approach statistical significance sufficiently (P = 0.34) to be 
deemed a meaningful outcome for progression to Phase 3. Thus, a trial of 48 weeks is required 


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for observation of sufficient change in FEV1 to assess the therapeutic effect of drugs with anti-
inflammatory effect in CF. 
3.2.3 
Study Endpoints 
The primary, secondary, and exploratory efficacy endpoints in this study are aligned with 
academic and regulatory endpoints for the clinical development of a treatment for CF.26  
Pulmonary exacerbations are defined as treatment with oral, inhaled, or intravenous (IV) 
antibiotic(s) for ≥4 of symptoms/signs per the criteria of Fuchs et al,27 (modified Fuchs criteria) 
the standard definition used in clinical trials of CF.28 
The exploratory endpoint of HRQOL will be evaluated using the CFQ-R, a validated disease-
specific HRQOL measure for children, adolescents, and adults with CF.29,30,31 It is a profile 
measure of HRQOL with several different domains, including physical functioning, vitality, 
health perceptions, respiratory symptoms, treatment burden, role functioning, emotional 
functioning, and social functioning. 
3.3 
Independent Data Monitoring Committee 
An IDMC will be formed to periodically (approximately every 8 weeks) review the 
accumulating study data. The primary responsibility of the IDMC will be to monitor subject 
safety (including pulmonary exacerbations) and study conduct. The IDMC will have access to 
both safety and efficacy data. The IDMC will be requested to avoid formal evaluations of 
efficacy for the purpose of discontinuing the trial early for benefit. As such, no adjustment for 
multiple testing will be required. The IDMC will review the study data in accordance with a 
written charter.  
3.4 
Study Duration  
The duration of enrollment is estimated to be 13 months; the actual duration of enrollment may 
be longer. Each subject will be followed for approximately 52 weeks after enrollment, so the 
duration of the study is estimated to be about 25 months. 


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4 SUBJECT POPULATION 
4.1 
Inclusion Criteria 
Patients are eligible to participate in the study if they meet all of the following inclusion criteria: 
1. 18 to 30 years of age inclusive at the time of Screening 
2. Documented, confirmed diagnosis of pulmonary CF (defined as follows):  
 CF signs and symptoms AND 
 Either 2 CFTR mutations on genetic testing OR sweat chloride ≥60 mEq/L 
3. Medically stable, in the Investigator’s opinion  
4. At least 1 pulmonary exacerbation, based on the Investigator’s judgment, in the 12 months 
before Screening 
5. Resolution of any pulmonary exacerbation of CF at least 14 days before Screening, in the 
Investigator’s opinion 
6. On a stable regimen of CF treatments with no change for at least 14 days before Screening 
and between Screening and Baseline 
7. If on ivacaftor or ivacaftor-lumacaftor combination, on a stable regimen for at least 8 weeks 
before Baseline 
8. No clinical or radiological evidence, per the Investigator’s site procedures, of clinically 
significant lung abnormalities (e.g., major atelectasis, pneumothorax)  
9. FEV1 ≥50 percent predicted at Screening 
10. Resting oxygen saturation >92% on room air 
11. Body mass index (BMI) ≥17.0 kg/m2 
12. No smoking (including electronic cigarettes) for at least 6 months before Screening and 
agreement not to use such products for the duration of the study 
13. Females of childbearing potential must have a negative pregnancy test at Screening (unless 
surgically sterile) and must agree to use an effective contraception method from screening 
throughout the duration of the study (refer to Section 5.10.2 for definition of acceptable 
effective methods). 
14. Able to perform spirometry according to European Respiratory Society/American Thoracic 
Society guidance 32 
15. Able to swallow investigational product (IP) whole 
16. Able to comply with the study procedures, in the opinion of the Investigator 
17. Has provided informed consent to participate in the study 


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4.2 
Exclusion Criteria 
Patients are eligible to participate in this study if they meet none of the following exclusion 
criteria: 
1. In the opinion of the Investigator, any significant clinical/laboratory/radiological/spirometric 
sign of unstable or unexpectedly deteriorating respiratory disease within 14 days before 
Screening or between Screening and Baseline (These clinical/laboratory/radiological/ 
spirometric signs include, but are not limited to, features suggestive of a pulmonary 
exacerbation as suggested by the modified Fuchs’ criteria.) 
2. A medical condition that is unstable, could be adversely impacted by participation in the 
study, or could impact assessment of the study results, in the opinion of the Investigator  
3. History of organ transplantation 
4. History of either alcoholism or drug abuse in the opinion of the investigator  
 
5. Clinically significant hemoptysis (e.g., > approximately 30 cc per episode, or clinically 
significant in the Investigator’s opinion) within 180 days before Screening 
6. Colonization with organisms associated with a more rapid decline in respiratory function in 
CF patients (e.g. all Burkholderia species, Mycobacterium abscessus). Subjects with a 
history of a positive culture could be considered free of colonization if she/he has had 6 
subsequent respiratory tract cultures negative for these bacteria within the past 24 months 
prior to Screening, with one of these cultures obtained within 6 months prior to Screening  
7. Active allergic bronchopulmonary aspergillosis at Screening or at Baseline 
8. Any clinically significant ECG abnormality, in the Investigator’s opinion 
9. Positive serology for HIV-1 or HIV-2 antibody, hepatitis C virus antibody, or hepatitis B 
surface antigen at Screening 
10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2  the upper limit of 
normal (ULN) at Screening  
11. Bilirubin >1.25  ULN at Screening. Subjects with known Gilbert’s syndrome can be 
included with bilirubin >1.25 x ULN  
12. Any subject with cirrhosis of the liver  
13. Any subject with portal hypertension 
14. Neutrophil count <1.5  109/L at Screening 
15. Platelet count <150,000/µl at Screening 
16. Clinically unstable pancreatic function, in the opinion of the Investigator. Evidence of 
unstable pancreatic function could include: 
 Clinically significant weight loss (≥5% after a previously stable period) 
 Evidence of uncontrolled hyperglycemia or recent hypoglycemia 
 Change in pancreatic enzyme requirements in the 60 days before Screening  


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17. Use of systemic corticosteroids, or systemic antimicrobial therapy (other than chronic 
antimicrobial use, e.g. azithromycin, flucloxacillin, itraconazole) within 14 days before 
Screening or between Screening and Baseline 
18. Regular use (>3 times per week) of a high-dose NSAID (e.g., >1.6 g ibuprofen/day) within 
60 days before Screening or between Screening and Baseline  
19. Participation in a clinical trial for any medical/device product within 30 days before 
Screening (participation in a noninterventional or observational study is permitted)  
20. Pregnant or nursing women 


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5 INVESTIGATIONAL PRODUCTS 
5.1 
CTX-4430 
CTX-4430 (drug substance) is 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-
diazabicyclo[2.2.1]hept-2-yl]methyl]-benzoic acid. It is a chiral molecule that is manufactured as 
a single isomer (S, S configuration) that does not racemize. In solution, CTX-4430 behaves as a 
zwitterion with a terminal carboxyl group and a tertiary amine group.   
CTX-4430 is formulated as a powder blend in size 0 hard gelatin capsules of 50 mg or 100 mg 
dosage strength per capsule for oral administration. Excipients are mannitol, microcrystalline 
cellulose, crospovidone, magnesium stearate, and silicon dioxide. Each bottle contains 
36 capsules.  
5.2 
Placebo  
Placebo capsules are identical to the CTX-4430 capsules except that they do not contain the drug 
substance.  
5.3 
Packaging and Labeling 
CTX-4430 and placebo are packaged in 75 cc capacity round, white high-density polyethylene 
(HDPE) bottles fitted with a 38 mm white, screw-top HDPE closure. Each bottle contains 
36 capsules and is labelled in accordance with national requirements for clinical trial supplies. 
5.4 
Storage 
IP should be stored in the containers in which they are supplied at controlled room temperature 
(15°C to 25°C / 59°F to 77°F), and protected from ultraviolet light. 
Each investigational site will keep a regular record of maximum and minimum temperature 
readings in the IP storage area throughout the conduct of the study. 
5.5 
Screening 
The Screening Period will occur within 21 days before the first dose of study drug to confirm 
that subjects meet the selection criteria for the study. The assessments to be conducted are shown 
in 6.3.1. The investigator (or an appropriate authorized designee) will obtain informed consent 
from each subject.  
Based on investigator’s judgement, borderline abnormal laboratory tests which may exclude the 
subject, may be repeated once within 7 days of the screening visit without the subject being 
considered a screen fail. The medical monitor must be consulted for approval in such cases. 
In addition, subjects who fail to meet the ATS/ERS criteria for quality (acceptability, 
reproducibility, and end of test criteria) at screening may be retested once without being 
considered a screen failure. This retest should occur at least one day after the initial screening 


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visit and should be completed within 7 days of the original screening visit date. Final decision on 
screen failure will be based upon FEV1 data after review with the medical monitor. 
Rescreening: 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated. Subjects may only be rescreened once. If 
a subject is rescreened, the screening window begins at that time. 
 
5.6 
Randomization 
Upon determination that a subject meets all eligibility criteria, the subject will be randomized to 
treatment assignment via an interactive Web randomization system (IWRS). Each subject will be 
assigned to CTX-4430 50 mg, CTX-4430 100 mg, or placebo in a blinded 1:1:1 fashion by 
means of a computer-generated randomization list stratified by Baseline FEV1 percent predicted 
(50 to 75% and >75%), number of pulmonary exacerbations in the 12 months before Screening 
(1 or >1), and use of CFTR-modulating therapy such as ivacaftor or lumacaftor (yes/no).   
5.7 
Blinding and Unblinding 
Investigators, subjects, and all study staff with direct subject contact will be blinded to treatment 
assignment. All Celtaxsys study team staff members and contract research organization study 
team members will remain blinded unless specifically designated as unblinded and independent 
from the study team.  Such independent, unblinded study personnel may include drug 
distribution and IWRS vendor staff.  Pharmacovigilance staff will be unblinded as necessary for 
reporting to regulatory authorities, with appropriate controls to assure that access to any 
unblinded information is restricted to the safety reporting staff.  The sponsor will maintain a list 
of any designated individuals at the vendors or sponsor that are designated as unblinded. 
The investigator will ensure that blinding is broken only in accordance with the protocol 
conditions for unblinding due to medical necessity or safety reasons.   
In the case of a medical emergency, where the appropriate treatment of the subject requires 
knowledge of the IP, CTX-4430 or placebo, the investigator may break the randomization code 
at any time for an individual subject through the IWRS system.  Detailed procedures to break the 
blind will be provided to the investigator. In such cases, the AE necessitating the emergency 
blind break will be clearly justified, explained in writing, captured on the SAE form (if due to a 
SAE) in accordance with the procedures indicated in section 8.6., and must be reported to the 
medical monitor immediately.  The Sponsor medical team, for matters relating to safety concerns 
and associated regulatory reporting, may unblind individual subjects at any time. 
5.8 
Administration of Investigational Products 
The first dose of IP will be taken at the investigational site during Visit 2 (Baseline). Thereafter, 
the subject will take a capsule each day with a full glass of water (about 250 mL or 8 oz) at about 
the same time every day with breakfast.   


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5.9 
Concomitant Medications 
 Chronic use of systemic corticosteroids, and regular use (>3 times per week) of high-dose 
NSAIDs (e.g., >1.6 g ibuprofen/day) is prohibited during the study. If a need for any of these 
treatments arises during the study, the subject must be discontinued from the study. 
All concomitant medications, including over-the-counter medicines, will be reported in the 
electronic case report form (eCRF).   
5.10 Other Study Restrictions 
5.10.1 
Subject Activity Restrictions 
Subjects must not smoke during the study. 
5.10.2 
Contraception 
Women of childbearing potential must use an effective method of contraception until 28 days 
after taking the last dose of IP. Acceptable effective methods of contraception include the 
following methods:  
1. Monogamous relationship with vasectomized partner,  
2. Licensed hormonal methods associated with inhibition of ovulation (e.g., combination 
oral contraceptive pills, progestin-only hormonal contraception that inhibits ovulation) 
o For women who are receiving ivacaftor-lumacaftor combination therapy, 
hormonal contraception, including oral, injectable, transdermal and implantable, 
is considered to be unreliable and hence cannot be used as an effective method of 
contraception. In such patients who are on hormonal contraception, one of the 
following barrier methods of contraception should be added; male condom, 
diaphragm, cervical cap or female condom.  
3. Intrauterine contraceptive devices (including intrauterine hormonal systems). 
4. True abstinence for the subject, when this is in line with the preferred and usual lifestyle 
of the subject, can be considered an effective method of contraception based on the 
judgement of the investigator. Periodic abstinence is not an acceptable method of 
contraception. 
Based on the investigator’s judgement, the following acceptable methods of contraception may 
also be used: 
1. Double barrier methods of contraception, which is the use of a male condom plus either 
diaphragm or cervical cap, may be allowed. The male condom cannot be used with a 
female condom as a double barrier method of contraception due to risk of tearing. 
2. Male or female condom plus a spermicide, or diaphragm plus a spermicide may be 
allowed (acceptable methods if spermicide is regionally available)  


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If local regulations require the use of additional contraceptive measures, these must be followed. 
5.11 Compliance 
An investigational site staff member will count the capsules returned by each subject at Visits 3, 
5 to 9, 11, 13, and 15 and record the number of capsules returned. Subjects will be questioned in 
relation to any capsules which may have been lost or destroyed to gain a full understanding of 
the number of capsules taken during the treatment period. 


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6 STUDY PROCEDURES 
Refer to Appendix 1 for the Schedule of Events. 
6.1 
Blood Sample Volume 
Table 3 
Total Blood Volume Collected from Subjects During the Study 
Sample Type 
Number of 
Sampling Time 
Points 
Volume per 
Time Point 
Total Volume 
Screening laboratory tests: hematology, 
serum chemistry, serology, serum 
pregnancy (for women of childbearing 
potential only) 
1 
~ 15 mL 
~ 15 mL 
Hematology 
9 
~ 10 mL 
~ 90 mL 
Serum chemistry (may include hs-CRP) 
12 
~ 5 mL 
~ 60mL 
 
 
 
 
Total blood volume  
~ 215 mL 
hs-CRP = high-sensitivity C-reactive protein, 
 
6.2 
Guidelines for Study Procedures 
6.2.1 
Administration of CFQ-R 
Administered before spirometry, and collection of sputum, blood, and urine samples. The CFQ-R 
will be administered by the site staff. 
6.2.2 
Adverse Events 
See Section 8. 
6.2.3 
Body Mass Index 
Calculated as follows: weight (kg)/height (m)2. 
6.2.4 
Complete Physical Examination 
Examination performed by a licensed health care provider of, at a minimum, the following 
systems: skin, head, ears, eyes, nose and throat, respiratory, cardiovascular, gastrointestinal, 
neurological, musculoskeletal, and lymphatic systems. 
6.2.5 
Focused Physical Examination   
Examination performed by a licensed health care provider according to subject’s medical history 
and complaints. 


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6.2.6 
Hematology 
Hematocrit, hemoglobin, platelets red blood cell count, WBC count with differential, and 
absolute neutrophil count. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
6.2.8 
Pulmonary Exacerbation Checklist 
Pulmonary exacerbations are defined as treatment with oral, inhaled, or IV antibiotic(s) for ≥4 of 
symptoms/signs listed below per the modified Fuchs criteria 27. The date of onset of the 
pulmonary exacerbation will be recorded, which will be defined as the date of initiation of 
antibiotics for the pulmonary exacerbation. The pulmonary exacerbation checklist will capture 
the signs/symptoms listed below as well as the treatment with oral, inhaled, or IV antibiotics:  
 Change in sputum  
 New or increased hemoptysis 
 Increased cough 
 Increased dyspnea 
 Malaise, fatigue, or lethargy 
 Temperature >38°C 
 Anorexia or weight loss 


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 Sinus pain or tenderness 
 Change in sinus discharge 
 Change in physical examination of the chest 
 10% or more absolute decrease in FEV1 percent predicted from the previously recorded 
value  
 Radiographic changes indicative of pulmonary infection 
6.2.9 
Serum chemistry 
Albumin, alkaline phosphatase, ALT, AST, GGT, bicarbonate, bilirubin (total and direct), blood 
urea nitrogen, calcium, chloride, creatinine, glucose, phosphorus (phosphate), potassium, 
sodium, uric acid, total protein, and hs-CRP 
6.2.10 
Spirometry 
Spirometry will be performed before the sputum induction procedures.  
Subjects should take their concomitant medications as per their usual schedule. However, any 
short-acting bronchodilator (e.g. albuterol) should not be taken within 4 hours of scheduled time 
for spirometry, and any long-acting bronchodilator should not be taken within 12 hours (e.g. 
salmeterol) or 24 hours (e.g. tiotropium bromide) of scheduled time for spirometry. Every effort 
will be made to perform all tests for a given subject at the same time of day ±1 hour from the 
time of the Baseline measurement with the supplied study specific spirometry equipment. If 
possible, the same respiratory technician should conduct all tests for a subject. Efforts should be 
made to ensure a consistent approach to subject coaching to minimize variation during 
spirometry. It is essential to have reproducible “research grade” spirometry throughout the 
duration of the study. Operators will coach subjects to ensure optimal effort is achieved. If 
optimal results are not obtained after 4 attempts the subject should rest for 10 minutes before an 
additional maximum of 4 efforts are conducted. Further detail and instruction will be provided in 
the Pulmonary Function/Spirometry manual.    
Subjects who fail to meet the ATS/ERS criteria for quality (acceptability, reproducibility, and 
end of test criteria) at screening may be retested once without being considered a screen failure. 
This retest should occur at least one day after the initial screening visit and should be completed 
within 7 days of the original screening visit date.  For other visits, if a subject fails to adhere to 
protocol requirements, (e.g. bronchodilator use) or fails to meet ATS/ERS criteria for quality, 
then at the discretion of the investigator, the spirometry may be repeated once. The retest should 
occur at least one day after the initial visit but as soon as possible up to a maximum of 7 days. 
6.2.11 
Sputum Induction and Sample Collection 
The sputum induction and collection process will follow the Therapeutic Development Network 
Standard Operating Procedure (SOP) in the US and the Clinical Trials Network SOP in Europe. 
Any deviation from these SOPs will require prior approval from the Sponsor and will need to be 
documented.  


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The subject will be given 2 sterile jars of adequate volume to collect the sputum.  
6.2.12 
Urinalysis  
Macroscopic evaluation of bilirubin, blood, glucose, ketones, leukocyte esterase, nitrites, pH, 
protein, and specific gravity 
6.2.13 
Urine Alcohol and Drug Screen 
Alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates 
6.2.14 
Vital Signs 
Temperature, heart rate, blood pressure, and respiratory rate measured after the subject has been 
seated for 10 minutes 
6.2.15 
Women of Childbearing Potential 
To be considered not of childbearing potential, a woman must be postmenopausal with 
amenorrhea for at least 1 year prior to Screening and documented follicle-stimulating hormone 
level in the postmenopausal range or must have undergone one of the following sterilization 
procedures at least 180 days before the first IP dose: 
 hysteroscopy sterilization (with a copy of the confirmation test)  
 bilateral tubal ligation or bilateral salpingectomy  
 hysterectomy 
 bilateral oophorectomy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.3 
Screening Period  
6.3.1 
Visit 1:  Screening 
Subjects will be screened to assess eligibility criteria within 21 days before Baseline (first dose 
of IP). The following procedures will be performed: 
 Written informed consent. Subjects will consent to participation in the study and all study 
procedures by signing the study informed consent form (ICF). 
 
 
 Demographics and disease characteristics (including use of CFTR modulators such as 
ivacaftor or lumacaftor, use of dornase alfa, history of P aeruginosa colonization, number 
of pulmonary exacerbations in the last 12 months, date of last pulmonary exacerbation, 
chronic azithromycin use, CFTR genotype) 
 Medical history, including medication use 
 Complete physical exam 
 12-lead ECG 
 Height and weight, calculation of BMI 
 Vital signs 
 Pulse oximetry 
 Spirometry 


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 Collection of blood samples:  
o hematology 
o serum chemistry 
o serum pregnancy test for women of childbearing potential 
o HIV antibody, hepatitis C virus antibody, and hepatitis B surface antigen assays 
 Collection of urine samples: 
o urinalysis  
o alcohol and drug screen 
No study specific X-ray is required. If X-rays are available for subjects, they should be reviewed 
for any evidence of significant lung abnormalities (e.g., major atelectasis or pneumothorax). 
Subjects on cyclical inhaled antibiotic (e.g. tobramycin, amikacin) treatments should be 
scheduled for the Baseline visit such that they are about midway in the cycle of administration of 
the inhaled antibiotics on the day of the Baseline visit. 
The subject will be scheduled for the next visit, informed of the estimated length of the visit, and 
instructed to eat breakfast before the visit, take concomitant medications per Section 6.2.10.  
6.4 
Treatment Period 
6.4.1 
Visit 2:  Baseline (Within 21 days of Screening) 
The following procedures will be performed before IP administration: 
 Interim medical history  
 Recording of information about concomitant medications 
 Focused physical exam 
 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Administration of CFQ-R (must be performed before spirometry and collection of 
sputum, blood, and urine samples)  
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Sputum induction and sample collection (must be performed after spirometry) 
 Collection of blood samples:  


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o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential (review results before 
randomization) 
Upon determination that a subject meets all inclusion and no exclusion criteria, the subject will 
be randomized to the treatment assignment via an IWRS.   
   
IP will be dispensed to the subject, and the first dose of IP will be taken at the investigational site 
with a full glass of water (about 250 mL or 8 oz). The subject will be observed in the clinic for 
4 hours after IP administration. 
 
 
Vitals signs will be measured and recorded before discharge. 
Information about any AEs that occurred after IP administration will be recorded. 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast before the visit, take the IP with breakfast before the visit 
 and take concomitant medications per Section 6.2.10.  
 
 
6.4.2 
Visit 3:  Week 4 (28 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 


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 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis 
o urine pregnancy test for women of childbearing potential (review results before 
administering or dispensing of IP) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the subjects who are to be administered the IP in the clinic, the dose of IP will be taken at the 
investigational site with a full glass of water (about 250 mL or 8 oz).  
IP will be dispensed and the subject will be instructed to take the IP with a full glass of water 
(about 250 mL or 8 oz) at about the same time every day with breakfast. 


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The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast before the visit, take the IP with breakfast before the visit 
 and take concomitant medications per Section 6.2.10.  
 
If the subject takes the IP at home, 
he/she should be instructed to note the time of dosing. 
6.4.3 
Visit 4:  Week 6 (42 Days ± 5 Days After Visit 2) 
 Recording of information about any AEs and concomitant medications 
 Collection of blood samples:  
o serum chemistry 
For purposes of this visit, local laboratories may be used at the discretion of the site investigator 
if travel to the site presents a hardship to the subject. If a local laboratory test value is found to be 
abnormal and clinically significant, it should be verified by the central laboratory as soon as 
possible after the investigator becomes aware of the abnormal result. If a subject is unable to 
travel to the site due to hardship, recording of information about any AEs and concomitant 
medications should be done by telephone. 
6.4.4 
Visit 5:  Week 8 (56 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Sputum induction and sample collection (must be performed after spirometry) 
 Collection of blood samples:  


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o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential (review results before 
administering or dispensing of IP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the subjects who are to be administered the IP in the clinic, the dose of IP will be taken at the 
investigational site with a full glass of water (about 250 mL or 8 oz).  
IP will be dispensed and the subject will be instructed to take the IP with a full glass of water 
(about 250 mL or 8 oz) at about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast and take the IP with breakfast before the visit, and take 
concomitant medications per Section 6.2.10.. 
6.4.5 
Visit 6:  Week 12 (84 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 12 lead ECG  


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 Weight 
 Vital signs 
 Pulse oximetry 
 Administration of CFQ-R (must be performed before spirometry and collection of blood 
and urine samples)  
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast and take the IP with breakfast before the visit, and take 
concomitant medications per Section 6.2.10.  
6.4.6 
Visit 7:  Week 16 (112 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 


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 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o serum chemistry 
 Collection of urine samples: 
o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and to eat breakfast and take the IP with breakfast before the visit and take CF medications 
before the visit.   
6.4.7 
Visit 8:  Week 20 (140 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 Weight 
 Vital signs 
 Pulse oximetry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o serum chemistry 
 Collection of urine sample: 
o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 


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The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast and take the IP with breakfast before the visit, and take 
concomitant medications per Section 6.2.10.  
6.4.8 
Visit 9:  Week 24 (168 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Administration of CFQ-R (must be performed before spirometry and collection of 
sputum, blood, and urine samples)  
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Sputum induction and sample collection (must be performed after spirometry) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP (2 bottles) 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 


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The subject will be scheduled for the next study visit (phone call) and informed of the estimated 
length of the call.   
6.4.9 
Visit 10:  Week 28 (196 Days ± 5 Days After Visit 2) 
The following procedures will be performed during a phone call from the site to the subject: 
 Recording of information about any AEs and concomitant medications 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 If a pulmonary exacerbation is suspected, the subject must visit the clinic for further 
assessment (history, physical examination, and tests as determined by the Investigator) to 
determine whether a pulmonary exacerbation has occurred. 
 The subject will be instructed to contact the site if she/he has any symptoms suggestive of 
a pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast and take the IP with breakfast before the visit, and take 
concomitant medications per Section 6.2.10. ( 
6.4.10 
Visit 11:  Week 32 (224 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  


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o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP (2 bottles) 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit (phone call) and informed of the estimated 
length of the call.   
6.4.11 
Visit 12:  Week 36 (252 Days ± 5 Days After Visit 2) 
Same as Visit 10 (Section 6.4.9) 


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6.4.12 
Visit 13:  Week 40 (280 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 12 lead ECG  
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential (review results before 
dispensing of IP) 
 Dispensing of IP (2 bottles) 
The subject will be instructed to take the IP with a full glass of water (about 250 mL or 8 oz) at 
about the same time every day with breakfast. 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit (phone call) and informed of the estimated 
length of the call.   
6.4.13 
Visit 14:  Week 44 (308 Days ± 5 Days After Visit 2) 
Same as Visit 10 (Section 6.4.9)  
Subjects on cyclical inhaled antibiotic (e.g. tobramycin, amikacin) treatments should be 
scheduled for the next visit (Week 48) such that they are about midway in the cycle of 
administration of the antibiotics on the day of the visit. 


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6.4.14 
Visit 15:  Week 48 (336 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Collection of IP from previous study visit and count of capsules 
 Recording of information about any AEs and concomitant medications 
 Complete physical exam 
 12-lead ECG 
 Weight 
 Vital signs 
 Pulse oximetry 
 Administration of CFQ-R (before spirometry and collection of sputum, blood, and urine 
samples)  
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Sputum induction and sample collection (must be performed after spirometry) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential 
The subject will be instructed to contact the site if she/he has any symptoms suggestive of a 
pulmonary exacerbation. 
The subject will be scheduled for the next study visit, informed of the estimated length of the 
visit, and instructed to eat breakfast before the visit, and take concomitant medications per 
Section 6.2.10.  


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6.5 
Follow-Up Period 
6.5.1 
Visit 16:  Week 52 (364 Days ± 5 Days After Visit 2) 
The following procedures will be performed: 
 Recording of information about any AEs and concomitant medications 
 Focused physical exam 
 Weight 
 Vital signs 
 Pulse oximetry 
 Spirometry 
 Pulmonary exacerbation checklist per modified Fuchs criteria (recorded directly in the 
eCRF) 
 Collection of blood samples:  
o hematology 
o serum chemistry (includes hs-CRP) 
 Collection of urine samples: 
o urinalysis  
o urine pregnancy test for women of childbearing potential 


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7 SUBJECT AND STUDY DISCONTINUATION 
Subjects who terminate the study early after randomization may not be replaced, regardless of 
the reason for withdrawal. 
7.1 
Screen Failures 
Subjects who sign and date the ICF but who do not meet the eligibility criteria (Section 4) or 
who decide not to move forward with the Baseline visit are defined as screen failures. Each 
Investigator will maintain a screening log that lists all subjects screened and any reasons for 
screen failure. A copy of this log will be retained in the Investigator’s study files.   
7.2 
Premature Discontinuation  
Any subject who becomes pregnant during the study must be immediately and permanently 
discontinued from study treatment. 
 
 
In addition, a subject may be prematurely discontinued from study treatment for any of the 
following reasons: 
 AE 
 Subject noncompliance or unwillingness to comply with the procedures required by the 
protocol 
 Protocol violation (e.g., violation of eligibility criteria or receipt of the incorrect IP or 
dose) 
 Investigator discretion 
 Sponsor request 
Any subject who discontinues from study treatment for any reason should not be 
withdrawn/discontinued from the study and should complete the remaining study visits. 
Pulmonary exacerbations can occur in the patient population being studied. In case of a 
pulmonary exacerbation, the subject should be continued on the IP unless she/he takes a 
prohibited concomitant medication (Section 5.9), or, in the opinion of the Investigator, should be 
discontinued from study treatment in view of being medically unstable.  
Subjects who discontinue IP for any reason (including because of an AE) should not be 
withdrawn/discontinued from the study and should complete remaining study visits. If IP is 
discontinued, it may be restarted at the discretion of the investigator after discussion with the 
medical monitor. 
All subjects are free to withdraw/discontinue from participation at any time, for any reason, 
specified or unspecified, and without prejudice.  
Reasonable attempts will be made by the Investigator to provide a reason for subject 
withdrawals/discontinuations from the study. The reason for the subject’s 


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withdrawal/discontinuation from the study will be specified in the source documents. Subjects 
who withdraw/discontinue from the study should be encouraged to visit the clinic for an Early 
Termination visit; the procedures to be performed at this Early Termination visit are detailed in 
the Schedule of Events (Appendix 1). 
7.3 
Study or Site Termination 
Conditions may arise during the study that could prompt the Sponsor to halt the study or to 
terminate study conduct at a study site. Conditions that may prompt such considerations include, 
but are not limited to, the following events: 
 The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 
 A decision on the part of Sponsor to suspend, discontinue, or shorten the study 
 Failure of the Investigator to enroll eligible subjects into the study 
 Failure of Investigator to comply with International Conference of Harmonisation 
Tripartite Guideline: Guideline For Good Clinical Practice E6 (R1) (ICH-GCP) 
guidelines or applicable regulations 
 Submission of false information from the research facility to the Sponsor, a monitor, a 
Regulatory Authority, or an Institutional Review Board/Ethics Committee (IRB/EC) 
 Insufficient adherence to protocol requirements 
 A conflict of interest for the Investigator, his/her institution, or site personnel that would 
negatively impact the integrity of the clinical trial 
 The Institution or IRB/EC under for-cause investigation by a Regulatory Authority 


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8 ADVERSE EVENTS 
8.1 
Reporting Responsibilities 
AEs will be reported for each subject from the signing of the study ICF through study 
completion or early termination. It is the responsibility of the Investigator to assess the severity 
and causality of all AEs and whether or not the event began before or after initiating study 
treatment. Data describing AEs will be entered in the subject’s medical record and eCRF, and as 
appropriate, in an SAE report. SAEs will be reported to the Sponsor as described in Section 8.6. 
Subjects who experience AEs, whether or not serious, should receive appropriate treatment and 
medical supervision as clinically indicated. All AEs must be followed until resolution, 
stabilization, or a time that is mutually agreed upon between the Medical Monitor and the 
Investigator.  
8.2 
Definitions 
8.2.1 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and does not necessarily have a causal relationship with this product.  For purposes of this trial, 
AEs will be reported from the signing of the study ICF through study completion or early 
termination. A TEAE is an AE that occurs after the first dose of IP. 
8.2.2 
Serious Adverse Event 
An AE is considered serious if, in the opinion of either the Investigator or the Sponsor, it meets 
any of the following criteria: 
 Results in death 
 Is life-threatening (an AE is considered life-threatening if, in the opinion of either the 
Investigator or the Sponsor, its occurrence places the subject at immediate risk of death. 
It does not include an AE that, had it occurred in a more severe form, might have caused 
death.) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in a persistent or significant disability/capacity 
 Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
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If it is not certain that an event meets the above definitions of an SAE, the Investigator should 
contact the Medical Monitor to discuss. 
8.2.3 
Severity Assessment 
The Investigator will assess the severity of each AE according to the following criteria:  
 Mild (Grade 1):  awareness of signs or symptoms but easily tolerated and are of minor 
irritant type. Symptoms do not require therapy or a medical evaluation. Signs and 
symptoms are transient. 
 Moderate (Grade 2):  events that introduce a low level of inconvenience or concern to 
the subject but are usually improved by simple therapeutic measures. Moderate 
experiences may cause some interference with function. 
 Severe (Grade 3):  events that generally require systemic drug therapy or other 
treatment. They are usually incapacitating. 
8.2.4 
Causality Assessment 
The Investigator will assess causality of each AE in accordance with the following definitions: 
 Not related:  The event is clearly related to other factors such as the subject’s clinical 
state, therapeutic interventions or concomitant drugs administered to the subject. This is 
especially so when an event occurs prior to the commencement of treatment with the IP. 
 Unlikely:   The event was most likely produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or a concomitant drug administered to the subject 
and does not follow a known response to the IP. 
 Possible: The event follows a reasonable temporal sequence from the time of IP 
administration or follows a known response to the IP but could have been produced by 
other factors such as the subject's clinical state, other therapeutic interventions, or 
concomitant drugs administered to the subject. 
 Probable: The event follows a reasonable temporal sequence from the time of IP 
administration and follows a known response to the IP and cannot be reasonably 
explained by other factors such as the subject's clinical state, other therapeutic 
interventions, or concomitant drugs administered to the subject. 
 Definite: The event follows a reasonable temporal sequence from the time of IP 
administration and follows a known response to the IP and cannot be reasonably 
explained by other factors such as the subject's clinical state, other therapeutic 
interventions, or concomitant drugs administered to the subject and in addition one or 
more of the following: 
o Occurs immediately following IP administration  
o Improves on stopping the IP 
o Reappears on repeat exposure to the IP 


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8.2.5 
Assessment of Expectedness 
Each SAE considered to be possibly, probably, or definitely related to the IP must be assessed 
for expectedness to determine whether it is reportable as a SUSAR (Suspected Unexpected 
Serious Adverse Reaction). The Reference Safety Information for this study, against which 
expectedness assessments are made, can be found in the IB. Determination of the expectedness 
of an event is the responsibility of the Sponsor. 
8.3 
Clinical Laboratory Abnormalities 
Any laboratory abnormality deemed clinically significant by the Investigator will reported as an 
AE. A clinically significant abnormality is a confirmed abnormality (by repeat test) that is 
changed sufficiently from Screening/Baseline so that in the judgment of the Investigator an 
alteration in management is warranted. This alteration may include monitoring the laboratory test 
further, initiating other diagnostic tests or procedures, changing ongoing treatment, or 
administering new treatment.   
Whenever possible, the underlying medical diagnosis (e.g., anemia) should be reported as the AE 
term. Repeated additional tests or other evaluations required to establish the significance and 
etiology of an abnormal result should be obtained when clinically indicated.  
8.4 
Physical Exam Abnormalities 
Any physical exam abnormality deemed clinically significant by the Investigator at Screening or 
Baseline will be reported as medical history. Any physical exam abnormality emergent after the 
administration of IP, or abnormality that has worsened since Screening or Baseline reporting, 
that is deemed clinically significant by the Investigator, will be reported as an AE.   
8.5 
Pregnancy 
A subject who becomes pregnant during the trial must discontinue IP use. All pregnancies in 
female subjects that occur during the trial must be reported to the Sponsor and followed to 
conclusion. The outcome of each pregnancy must be reported on the Pregnancy Report Form.   
Pregnancy alone is not an AE, nor is an induced elective abortion to terminate a pregnancy 
without medical reason. However, an induced therapeutic abortion to terminate a pregnancy 
because of complications or medical reasons must be reported as an SAE. The underlying 
medical diagnosis for this procedure should be reported as the SAE term. A spontaneous 
abortion is always considered an SAE. 


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8.6 
Reporting of Serious Adverse Events  
SAEs must be reported to the Sponsor or designee within 24 hours of awareness of the event. If 
at the time the Investigator submits an initial SAE report the event has not resolved, the 
Investigator must provide a follow-up report as soon as the event resolves (or upon receipt of 
significant information if the event is still ongoing). All SAEs must be followed until resolution, 
stabilization, or a time that is mutually agreed upon between the Medical Monitor and the 
Investigator.  
An SAE report should be sent to the Sponsor’s designee: 
 
 
 
After review of the initial SAE report, additional documentation (e.g., clinic or hospital records, 
or procedure reports) may be requested 
8.7 
Reporting to Regulatory Authorities and Institutional Review Boards/Ethics 
Committees  
Reporting of AEs, including SUSARs, will be carried out in accordance with applicable 
regulations.  
 


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9 STATISTICAL CONSIDERATIONS 
9.1 
Sample Size 
The sample size calculation was performed with the following assumptions: 
 1:1:1 ratio of 50 mg CTX-4430, 100 mg CTX-4430, and placebo 
 Differences between average treatment effect of 50 mg/100 mg CTX-4430 and placebo 
response of 3.5 units at 48 weeks 
 Common standard deviation (SD) of 7 units 
 Power of at least 90% 
 One-sided alpha = 0.05  
A sample size of 156 subjects (52:52:52) is required on the basis of the above assumptions for 
the primary, overall comparison of CTX-4430 versus placebo. Although the primary analysis 
will be based upon the Full Analysis Population (FAP), it is also of interest to be able to have a 
sufficient number of subjects to support analyses in the Per-protocol Population (PP). It is 
expected that approximately 80% of randomized subjects will be included in the PP. As such, the 
number of randomized subjects is increased to 195 (65:65:65). 
9.2 
Analysis Conventions 
The primary efficacy analysis will be based upon an average over the 2 doses of CTX-4430 with 
testing at a 1-sided 0.05 level of significance. If this comparison is significant, additional tests 
will be conducted. Analyses for other endpoints will use 2-sided tests at the 0.05 level. 
Data collected in this study will be reported using summary tables and patient data listings. For 
categorical variables, frequencies, and percentages will be presented. For continuous variables, 
the number of subjects (n), mean, SD, median, minimum, and maximum will be presented. 
Unless otherwise indicated, confidence intervals will be 95% 2-sided intervals. 
9.3 
Subject Populations 
 Randomized Population:  All subjects randomized to an active treatment or placebo will 
be included in the Randomized Population. Subjects in the Randomized Population will 
be analyzed according to their randomized treatment group. 
 Full Analysis Population:  All subjects randomized to and receiving at least 1 dose of 
assigned treatment will be included in the FAP. Subjects in the FAP will be analyzed 
according to their randomized treatment group. 
 Safety Population:  All subjects randomized to and receiving at least 1 dose of assigned 
treatment will be included in the Safety Population. All safety analyses will be performed 
using the Safety Population according to the actual treatment received.  
 Per-Protocol Population:  Subjects in the FAP who met all study inclusion/exclusion 
criteria and have at least 80% of assigned treatment doses at the time of their 48 week 


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assessment will be included in the PP. All subjects in the PP will be analyzed according 
to the actual treatment received.    
9.4 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics (including medical history and prior medications) will 
be summarized descriptively overall and by treatment group. 
9.5 
Subject Disposition 
The number of screened subjects, screen failures, randomized subjects, treated subjects, subjects 
who completed the study, and subjects who discontinued the study will be summarized by 
treatment group. Reasons for discontinuation will also be summarized. 
The number of subjects in each subject population and the reasons for inclusion in the FAP but 
not in the PP will be summarized by treatment group. 
9.6 
Analysis 
9.6.1 
Primary Efficacy Endpoint 
The primary efficacy analysis of change from Baseline to Week 48 in FEV1 percent predicted 
will be performed on the FAP. The primary efficacy evaluation will compare the combined, 
average absolute change from Baseline in FEV1 percent predicted of the 50 mg and 100 mg 
CTX-4430 treatment groups versus the placebo group. 
The primary analysis will be based upon an analysis of variance (ANOVA) in which the average 
of the Week 48 change from Baseline in FEV1 for the 2 CTX-4430 doses is compared to that in 
the placebo group. The ANOVA model will contain a separate term for each dose group with the 
average over the 2 CTX-4430 doses created by averaging the parameters estimates from the 
ANOVA model. In addition to terms for treatment group, the ANOVA will include stratification 
for the factors used for randomization. For subjects missing their Week 48 assessment, the 
average placebo change from Baseline to Week 48 will be imputed. Descriptive statistics will be 
presented by treatment group and averaged CTX-4430 dose. 
If the primary analysis (aggregate CTX-4430 effect) reaches the 0.05 level of significance 
(1-sided), the individual CTX-4430 doses will be compared to the placebo arm using Dunnett's 
procedure at the 0.05 (2-sided) alpha level. This procedure maintains the type I error at the usual 
0.05 (2-sided) level for the individual dose comparisons with placebo while allowing a proof of 
concept test for the pooled comparison at the 0.05 (1-sided). This approach is consistent with the 
Fleming and Richardson approach to Phase 2 screening trials in which a screening trial, if 
positive at the more stringent 0.05 2-sided level after preliminary testing, can be treated as 
providing a more definitive statistical test and may reduce the amount of additional confirmatory 
trial data that is needed.33. No other adjustments for multiplicity will be used and other statistical 
analyses will be viewed as supportive. 


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Sensitivity analyses for the primary analysis will be conducted in which 1) the last available data 
is used (last observation carried forward), 2) the primary analysis is repeated using observed data 
only, and 3) using a rank based analysis where missing data are assigned the worst rank.34  
In addition to the univariate ANOVA, a mixed model repeated measures analysis of change from 
Baseline in FEV1 percent predicted at each post-Baseline visit using all available data will be 
used to explore the consistency of the treatment effect over time. The model will include 
treatment (all 3 doses), visit, and treatment-by-visit interaction with additional factors for the 
randomization strata.   
The primary analysis will be repeated on the PP as a supportive analysis. 
9.6.2 
Secondary and Exploratory Endpoints 
Clinical Endpoints 
The spirometry-based secondary endpoints will be analyzed using the same methods as the 
primary endpoint. For time points prior to 48 weeks, only descriptive statistics will be presented. 
Pulmonary exacerbations will be analyzed both as the time to first pulmonary exacerbation and 
the number of pulmonary exacerbations.  
Biomarker Endpoints 
The analyses of biomarkers (sputum DNA and elastase, serum hs-CRP) will be based upon 
descriptive statistics by treatment group. In addition to the basic descriptive statistics, confidence 
intervals for the differences between the CTX-4430 groups and placebo will be presented. 
Exploratory Endpoints   
Analyses of sputum bacterial density (P aeruginosa, Burkholderia cepacia complex, 
Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Staphylococcus aureus 
(including methicillin–resistant S aureus and small colony variants of S aureus [CFUs]) and 
HRQOL will be based upon descriptive statistics by treatment group. In addition to the basic 
descriptive statistics, confidence intervals for the differences between the CTX-4430 groups and 
placebo will be presented. 
 
 
  
 
 
 


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9.6.3 
Safety and Tolerability Endpoints 
Extent of Exposure 
Treatment exposure and treatment compliance will be summarized by treatment group. 
Adverse Events 
The Investigator’s verbatim term for each AE will be mapped to system organ class and 
preferred term using the latest version of the Medical Dictionary for Regulatory Activities. 
TEAEs will be summarized by system organ class and preferred term; a subject will only be 
counted once per system organ class and once per preferred term within a treatment. Subject 
counts and percentages and event counts will be presented for each treatment group and totaled 
for all treatment groups for the following: 
 All TEAEs 
 All TEAEs by severity 


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 All TEAE by relationship  
 All SAEs 
 TEAEs leading to discontinuation of study participation 
Listings will be presented by subject for all TEAEs, all SAEs, TEAEs with death as the outcome, 
and TEAEs leading to discontinuation from the study.   
Events recorded prior to the initiation of study treatment will be listed separately. 
Concomitant Medications 
Concomitant medications will be coded using the most current WHO Drug Dictionary and 
summarized by drug class and medication term with results presented by treatment group. A 
listing of prior and concomitant medications will also be presented. 
Clinical Laboratory Evaluations 
Clinical laboratory results at each time point and change from Baseline will be displayed using 
summary statistics (n, mean, SD, median, minimum and maximum values) by treatment group. 
Listings of laboratory data will also be presented. Within each listing, laboratory values outside 
the normal ranges will be flagged as either high or low. In addition, shift tables will be presented 
to display the shift in the normal range categories (low, normal, high) from Baseline to each 
specified time point. Baseline is defined as the latest result obtained prior to first IP 
administration.   
Weight, Pulse Oximetry, Vital Signs, Electrocardiogram Parameters 
Values at each time point and change from Baseline for weight, pulse oximetry, vital sign 
measurements (systolic and diastolic blood pressure, pulse, respiration rate, and temperature), 
and ECG parameters will be summarized with descriptive statistics (n, mean, SD, median, 
minimum, and maximum) at each time point by treatment group. Baseline is defined as the latest 
result obtained prior to first IP administration. In addition, shift tables will be presented to 
display the shift in the normal range categories (abnormal/normal) from Baseline to each 
specified time point. Listings of these data will also be presented. 
9.7 
Interim Analysis by IDMC 
An IDMC will be formed to periodically review (approximately every 8 weeks) the 
accumulating study data. The primary responsibility of the IDMC will be to monitor subject 
safety (including pulmonary exacerbations) and study conduct. The IDMC will have access to 
both safety and efficacy data. The IDMC will be requested to avoid formal evaluations of 
efficacy for the purpose of discontinuing the trial early for benefit. As such, no adjustment for 
multiple testing will be required. The IDMC will review the study data in accordance with a 
written charter. 


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10 ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES 
10.1 Ethical Conduct of the Study 
The trial will be conducted in compliance with the protocol, applicable GCP 
standards/guidelines, and applicable regulations. The procedures set out in this study protocol 
pertaining to the conduct, evaluation, and documentation of this study are designed to ensure that 
the Sponsor and the Investigators abide by ICH-GCP and applicable regulations. Compliance 
also constitutes compliance with the ethical principles that have their origins in the Declaration 
of Helsinki. 
10.2 Institutional Review Board Approval 
This protocol, ICFs, and any subsequent modifications to these documents will be reviewed and 
approved by the relevant IRB(s)/EC(s) responsible for oversight of the study. A letter from the 
IRB/EC indicating approval of the study to be conducted by the Investigator will be provided to 
the Sponsor before initiation of any enrollment at that site. All reviews and approvals by the 
IRB/EC will be in accordance with applicable regulations. 
10.3 Informed Consent 
The ICF must be signed and dated before performance of any study-related procedures. The 
original signed ICF for each subject must be filed with records kept by the Investigator. A copy 
of the ICF must be provided to the subject.   
10.4 Confidentiality 
Personal study subject data collected and processed for the purposes of this study will be 
managed by the Investigator and the investigational site staff with adequate precautions to ensure 
the confidentiality of these data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors, and other authorized agents of the Sponsor; the IRB(s)/EC(s) approving this 
research; and any applicable Regulatory Authorities will be granted direct access to the study 
subjects’ original medical records for verification of clinical trial procedures and data without 
violating the subjects’ confidentiality, to the extent permitted by the law and regulations. In any 
presentation of the results of this study at meetings or in publications, the subjects’ identity will 
remain confidential.    
10.5 Protocol Amendments 
Any changes to the protocol will be made in writing by the Sponsor in the form of a protocol 
amendment. Except when necessary to eliminate immediate hazards to the subjects, changes will 
not be implemented until approval by the IRB/EC and Regulatory Authority, if required. 


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10.6 Case Report Forms  
An eCRF will be used to record all subject data specified by this protocol. The eCRF must be 
completed by designated and trained investigational site personnel. The eCRF will be signed by 
the Investigator or a Subinvestigator listed on Form FDA 1572. It is the responsibility of the 
Investigator to ensure the eCRFs are completed and submitted to the Sponsor (or designee) in an 
accurate and timely manner. The processing of eCRFs will include an audit trail (to include 
changes made, reason for change, date of change, and person making change).   
10.7 Source Document Maintenance 
Source documents are defined as the original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents may include, but are not limited to, 
study progress notes, e-mail correspondence, computer printouts, laboratory data, and IP 
accountability records. All source documents produced in this study will be maintained by the 
Investigators and made available for monitoring and audit by the Sponsor’s representatives, and 
inspection by the IRB/EC or Regulatory Authorities. 
10.8 Retention of Records 
Each Investigator will maintain all study records and documents pertaining to the conduct of this 
study and the distribution of IPs (including, but not limited to, medical records, eCRFs, ICFs, 
and IP accountability records) in accordance with applicable regulations. No study records 
should be destroyed without authorization from the Sponsor. 
10.9 Study Monitoring 
Site monitoring visits will be conducted by an authorized Sponsor representative (the monitor) in 
accordance with ICH-GCP and applicable regulations. The monitor will review eCRFs, source 
documents, ICFs, and other study records to verify that the rights and well-being of subjects are 
protected; the reported trial data are accurate, complete, and verifiable from source documents; 
and the conduct of the trial is in compliance with the currently approved version of the protocol, 
ICH-GCP, and applicable regulations. 
10.10 Protocol Deviations 
The Investigator is responsible for reporting protocol deviations to the IRB/EC in accordance 
with applicable regulations. Additionally, the following protocol violations will be reported in 
the eCRF: 
 Violation of eligibility criteria 
 Receipt of the incorrect IP or dose 
 Receipt of a prohibited concomitant medication 


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10.11 Financial Disclosure 
Investigators participating in this study will provide accurate financial disclosure information to 
the Sponsor as required by 21 Code of Federal Regulations Part 54. Investigators will update the 
financial information if any relevant changes occur during the study and for 1 year after 
completion of the study. 
10.12 Publication and Disclosure Policy 
Investigators and their staff shall hold confidential, and not disclose directly or indirectly to any 
third party other than those persons involved in the study who have a need to know, the protocol, 
the data arising out of the study, and any other information related to the study or to Sponsor’s 
products or research programs that is provided to the Investigator. All such persons must be 
instructed not to further disseminate this information to others. Investigators shall not use the 
Confidential Information for any purpose other than the study. The foregoing obligations of 
confidence and non-use assumed by the Investigator shall not apply to: (a) information which at 
the time of disclosure is in the public domain; (b) information which thereafter lawfully becomes 
part of the public domain other than disclosure by or through the Investigator; (c) information 
which, as evidenced by the Investigator’s written records, was known by the Investigator prior to 
Celtaxsys disclosure; (d) information which is lawfully disclosed to the Investigator by a third 
party not under any obligation of confidence to Celtaxsys; or (e) information which is required to 
be disclosed by law or government Regulatory Authority, provided reasonable advance notice of 
such disclosure is given to Celtaxsys.  
All data and discoveries arising out of the study, patentable or non-patentable, shall be the sole 
property of Celtaxsys, Inc. Celtaxsys reserves the right of prior review of any publication or 
presentation of information related to the study. Celtaxsys may use these data now or in the 
future for presentation or publication at Celtaxsys’ discretion or for submission to government 
Regulatory Authorities. 
Celtaxsys adheres to the general principles of publication of scientific data as articulated by the 
International Committee of Medical Journal Editors and acknowledges its responsibility to 
publish results of clinical trials. Persons that fulfill the criteria for authorship 
(http://www.icmje.org/recommendations/) may be authors for publications on the basis of their 
contributions to the design, conduct, results, and/or analysis of this clinical trial. Investigators 
will have access to the data from this clinical trial for the preparation of scientific presentations 
and publications, in accordance with their institutional agreements with Celtaxsys, subject to the 
requirements of confidentiality. Celtaxsys reserves the right to review, within a reasonable time 
frame, results or analyses from data generated in this study that are intended for public 
presentation, including scientific meetings. 
In signing this protocol, the Investigator agrees to the release of the data from this study and 
acknowledges the above confidentiality and publication policy. The provisions of this release 
shall survive the completion of the study.  


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11 REFERENCES 
1. Cystic Fibrosis Foundation. About CF: causes, signs & symptoms. 
http://www.cff.org/AboutCF/. Accessed March 16, 2015. 
2. Cystic Fibrosis Trust. Frequently Asked questions. http://www.cysticfibrosis.org.uk/about-
cf/frequently-asked-questions#na. Accessed March 16, 2015. 
3. Cystic Fibrosis Foundation. CF mutations. 
http://www.cff.org/AboutCF/Testing/Genetics/CFMutations/. Accessed March 16, 2015. 
4. British Lung Foundation. Children’s lung conditions. 
http://www.blf.org.uk/Conditions/Detail/Inherited-conditions. Accessed March 16, 2015. 
5. World Health Organization. The molecular genetic epidemiology of cystic fibrosis. Geneva: 
World health Organization; 2004. 
http://www.cfww.org/docs/who/2002/who_hgn_cf_wg_04.02.pdf. Accessed March 16, 2015. 
6. McCormick J, Mehta G, Oleson HV, et al. Comparative demographics of the European cystic 
fibrosis population: a cross-sectional database analysis. Lancet. 2010;375:1007-1013. 
7. Ellaffi M, Vinsonneau C, Coste J, et al. One-year outcome after severe pulmonary 
exacerbation in adults with cystic fibrosis. Am J Respir Crit Care Med. 2005;171:158-164. 
8. Aaron SD, Ramotar K, Ferris W, et al. Adult cystic fibrosis exacerbations and new strains of 
Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2004;169:811-815.  
9. Chmiel JF, Konstan MW. Anti-inflammatory medication for cystic fibrosis lung disease: 
selecting the most appropriate agent. Treatments in Resp Med. 2005;4:255-273.  
10. Rao NL, Riley JP, Banie H, et al. Leukotriene A4 hydrolase inhibition attenuates Allergic 
airway inflammation and hyperresponsiveness. Am J Respir Crit Care Med. 2010;181:899–
907. 
11. O'Driscoll BR, Cromwell O, Kay AB. Sputum leukotrienes in obstructive airways diseases. 
Clin Exp Immunol. 1984;55:397-404. 
12. Carpagnano GE, Barnes PJ, Geddes DM, et al. Increased leukotriene B4 and interleukin-6 in 
exhaled breath condensate in cystic fibrosis. Am J Respir Crit Care Med. 2003;167:1109-
1112.. 
13. Woolhouse IS, Bayley DL, Stockley RA. Sputum chemotactic activity in chronic obstructive 
pulmonary disease: effect of α1-antitrypsin deficiency and the role of leukotriene B4 and 
interleukin 8. Thorax. 2002;57:709-714. 
14. Tirouvanziam R. Neutrophilic inflammation as a major determinant in the progression of 
cystic fibrosis. Drug News Perspect. 2006;19:609-614.  
15. Konstan MW, Krenicky JE, Finney MR, et al. Effect of ibuprofen on neutrophil migration in 
vivo in cystic fibrosis and healthy subjects. J Pharmacol Exp Ther. 2003;306:1086-91.  
16. Konstan MW, Schluchter MD, Xue W, et al. Clinical use of ibuprofen is associated with 
slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 
2007;176:1084-1089.  


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17. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic 
fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-1672. 
18. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–Ivacaftor in patients with cystic 
fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015. May 17. [Epub ahead of 
print].  
19. Rowe, SN, Heltsche SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis 
transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic 
fibrosis. Am J Respir Crit Care Med. 2014:190:175-184. 
20. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with 
cystic fibrosis. N Engl J Med. 1995;332:848-54. 
21. Konstan MW, Vargo KM, Davis PB. Ibuprofen attenuates the inflammatory response to 
Pseudomonas aeruginosa in a rat model of chronic pulmonary infection. Implications for 
antiinflammatory therapy in cystic fibrosis. Am Rev Respir Dis. 1990;141:186-192. 
22. Elborn JS, Perrett J, Forsman-Semb K, et al . Efficacy, safety and effect on biomarkers of 
AZD9668 in cystic fibrosis. Eur Respir J. 2012;40:969-976.  
23. Moss RB, Mistry SJ, Konstan MW, et al. Safety and early treatment effects of the CXCR2 
antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros. 2013;12:241-248.  
24. Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of azithromycin on pulmonary 
function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a 
randomized controlled trial. JAMA. 2010;303:1707-1715.  
25. National Institutes of Health. NAC Phase IIB: A Multi-Center, Phase IIB, Randomized, 
Placebo-controlled, Double-Blind Study Of The Effects Of N-Acetylcysteine On Redox 
Changes and Lung Inflammation In Cystic Fibrosis Patients. 
https://clinicaltrials.gov/ct2/show/NCT00809094?term=NCT00809094&rank=1. Accessed 
March 16, 2015. 
26. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline 
on the Clinical Development of Medicinal Products for the Treatment of Cystic Fibrosis. 
London: European Medicines Agency; 2009. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500003507.pdf. Accessed March 16, 2015. 
27. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human 
DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with 
cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637–642. 
28. Bilton D, Canny G, Conway S, et al. Pulmonary exacerbation: Towards a definition for use 
in clinical trials. Report from the EuroCare CF Working Group on outcome parameters in 
clinical trials. J Cyst Fibros. 2011; 10 Suppl 2:S79-S81. 
29. Henry B, Aussage P, Grosskopf C, Goehrs JM, et al. Development of the Cystic Fibrosis 
Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life 
Res. 2003;12:63-76.  
30. Modi AC, Quittner AL. Validation of a disease-specific measure of health-related quality of 
life for children with cystic fibrosis. J Pediatr Psychol. 2003;28:535-545. 


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31. Quittner AL, Sweeny S, Watrous M, et al. Translation and linguistic validation of a disease-
specific quality of life measure for cystic fibrosis. J Pediatr Psychol. 2000;25:403-414.  
32. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26(2):319-338. 
33.  Fleming TR, Richardson BA. Some design issues in trials of microbicides for the prevention 
of HIV infection. J Infect Dis. 2004;190:666-674.  
34. Lachin JM. Worst-rank score analysis with informatively missing observations in clinical 
trials. Control Clin Trials. 1999;20:408-422. 
 


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Appendix 1 Schedule of Events  
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Early 
Term 
Visit Name/Weeka Screening Baseline 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Informed consent (study ICF 
 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & disease characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam c 
Xc 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Xc 
X 
X 
12-lead ECG 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Height, calculation of BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signs 
X 
Xd 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
CFQ-Re 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Spirometry 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Pulmonary exacerbation checklist 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sputum sample f 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Hematology  
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Serum chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
hs-CRP 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Serum pregnancy test g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV & HCV antibodies, HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urine pregnancy test g 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Urine alcohol and drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Xh 
Xh 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
IP dispensing  
 
X 
X 
 
X 
X 
X 
X 
Xi 
 
Xi 
 
Xi 
 
 
 
 
IP collection and capsule count 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
AE & concomitant medication recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BMI = body mass index, CFQ-R = Cystic Fibrosis Questionnaire – Revised; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus, hs-CRP = high-sensitivity C-reactive protein: ICF = informed consent form; IP = investigational product; 
. 
a 
Baseline visit within 21 days of Screening, window for other visits: ±5 days 
b 
Visits 10, 12, and 14 will be conducted via phone call. 
c 
Complete physical exam at Screening and Week 48, focused physical exam at all other visits 
d 
Predose and before discharge 
e 
To be administered before spirometry and sample collection 
f  
After spirometry 
g 
For women of childbearing potential  
 
 
  
I 
2 bottles of IP must be dispensed


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Appendix 2 Protocol Amendments and Summary of Changes 
Amendment 1, Protocol Version 2.0, 17 July 2015 
The overall purposes of this amendment are as follows:  
 Further specify organisms to be evaluated in sputum culture  
 Provide a clearer definition for pulmonary exacerbation, consistent with the modified 
Fuchs criteria 
 Shorten the requirement for stable exposure to CFTR modulators from 12 weeks to 8 
weeks 
 Clarify the time for reporting SAEs to the Sponsor  
 Change the contact name for reporting SAEs to the Sponsor  
 Revise safety evaluations and contraception requirements in response to comments for 
consideration from the US FDA (14 July 2015) 
Amendment 2, Protocol Version 3.0, 05 September 2015 
The overall purposes of this amendment are as follows: 
 To align the protocol with the Reference Safety Information section in the revised version 
of the Investigator Brochure 
 Clarify blinding and unblinding overview 
Amendment 2, Protocol Version 3.1, 30 September 2015 
The overall purposes of this amendment are as follows: 
 Clarify the reasons for premature discontinuation of study treatment 
A summary of changes is provided in the table following; deleted text is identified in 
strikethrough, and new text is identified in bold italics. 
Amendment 3, Protocol Version 4.0, 19 November 2015 
The overall purposes of this amendment are as follows: 
 
 
 
 To provide additional options for subjects on ivacaftor-lumacaftor combination given the 
unreliability of hormonal contraception for these subjects. 
 Additional urine pregnancy tests to more closely monitor women of childbearing 
potential. 
 Clarify Screening period and allow rescreening of subjects with approval of medical 
monitor. 


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 Further clarify the reasons for premature discontinuation of study treatment. 
 Modified Exclusion Criteria: 
o Only excluding mycobacterium abscessus which is the species specifically 
associated with a more rapid decline in lung function.    
 
 
  
o Further clarification on exclusion of concurrent clinical trial participants. 
 Changed storage temperatures of study drug to be consistent with stability data. 
 
A summary of changes is provided in the table following; deleted text is identified in 
strikethrough, and new text is identified in bold italics 
 
 
Amendment 4, Protocol Version 5.0, 04 May 2016 
 
The overall purposes of this amendment are as follows: 
 
 To clarify the tobacco inclusion criteria that any type of smoking is not permitted due to 
its adverse effects on pulmonary function. 
 The drug screen exclusion criteria was modified to allow for investigator judgement in 
the case of a positive drug screen with prescription medications or therapeutic use of 
marijuana 
 The colonization exclusion criteria was modified to allow for subjects who have multiple 
negative cultures within the past year to be included. 
 To remove the exclusion for montelukast and other 5-LO inhibitors that are not in the 
same leukotriene pathway as CTX-4430. Some of these agents are very commonly used 
by CF patients and should have no impact on the study.  
 Abstinence was added as a form of acceptable contraception since it is a highly effective 
form of contraception that is used by many young women with CF.  Requiring another 
form of contraception adds unnecessary risk. Double barrier and barrier plus spermicide 
forms of contraception were added for subjects at the discretion of the investigator.  
 The time following completion of another clinical trial has been reduced from 60 to 30 
days to be consistent with studies in this therapeutic area.  
 To clarify that subjects whose spirometry fails quality criteria do not screen fail, but can 
be retested once within 7 days. At other visits, the investigator can use his discretion to 
repeat spirometry that fails quality criteria 
 
A summary of changes is provided in the table following; deleted text is identified in 
strikethrough, and new text is identified in bold italics. 


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Amendment 1, Protocol Version 2.0, 17 July 2015 Summary of Changes Table 
 
Section 
Changed Text 
Rationale 
Title Page 
 
 
  
 
Personnel change, area code 
change 
Synopsis, Study Design 
Study Design: 
Clarification 
Synopsis, Study Design 
3.1  Study Design 
A blood sample will be collected before the first dose and at Weeks 4, 8, 12, 24, 
32, 40, 48, and 52 for measurement of hs-CRP. 
FDA comments for 
consideration 
Synopsis, Study Design 
3.1  Study Design 
Hematology, serum chemistry, and urinalysis will be evaluated at Screening, 
before the first dose and at Weeks 4, 8, 12, 24, 32, 40, 48, and 52.  
FDA comments for 
consideration 
Synopsis, Study Design 
3.1  Study Design 
A 12-lead electrocardiogram (ECG) will be performed at Screening, before the 
first dose and at Weeks 4, 8, 12, 24, 32, 40, and 48. 
FDA comments for 
consideration 
Synopsis, Criteria for 
Evaluation 
Bacterial Density:  presence/absence and quantitative counts (CFUs) of 
bacteria in sputum: Pseudomonas aeruginosa, Burkholderia cepacia complex, 
Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and 
Staphylococcus aureus (including methicillin–resistant Staphylococcus  
S aureus and other bacteria small colony counts (CFUs) in sputum variants of 
S aureus)  
Further specification of 
organisms to be evaluated in 
sputum culture 
1.1  Cystic Fibrosis 
The most recent advance in the treatment of CF is correction or  modulation of 
the abnormal CFTR protein. Currently, ivacaftor is the only CFTR therapy 
approved for the treatment of CF.17 It is indicated only for the small percentage of 
CF patients (approximately 6%) who have the G551D and functionally similar 
gating mutations. Trials with correctors and modulators potentiators for other 
classes of CFTR genetic mutations (such as ataluren) and with combinations of 
correctors and modulators potentiators (such as the ivacaftor/lumacaftor 
combination 18) are ongoing. However, even these targeted therapies may not 
address the dysregulated inflammatory response, as exemplified by the GOAL 
study.19 
Clarification and addition of 
references 


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Section 
Changed Text 
Rationale 
3.2.3  Study Endpoints 
Pulmonary exacerbations are defined by as treatment with oral, inhaled, or 
intravenous (IV) antibiotic(s) for ≥4 of symptoms/signs per the criteria of 
Fuchs et al (modified Fuchs criteria) the standard definition used in clinical trials 
of CF 
Clarification 
4.1  Inclusion Criteria 
7. If on ivacaftor or ivacaftor-lumacaftor combination, on a stable regimen for at 
least 3 months 8 weeks before Baseline 
 
Based on Phase 3 data for 
either ivacaftor or the 
combination of ivacaftor-
lumacaftor, the peak effect on 
FEV1 occurs within 8 weeks 
of treatment, and no 
additional improvement is 
seen with further therapy. 
4.1  Inclusion Criteria 
18. Females of childbearing potential must have a negative pregnancy test at 
Screening (unless surgically sterile) and must agree to use a highly 
effective contraception methods from screening throughout the duration of 
the study treatment (refer to Section 5.9.2 for definition of highly effective 
methods). 
In consideration of the FDA 
comments for consideration 
regarding contraception in 
women of childbearing 
potential 
4.2  Exclusion Criteria 
4. History of either alcoholism or drug abuse within 2 years before Screening  
5. Positive alcohol and or drug test at Screening 
Clarification 
5.9.2  Contraception 
Women of childbearing potential must use an highly effective method of 
contraception until 28 days after taking the last dose of IP. Highly eEffective 
methods of contraception include the following methods: monogamous 
relationship with vasectomized partner, licensed hormonal methods associated 
with inhibition of ovulation (e.g., combination oral contraceptive pills, 
progestin-only hormonal contraception that inhibits ovulation) or 
intrauterine devices (including intrauterine hormonal systems) 
monogamous relationship with vasectomized partner, licensed hormonal 
methods (e.g., oral contraceptive pills) or intrauterine devices, or a barrier 
method (e.g., condom, diaphragm) with spermicide. 
In consideration of the FDA 
comments for consideration 
regarding contraception in 
women of childbearing 
potential 


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Section 
Changed Text 
Rationale 
6.1  Blood Sample Volume 
Table 3 Total Blood Volume 
Collected from Subjects During 
the Study 
 
Sample Type 
Number of 
Sampling 
Time Points 
Volume per 
Time Point 
Total Volume 
Screening laboratory tests….. 
1 
~ 15 mL 
~ 15 mL 
Hematology 
9 7  
~ 10 mL 
~ 90 70 mL 
Serum chemistry (including hs-CRP) 
9 7  
~ 5 mL 
~ 40 35 mL 
 
 
 
 
Total blood volume ~ 200 170 mL 
 
Increased number of samples 
per FDA comments for 
consideration 
6.2.8  Pulmonary 
Exacerbation Checklist 
Components of the modified Fuchs criteria for pulmonary exacerbation will be 
evaluated by completing a checklist:  
• 
Treatment with oral, inhaled, or intravenous antibiotic(s)   
Pulmonary exacerbations are defined as treatment with oral, inhaled, or IV 
antibiotic(s) for ≥4 of symptoms/signs listed below per the modified Fuchs 
criteria. The pulmonary exacerbation checklist will capture the 
signs/symptoms listed below as well as the treatment with oral, inhaled, or 
IV antibiotics: 
Clarification 
6.4.2  Visit 3:  Week 4 (28 
Days ± 5 Days After Visit 2) 
6.4.9 
Visit 10:  Week 32 
(224 Days ± 5 Days After Visit 
2) 
6.4.11 Visit 12:  Week 40 
(280 Days ± 5 Days After Visit 
2) 
 
12-lead ECG 
 
FDA comments for 
consideration 
6.4.9 
Visit 10:  Week 32 
(224 Days ± 5 Days After Visit 
2) 
6.4.11 Visit 12:  Week 40 
(280 Days ± 5 Days After Visit 
2) 
 
Collection of blood samples:  
o 
hematology 
o 
serum chemistry 
 
Collection of urine samples: 
o 
urinalysis  
FDA comments for 
consideration 
8.6  Reporting of Serious 
Adverse Events 
SAEs must be reported to the Sponsor or designee within 1 business day 24 
hours of awareness of the event. 
Clarification 


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Section 
Changed Text 
Rationale 
8.6  Reporting of Serious 
Adverse Events 
 
 
 
 
 
 
  
 
After review of the initial SAE report, the Medical Monitor may request additional 
documentation (e.g., clinic or hospital records, or procedure reports).additional 
documentation (e.g., clinic or hospital records, or procedure reports) may 
be requested. 
Delegation of safety function 
9.6.2  Secondary and 
Exploratory Endpoints 
Analyses of sputum bacterial density (P aeruginosa, methicillin-resistant 
Staphylococcus aureus, and other bacteria colony counts [CFUs]) Burkholderia 
cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas 
maltophilia, and Staphylococcus aureus [including methicillin–resistant S 
aureus and small colony variants of S aureus (CFUs)] and HRQOL will be 
based upon descriptive statistics by treatment group. 
Further specification of 
organisms to be evaluated in 
sputum culture 
11  References 
17. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in 
patients with cystic fibrosis and the G551D mutation. N Engl J Med. 
2011;365:1663-1672. 
18. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–Ivacaftor in 
patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl 
J Med. 2015. May 17. [Epub ahead of print]. 
New references added 
Appendix 1  Schedule of 
Events 
[ECG and sample collection time points added in accordance with changes in 
Sections 6.4.2, 6.4.9, and 6.4.11] 
FDA comments for 
consideration 
 
 
 
 
 
 
 
 


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Amendment 2, Protocol Version 3.0, 05 September 2015 Summary of Changes Table 
 
 
 
Section 
Changed Text 
Rationale 
1.2.2, Clinical Trials of CTX-
4430 
Headache was the most common adverse event considered by the 
investigators to be related to the use of CTX-443 (13%). 
VHP recommendation, 
clarification on expected AEs 
5.6, Blinding and Unblinding 
Unblinding of treatment assignment is discouraged. In the event of a medical 
emergency for which the identity of the treatment assignment is critical to the 
care of a subject the Investigator should call the Medical Monitor to discuss 
unblinding. In the event that unblinding is deemed necessary, the treatment 
assignment will be provided to the Investigator via the IWRS. A decision to 
discontinue a subject from further IP administration is not a rationale to unblind 
the treatment assignment 
All Celtaxsys study team staff members and contract research organization 
study team members will remain blinded unless specifically designated as 
unblinded and independent from the study team.  Such independent, 
unblinded study personnel may include drug distribution and IWRS vendor 
staff.  Pharmacovigilance staff will be unblinded as necessary for reporting 
to regulatory authorities, with appropriate controls to assure that access to 
any unblinded information is restricted to the safety reporting staff.  The 
sponsor will maintain a list of any designated individuals at the vendors or 
sponsor that are designated as unblinded. 
 
The investigator will ensure that blinding is broken only in accordance with 
the protocol conditions for unblinding due to medical necessity or safety 
reasons.   
 
In the case of a medical emergency, where the appropriate treatment of the 
subject requires knowledge of the IP, CTX-4430 or placebo, the investigator 
may break the randomization code at any time for an individual subject 
through the IWRS system.  Detailed procedures to break the blind will be 
provided to the investigator. In such cases, the AE necessitating the 
emergency blind break will be clearly justified, explained in writing, 
captured on the SAE form (if due to a SAE) in accordance with the 
procedures indicated in section 8.6., and must be reported to the medical 
monitor immediately.   
VHP recommendation, further 
clarification on blinding and 
unblinding 
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Administrative 
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Amendment 2, Protocol Version 3.1, 30 September 2015 Summary of Changes Table 
 
 
 
 
Section 
Changed Text 
Rationale 
7.2, Premature 
Discontinuation 
Any subject who becomes pregnant during the study must be immediately 
discontinued from study treatment. 
In addition, A a subject may be prematurely discontinued from study treatment, 
but not necessarily from the study, for any of the following reasons: 
 
AE 
 
Subject noncompliance or unwillingness to comply with the procedures 
required by the protocol 
 
Protocol violation (e.g., violation of eligibility criteria or receipt of the 
incorrect IP or dose) 
 
Pregnancy 
 
Investigator discretion 
 
Sponsor request 
Any subject who discontinues from study treatment for any reason should 
not be withdrawn/discontinued from the study and should complete the 
remaining study visits. 
VHP recommendation, further 
clarification on reasons for 
discontinuing study treatment 
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Administrative 
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Amendment 3, Protocol Version 4.0, 19 November 2015 Summary of Changes Table 
 
Section 
 
Changed Text 
 
Rationale 
Cover Page 
 
EudraCT number added per 
EU Requirement 
Cover Page/Headers/Footers 
Update version number and date 
Administrative 
changes/version control 
Table of Contents 
Visit 4:  Week 6 (42 Days ± 5 Days After Visit 2) 
5.5 Screening 
5.10.3 Contraception in women on ivacaftor-lumacaftor combination 
 
 
Updated to match protocol 
 
Synopsis 
Study Design 
Hematology, serum chemistry, and urinalysis will be evaluated at Screening, 
before the first dose and at Weeks 4, 8, 12, 24, 32, 40, 48, and 52. Serum 
chemistry will be evaluated at Screening, before the first dose and at 
Weeks 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, and 52. 
 
Added Serum Chemistry to a 
new Week 6 Visit and to the 
16 and 20 Week Visits 
 
 
 
List of Abbreviations 
GGT - Gamma-glutamyltransferase 
Updated List 
 
 
 
 
3.1 Overall Study Design 
 
 
 
 
 
 
 
 
3.1 Overall Study Design 
 
Hematology, serum chemistry, and urinalysis will be evaluated at Screening, 
before the first dose and at Weeks 4, 8, 12, 24, 32, 40, 48, and 52. Serum 
chemistry will be evaluated at Screening, before the first dose and at 
Weeks 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, and 52. 
Added Serum Chemistry to a 
new Week 6 Visit and to the 
16 and 20 Week Visits 
 
 
 
4.2 Exclusion Criteria 
7. Positive culture for Burkholderia cepacia complex or Mycobacterium 
abscessus species within 24 months before Screening or between Screening 
and Baseline 
Only excluding 
mycobacterium abscessus 
which is the species 


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11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >
the upper limit of normal (ULN) at Screening 
  
 
20. Participation in a clinical trial for any medical/device product within 60 days 
before Screening or between Screening and Baseline (participation in a 
noninterventional or observational study is permitted) 
 
specifically associated with a 
more rapid decline in lung 
function.    
 
 
 
Further clarification on 
exclusion of concurrent 
clinical trial participants. 
Section 5.4  Storage 
IPs should be stored in the containers in which they are supplied at controlled 
room temperature (15°C to 3025°C / 59°F to 8677°F), and protected from 
ultraviolet light. 
Changed storage 
temperatures to be consistent 
with the IP stability data. 
Section 5.5 Screening 
The Screening Period will occur within 21 days before the first dose of 
study drug to confirm that subjects meet the selection criteria for the 
study. The assessments to be conducted are shown in 6.3.1. The 
investigator (or an appropriate authorized designee) will obtain informed 
consent from each subject. 
 
Rescreening: 
Subjects may only be rescreened with the approval of the medical monitor. 
If a subject is rescreened, all screening assessments will be repeated. 
Subjects may only be rescreened once. If a subject is rescreened, the 
screening window begins at that time. 
Clarifies Screening period 
and may allow rescreening of 
subjects with approval of 
medical monitor. 
5.7 Blinding and Unblinding 
The Sponsor medical team, for matters relating to safety concerns and 
associated regulatory reporting, may unblind individual subjects at any 
time. 
Clarifies role of sponsor 
medical team on unblinding 
5.10.3 Contraception in 
women on ivacaftor-
lumacaftor combination 
In female subjects of childbearing potential who are receiving ivacaftor-
lumacaftor combination therapy, hormonal contraception is considered to 
be unreliable and hence cannot be used as a highly effective method of 
contraception. These study subjects must either use another method of 
highly effective contraception from the list above (section 5.10.2), or one of 
these following two alternative methods of contraception:  
 
1) For women who are continuing a hormonal method of contraception, or 
willing to begin using one, one of the following barrier methods of 
contraception should be added;  
     a. 
Male condom 
     b. 
Diaphragm 
Added section to provide 
additional options for subjects 
on ivacaftor-lumacaftor 
combination given the 
unreliability of hormonal 
contraception for these 
subjects. 


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     c. 
Cervical cap 
     d. 
Female condom 
2) In women who are not on a hormonal method of contraception, one of 
the following methods of contraception should be used.  
     a. 
Double barrier methods of contraception which is the use of a male 
condom, plus either diaphragm or cervical cap. The male condom cannot 
be used with a female condom as a double barrier method of contraception 
due to risk of tearing 
     b. 
Male or female condom plus a spermicide, or diaphragm plus a 
spermicide (acceptable methods if spermicide is regionally available) 
If local regulations require the use of additional contraceptive measures, 
these must be followed. 
6.1 Blood Sample Volume 
Table 3 
Sample Type 
Number of 
Sampling 
Time Points 
Volume per 
Time Point 
Total Volume 
Screening laboratory tests….. 
1 
~ 15 mL 
~ 15 mL 
Hematology 
9 
~ 10 mL 
~ 90 mL 
Serum chemistry (including may 
include hs-CRP) 
912 
~ 5 mL 
~ 45 60 mL 
 
 
 
 
Total blood volume ~ 200 215 mL 
Adjusted Blood Volumes 
based on added serum 
chemistry tests. 
6.2.8 Pulmonary Exacerbation 
Checklist 
The date of onset of the pulmonary exacerbation will be recorded, which 
will be defined as the date of initiation of antibiotics for the pulmonary 
exacerbation. 
Clarified documentation of 
the starting date of any 
Pulmonary Exacerbation. 
6.2.9 Serum Chemistry 
Albumin, alkaline phosphatase, ALT, AST, GGT, bicarbonate, bilirubin (total and 
direct), blood urea nitrogen, calcium, chloride, creatinine, glucose, phosphorus 
(phosphate), potassium, sodium, uric acid, total protein, and hs-CRP 
 
Added GGT to the liver 
function test panel.  
6.2.11  Sputum Induction and 
Sample Collection 
The subject will be given 2 sterile jars of adequate volume to collect the sputum. 
The filled jars with lids will be weighed and recorded. Every effort should be 
made to use the same study scale for weighing filled jars with lids. 
 
Removed requirement to 
weigh jars of sputum at the 
site as this will be performed 
at the central laboratory. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4 Treatment Period 
6.4.2, 6.4.5, 6.4.6, 6.4.7, 
6.4.8, 6.4.9, 6.4.11, 6.4.13 
 
o 
urine pregnancy test for women of childbearing potential (review 
results before administering or dispensing of IP) 
Additional urine pregnancy 
tests to more closely monitor 
women of childbearing 
potential.  
6.4 Treatment Period 
6.4.1, 6.4.2, 6.4.4, 6.4.5, 
6.4.8, 6.4.10, 6.4.12, 6.4.14, 
6.5.1 
o 
serum chemistry (includes hs-CRP) 
To clarify that the serum 
chemistry sample will be 
used to measure hs-CRP at 
these visits.  


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7.2 Premature Discontinuation Any subject who becomes pregnant during the study must be immediately and 
permanently discontinued from study treatment. 
 
 
 
 
Clarified that pregnant 
women will be permanently 
discontinued from study drug. 
 
 
 
 
7.2 Premature Discontinuation Subjects who discontinue IP for any reason (including because of an AE) should 
not be withdrawn/discontinued from the study and should complete remaining 
study visits. If IP is discontinued, it may be restarted at the discretion of the 
investigator after discussion with the medical monitor. 
 
To clarify that any restarting 
of study drug will occur only 
after consultation between 
the Investigator and the 
medical monitor. 
8.5 Pregnancy 
The outcome of each pregnancy must be reported on the Pregnancy Report 
Form eCRF.   
Correction on the mode of 
reporting.  
8.6 Reporting of Serious 
Adverse Events 
  
 
Correction of email address.  
 
 
 
 
 
  


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Created separate row for hs-CRP 
Renumbered Visits that will be conducted via phone call. 


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Amendment 4, Protocol Version 5.0, 04 May 2016 Summary of Changes Table 
 
Section 
 
Changed Text 
 
Rationale 
Cover Page/Headers/Footers 
Update version number and date 
Administrative 
changes/version control 
List of Abbreviations 
ATS – American Thoracic Society 
ERS – European Respiratory Society 
Updated List 
4.1 Inclusion Criteria 
12.  No smoking (including electronic cigarettes) for at least 6 months 
before Screening and agreement not to use such products for the duration 
of the study 
 
12. No use of tobacco or nicotine-containing products for at least 6 months 
before Screening and agreement not to use such products for the duration of the 
study 
Modified language to focus 
on exclusion of smoking. 
4.1 Inclusion Criteria 
13. Females of childbearing potential must have a negative pregnancy test at 
Screening (unless surgically sterile) and must agree to use an highly effective 
contraception method from screening throughout the duration of the study (refer 
to Section 5.10.2 for definition of highly acceptable effective methods) 
See rationale for Section 
5.10.2 below 
4.2 Exclusion Criteria 
4.  History of either alcoholism or drug abuse in the opinion of the investigator 
within 2 years before screening 
Added language to allow the 
investigator to use clinical 
judgement based on the 
knowledge of the subject 
4.2 Exclusion Criteria 
5. Positive alcohol or drug test at Screening.  
To allow the investigator to 
use results of the 
drug/alcohol screen at the 
screening visit, along with 
knowledge of the subject, to 
guide their decision on 
exclusion # 4. 
4.2 Exclusion Criteria 
6. 6. Colonization with organisms associated with a more rapid decline 
in respiratory function in CF patients (e.g. all Burkholderia species, 
Mycobacterium abscessus). Subjects with a history of a positive culture 
could be considered free of colonization if she/he has had 6 subsequent 
respiratory tract cultures negative for these bacteria within the past 24 
months prior to Screening, with one of these cultures obtained within 6 
months prior to Screening 
 
Positive culture for Burkholderia cepacia complex or Mycobacterium abscessus 
within 24 months before Screening or between Screening and Baseline 
To allow patients to enter the 
study if they have had 
negative cultures after an 
initial positive culture 


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4.2 Exclusion Criteria 
11. Bilirubin >1.25 x ULN at Screening. Subjects with known Gilbert’s 
syndrome can be included with bilirubin >1.25 x ULN 
Subjects with Gilbert’s 
syndrome can have elevated 
bilirubin in the absence of 
liver pathology 
4.2 Exclusion Criteria 
17. Use of a 5-lipoxygenase (5-LO) inhibitor (e.g., zileuton), leukotriene receptor 
antagonists (e.g. montelukast, zafirlukast), systemic corticosteroids, or systemic 
antibiotic antimicrobial therapy (other than chronic  antimicrobial use, e.g. 
azithromycin,  flucloxacillin, itraconazole  use for CF) within 14 days before 
Screening or between Screening and Baseline 
Rationale:  5 lipoxygenase 
inhibitors and leukotriene 
receptor antagonists are 
commonly used in patients 
with CF. Mechanistically, they 
are distinct from a LTA-4 
hydrolase inhibitor like CTX-
4430, and should not 
interfere with study 
assessments.  
Patients could be 
concomitantly on chronic 
antimicrobials. The intent of 
this exclusion is to exclude 
patients who could be acutely 
unstable and in need of 
treatment with systemic 
antimicrobials 
4.2 Exclusion Criteria 
19. Participation in a clinical trial for any medical/device product within 60 30 
days before Screening or between Screening and Baseline (participation in a 
noninterventional or observational study is permitted) 
Rationale: To facilitate 
participation of subjects with 
a rare disease in clinical trials 
5.5 Screening 
Based on investigator’s judgement, borderline abnormal laboratory tests 
which may exclude the subject, may be repeated once within 7 days of the 
screening visit without the subject being considered a screen fail. The 
medical monitor must be consulted for approval in such cases. 
 
In addition, subjects who fail to meet the ATS/ERS criteria for quality 
(acceptability, reproducibility, and end of test criteria) at screening may be 
retested once without being considered a screen failure. This retest should 
occur at least one day after the initial screening visit and should be 
completed within 7 days of the original screening visit date. Final decision 
on screen failure will be based upon FEV1 data after review with the 
medical monitor. 
To allow the investigators to 
use clinical judgement in 
repeating borderline lab tests 
 
 
For repeat spirometry, see 
rationale for Section 6.2.10 
below 
5.9 Concomitant Medications 
Use of 5-LO inhibitors, leukotriene receptor antagonists, c Chronic use of 
systemic corticosteroids, and regular use (>3 times per week) of high-dose 
NSAIDs (e.g., >1.6 g ibuprofen/day) is prohibited during the study…. 
See explanation of Exclusion 
Criteria 18 above 


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5.10.2 Contraception 
1. Monogamous relationship with vasectomized partner,  
2. Licensed hormonal methods associated with inhibition of ovulation (e.g., 
combination oral contraceptive pills, progestin-only hormonal contraception that 
inhibits ovulation) 
o 
For women who are receiving ivacaftor-lumacaftor combination 
therapy, hormonal contraception, including oral, injectable, transdermal 
and implantable,  is considered to be unreliable and hence cannot be used 
as an effective method of contraception. In such patients who are on 
hormonal contraception, one of the following barrier methods of 
contraception should be added; male condom, diaphragm, cervical cap or 
female condom.  
3. Intrauterine contraceptive devices (including intrauterine hormonal 
systems). 
4. True abstinence for the subject, when this is in line with the preferred 
and usual lifestyle of the subject, can be considered an effective method of 
contraception based on the judgement of the investigator. Periodic 
abstinence is not an acceptable method of contraception. 
Based on the investigator’s judgement, the following acceptable methods 
of contraception may also be used: 
1. Double barrier methods of contraception, which is the use of a male 
condom plus either diaphragm or cervical cap, may be allowed. The male 
condom cannot be used with a female condom as a double barrier method 
of contraception due to risk of tearing. 
2. Male or female condom plus a spermicide, or diaphragm plus a 
spermicide may be allowed (acceptable methods if spermicide is regionally 
available)  
If local regulations require the use of additional contraceptive measures, 
these must be followed. 
 
Contraception in women on ivacaftor-lumacaftor combination 
In female subjects of childbearing potential who are receiving ivacaftor-
lumacaftor combination therapy, hormonal contraception is considered to be 
unreliable and hence cannot be used as a highly effective method of 
contraception. These study subjects must either use another method of highly 
effective contraception from the list above (section 5.10.2), or one of these 
following two alternative methods of contraception:  
1) For women who are continuing a hormonal method of contraception, or 
willing to begin using one, one of the following barrier methods of contraception 
should be added;  
a. Male condom 
In the CF population, there 
are abstinent patients who 
are unwilling to initiate 
contraceptive measures. True 
abstinence is regarded as a 
highly effective form of 
contraception when in line 
with the preferred and usual 
lifestyle.  
 
In the prior version of the 
protocol, contraceptive 
methods were added for 
women who are on 
ivacaftor/lumacaftor 
combination therapy.    
 
These methods may be 
acceptable based on 
investigator judgement for 
other subjects  given they are 
effective methods of 
contraception. 
 
In nonclinical reproductive 
toxicity studies, oral doses of 
CTX-4430 equivalent to 680 
mg/day in humans did not 
exhibit adverse effects on 
fertility, implantation, 
pregnant females, or 
embryofetal development. 


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b. Diaphragm 
c. Cervical cap 
d. Female condom 
2) In women who are not on a hormonal method of contraception, one of the 
following methods of contraception should be used.  
a. Double barrier methods of contraception which is the use of a male condom, 
plus either diaphragm or cervical cap. The male condom cannot be used with a 
female condom as a double barrier method of contraception due to risk of tearing 
b. Male or female condom plus a spermicide, or diaphragm plus a spermicide 
(acceptable methods if spermicide is regionally available) 
If local regulations require the use of additional contraceptive measures, these 
must be followed. 
5.11 
Compliance 
An investigational site staff member will count the capsules returned by each 
subject at Visits 3, 5 to 89, 1110, 1213, and 14 15 and record the number of 
capsules returned. Subjects will be questioned in relation to any capsules which 
may have been lost or destroyed to gain a full understanding of the number of 
capsules taken during the treatment period. 
Corrected based on addition 
of Week 6 visit in Amendment 
3 
6.2.10 Spirometry 
Spirometry will be performed before the sputum induction procedures.  
Subjects should take their concomitant medications as per their usual 
schedule. However, any short-acting bronchodilator (e.g. albuterol) should 
not be taken within 4 hours of scheduled time for spirometry, and any long-
acting bronchodilator should not be taken within 12 hours (e.g. salmeterol) 
or 24 hours (e.g. tiotropium bromide) of scheduled time for spirometry.   
The timing will be such that the subject has taken CF medications, including 
inhaled medications, approximately 4 hours before spirometry.  
 
Subjects who fail to meet the ATS/ERS criteria for quality (acceptability, 
reproducibility, and end of test criteria) at screening may be retested once 
without being considered a screen failure. This retest should occur at least 
one day after the initial screening visit and should be completed within 7 
days of the original screening visit date.  For other visits, if a subject fails 
to adhere to protocol requirements, (e.g. bronchodilator use) or fails to 
meet ATS/ERS criteria for quality, then at the discretion of the investigator, 
the spirometry may be repeated once. The retest should occur at least one 
day after the initial visit but as soon as possible up to a maximum of 7 
days. 
Focus is now only on those 
medications which would 
have an impact on spirometry 
measures 
 
 
 
 
 
 
Clarifies that subjects who fail 
to meet ERS/ATS quality 
criteria can be retested once. 
6.3 Screening 
6.4 Treatment Period 
6.4.1, 6.4.2, 6.4.4, 6.4.5, 
6.4.7, 6.4.9, 6.4.14 
The subject will be scheduled for the next study visit, informed of the estimated 
length of the visit, and instructed to eat breakfast before the visit, take the IP with 
breakfast before the visit 
 and take CF 
concomitant medications per Section 6.2.10. (including inhaled medications) 
Harmonized language with 
Section 6.2.10 


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approximately 4 hours before spirometry is scheduled, and not to take any long-
acting beta-agonist within 12 hours before spirometry. 
 
 
6.4.11, 6.4.13 
Same as Visit 9 10 
Corrected based on addition 
of Week 6 visit in Amendment 
3 
Attachment 
Previous version of the protocol, Version 4.0 Amendment 3, November 19, 2015 
was submitted via paper submission to FDA and is now being submitted via 
electronic submission as an attachment to this protocol. 
 

SAP_001.pdf: 
Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
Protocol CTX-4430-CF-201 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate 
the Efficacy, Safety, and Tolerability of CTX-4430 Administered Orally Once-Daily for 48 Weeks in 
Adult Patients with Cystic Fibrosis 
Statistical Analysis Plan 
Prepared for: 
Celtaxsys 
Final Version 2.0 Date 15June2018 
Prepared by: 
 
 
VERSION HISTORY OF IMPLEMENTED PLANS 
Version 
Date 
1.0 
6 June 2018 
2.0 
15 June 2018 
Revision Author 
Comments 
 
Final Version 
 
Updated window convention 
for Week 48 and Week 52. 
Change done prior to 
unblinding. 
 -
 
Page 1 of 33 
 
 




Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
Table of Contents 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................. 5 
2. 
INTRODUCTION ....................................................................................................................... 6 
3. 
STUDY OBJECTIVES ............................................................................................................... 6 
4. 
STUDY DESIGN ......................................................................................................................... 7 
4.1 
GENERAL DESIGN ...................................................................................................................... 7 
4.2 
DISCUSSION OF STlIDY DESIGN .................................................................................................. 7 
4.3 
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS .............................................. 8 
4.4 
BLINDING .................................................................................................................................. 8 
4.5 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
5. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ................... 9 
5.1 
CHANGES IN THE CONDUCT OF THE STUDY ................................................................................ 9 
5.2 
CHANGES FROM THE ANALYSES PLANNED IN THE PROTOCOL .................................................... 9 
6. 
BASELINE, EFFICACY AND SAFETY EVALUATIONS .................................................... 10 
6.1 
SCHEDULE OF EVALUATIONS ................................................................................................... 10 
6.2 
TIME POINT ALGORITHMS ....................................................................................................... 11 
6. 2.1. 
Relative Study Day ........................................................................................................... 11 
6. 2. 2. 
Analysis Visit Windows ..................................................................................................... 11 
6.3 
BASELINE ASSESSMENTS ......................................................................................................... 12 
6.4 
EFFICACY VARIABLES ............................................................................................................. 12 
6. 4.1. 
Primary Efficacy Variable ................................................................................................ 12 
6. 4. 2. 
Secondary Efficacy Variables ........................................................................................... 13 
6.4.2.1. 
Spirometry .................................................................................................................... 13 
6. 4. 2. 2. 
Pulmonary exacerbations .............................................................................................. 13 
6. 4. 2. 3. 
Bio markers ................................................................................................................... 14 
6.4.2.4. 
BMI .............................................................................................................................. 14 
6.4.3. 
Additional Variables ......................................................................................................... 14 
 
 
 
6.6 
SAFETY ASSESSMENTS ............................................................................................................ 15 
6. 6.1. 
Extent of Exposure and Compliance to Study Treatment .................................................... 15 
6. 6. 2. 
Adverse Events ................................................................................................................. 15 
6. 6. 3. 
Clinical Laboratory Evaluations ....................................................................................... 16 
6.6.4. 
Vital Signs ........................................................................................................................ 17 
6. 6. 5. 
Weight and Pulse Oximetry ............................................................................................... 18 
6. 6. 6. 
Electrocardiogram ........................................................................................................... 18 
6. 6. 7. 
Physical Examination ....................................................................................................... 18 
7. 
STATISTICAL METHODS ..................................................................................................... 18 
7 .1 
GENERAL METHODOLOGY ....................................................................................................... 18 
7.2 
ADJUSTMENTS FOR COVARIATES ............................................................................................. 18 
7.3 
HANDLING OF DROPOUTS OR MISSING DATA ........................................................................... 19 
 
Page 3 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
7.4 
POOLING OF STRATA ............................................................................................................... 19 
7.5 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................................. 19 
8. 
STATISTICAL ANALYSIS ..................................................................................................... 19 
8.1 
DISPOSITION OF SUBJECTS ....................................................................................................... 19 
8.2 
PROTOCOL VIOLATIONS ........................................................................................................... 20 
8.3 
ANALYSIS POPULATIONS ......................................................................................................... 20 
8.3.1. 
Randomized Population .................................................................................................... 20 
8. 3. 2. 
Full Analysis Population. .................................................................................................. 20 
8. 3. 3. 
Safety Population ............................................................................................................. 20 
8. 3. 4. 
Per-Protocol Population. .................................................................................................. 20 
8.4 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................................................... 20 
8.5 
PRIOR AND CONCOMITANT THERAPY ....................................................................................... 20 
8. 6 
ANALYSIS OF EFFICACY PARAMETERS ..................................................................................... 21 
8. 6.1. 
Analysis of Primary Efficacy Variable .............................................................................. 21 
8. 6. 2. 
Analysis of Secondary Efficacy Variables ......................................................................... 22 
8. 6. 3. 
Subgroup Analyses ........................................................................................................... 24 
8. 6. 4. 
Exploratory Analyses ........................................................................................................ 24 
8. 7 
ANALYSIS OF SAFETY .............................................................................................................. 25 
8. 7.1. 
Extent of Exposure and Compliance to Study Treatment .................................................... 25 
• 
Extent ofExposure ............................................................................................................................................. 25 
• 
Measurements of Treatment Compliance ............................................................................................................ 25 
8. 7. 2. 
Adverse Events ................................................................................................................. 25 
8. 7.3. 
Clinical Laboratory Evaluations ....................................................................................... 26 
8. 7. 4. 
Vital Signs ........................................................................................................................ 26 
8. 7.5. 
Weight, BMI, and Pulse Oximetry ..................................................................................... 26 
8. 7. 6. 
Physical Examination Findings ......................................................................................... 26 
8. 7. 7. 
Electrocardiogram ........................................................................................................... 26 
9. 
AMENDMENT HISTORY ....................................................................................................... 27 
10. 
COMPUTER SOFTWARE ...................................................................................................... 27 
11. 
REFERENCES ......................................................................................................................... 27 
12. 
APPENDICES ........................................................................................................................... 29 
12.1 
APPENDIX 1: VARIABLE DEFINITIONS ......................................................................... 29 
12.2 
APPENDIX 2: STATISTICALANALYSISANDPROGRAMMINGDETAILS ................. 31 
 
Page 4 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
ANOVA 
BMI 
CF 
CFQ-R 
CFTR 
CFU 
Cl 
DNA 
ECG 
eCRF 
FAP 
FEF25-75% 
FEV1 
FVC 
HIV 
HRQOL 
hs-CRP 
ICF 
IDMC 
IP 
IWRS 
LOCF 
LTA4H 
LTB4 
PK 
pp 
SAE 
SD 
SOP 
TEAE 
WBC 
Table 1: Abbreviations and Definitions of Terms 
adverse event 
analysis of variance 
body mass index 
cystic fibrosis 
Cystic Fibrosis Questionnaire - Revised 
cystic fibrosis transmembrane regulator 
colony forming unit 
confidence interval 
deoxyribonucleic acid 
electrocardiogram 
electronic case report form 
Full Analysis Population 
forced expiratory flow during the middle portion of the forced vital 
capacity 
forced expiratory volume in 1 second 
forced vital capacity 
human immunodeficiency virus 
health-related quality of life 
high-sensitivity C-reactive protein 
informed consent form 
Independent Data Monitoring Committee 
investigational product 
interactive Web randomization system 
last observation carried forward 
leukotriene A4 hydrolase 
leukotriene B4 
pharmacokinetic 
Per-protocol Population 
serious adverse event 
standard deviation 
standard operating procedure 
treatment-emergent adverse event 
white blood cell 
 
Page 5 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
2. INTRODUCTION 
This document presents the statistical analysis plan (SAP) for Celtaxsys Protocol CTX-4430-CF-201: A 
Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate 
the Efficacy, Safety, and Tolerability of CTX-4430 Administered Orally Once-Daily for 48 Weeks in Adult 
Patients with Cystic Fibrosis. 
Cystic fibrosis (CF) is one of the most important causes of chronic pulmonary disease. About 70,000 
individuals are affected by CF worldwide. 1 CF pathology is characterized by a cycle of infection, 
inflammation, and airway obstruction. 
Leukotriene B4 (L TB4) is a powerful attractant and activator of inflammatory immune cells, particularly 
neutrophils. CF lung disease is characterized by significant neutrophilic infiltrates in the small airways and 
elevation of LTB4 in the airways.2,3 In destructive pulmonary diseases such as CF, inhibition of L TB4 
production has the potential to reduce both neutrophil influx and release of damaging neutrophil-derived 
enzymes such as elastase. 4,5 
CTX-4430 is a novel synthetic, small-molecule, LTA4H inhibitor being developed to address the 
underlying pulmonary inflammation in CF by reducing L TB4 production. 
This analysis plan is based on the final protocol Version 5.0 Amendment 4 dated 04MAY2016. 
The SAP provides the description of the analysis for the final analyses. 
3. STUDY OBJECTIVES 
The primary objectives of this study are: 
• 
To evaluate the safety and tolerability of CTX-4430 administered orally once-daily to CF subjects 
for 48 weeks 
• 
To evaluate the efficacy of CTX-4430 administered orally once-daily to CF subjects for 48 weeks 
as determined by the absolute change from Baseline in FEV1 (forced expiratory volume in 1 
second) percent predicted. 
The secondary objectives of this study are: 
• 
To evaluate the efficacy of CTX-4430 administered orally once-daily to CF subjects for 48 weeks 
as determined by the relative change from Baseline in FEV1 percent predicted 
• 
To evaluate the effect of CTX-4430 administered orally once-daily to CF subjects for 48 weeks on 
forced vital capacity (FVC) percent predicted and forced expiratory flow during the middle portion 
of the forced vital capacity (FEF2s-75%) percent predicted 
• 
To evaluate the effect of CTX-4430 administered orally once-daily to CF subjects for 48 weeks on 
time to first pulmonary exacerbation while in the study 
• 
To evaluate the effect of CTX-4430 administered orally once-daily to CF subjects for 48 weeks on 
the number of pulmonary exacerbations 
• 
To evaluate the effect of CTX-4430 administered orally once-daily to CF subjects for 48 weeks on 
specified biomarkers (sputum deoxyribonucleic acid [DNA] and elastase and serum high-
sensitivity C-reactive protein [hs-CRP]). 
The exploratory objectives of this study are: 
 
Page 6 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
• 
To evaluate the effect of CTX-4430 administered orally once-daily to CF subjects for 48 weeks on 
sputum bacterial density 
• 
 
• 
To evaluate the change from Baseline in subject's health-related quality of life (HRQOL) while on 
CTX-4430 administered orally once daily for 48 weeks as measured by the Cystic Fibrosis 
Questionnaire - Revised (CFQ-R). 
4. STUDY DESIGN 
4.1 General Design 
This study is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group, multicenter study to 
evaluate the safety and efficacy of CTX-4430 administered once-daily for 48 weeks for treatment of CF. A 
total of 195 pulmonary CF subjects who meet all the inclusion and no exclusion criteria and provide 
written informed consent will be randomized to receive 50 mg CTX-4430, 100 mg CTX-4430, or placebo 
in a 1 :1 :1 ratio for 48 weeks. 
Subjects will be screened to assess eligibility criteria within 21 days before Baseline (first dose of 
investigational product [IP]). At the screening visit, subjects will consent to participation in the study and 
all study procedures by signing the study informed consent form (ICF). Upon determination that a subject 
meets all inclusion and no exclusion criteria, the subject will be randomized at Baseline to the treatment 
assignment via an interactive Web randomization system (IWRS). Follow-up visits will be conducted 
approximately every 4 weeks from Week 4 to Week 52 (4 weeks after completion of treatment). 
An Independent Data Monitoring Committee (IDMC) will periodically (approximately every 8 weeks) 
review the accumulating study data. The primary responsibility of the IDMC will be to monitor subject 
safety (including pulmonary exacerbations) and study conduct. The IDMC will have access to both safety 
and efficacy data. The IDMC will be requested to avoid formal evaluations of efficacy for the purpose of 
discontinuing the trial early for benefit. As such, no adjustment for multiple testing will be required. The 
IDMC will review the study data in accordance with a written charter. 
4.2 Discussion of Study Design 
A trial of 48 weeks is warranted for study of anti-inflammatory treatments in CF, even at the Phase 2 
stage, since the expected major impact of this class of treatment will be to reduce the rate decline in 
FEV1. Current Cystic Fibrosis Foundation registry data (see Table 2) indicate that the expected rate of 
FEV1 decline is in the range of 3.3 to 5.1 % per year in subjects with at least one pulmonary exacerbation 
in the prior year. Variability (as coefficient of variation, CV) of FEV1 percent predicted in CF trials typically 
ranges from 7 to 10%, meaning that CV will be on the order of twice the size of the anticipated FEV1 
change over the course of a year. Thus, 48 weeks is the optimum duration for discerning an effect on rate 
of FEV1 decline that enables projection of anticipated effect size and powering for Phase 3 studies while 
minimizing total patient enrollment in Phase 2 . 
T bl 2 
a e 
A nnua 
Baseline FEV1 Range 
(Percent Predicted) 
50 to 59 
I Ch 
. FEV 
angem 
till 
a 1en s 
[Je 
0 
CF P f 
t A 
d 18 t 30 Y 
N 
531 
25% 
Mean 
Percentile 
-3.3 
-6.8 
 
Page 7 of 33 
50% 
Percentile 
-3.0 
ears 
75% 
Percentile 
0.7 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
60 to 79 
965 
-3.3 
-7.5 
-2.9 
1.2 
80 to 99 
598 
-3.8 
-7.0 
-3.2 
0.5 
2:100 
94 
-5.1 
-8.0 
-3.0 
0.1 
Source: Cystic Fibrosis Foundation registry data. 
4.3 Method of Assignment of Subjects to Treatment Groups 
Upon determination that a subject meets all eligibility criteria, the subject will be randomized to treatment 
assignment via an IWRS. Each subject will be assigned to CTX-4430 50 mg, CTX-4430 100 mg, or 
placebo in a blinded 1 :1 :1 fashion by means of a computer-generated randomization list stratified by FEV1 
percent predicted at the Screening visit (50 to 75% and > 75%), number of pulmonary exacerbations in the 
12 months before Screening (1 or >1), and use of cystic fibrosis transmembrane regulator (CFTR) 
modulating therapy such as ivacaftor or ivacaftor + lumacaftor (yes/no). 
A centralized randomization schedule will be generated by the unblinded statistician 
 
 who will not be involved in the conduct or analysis of the study, 
using a validated system. The schedule will have randomization numbers assigned to the 3 study 
treatments in blocks of 3 to achieve a 1 :1 :1 ratio of study treatment (i.e., an equal number of subjects in 
each treatment group). Each eligible subject will be assigned to the next sequential randomization 
number based upon the stratification factors above and will receive the corresponding study treatment. 
The randomization schedule will be kept strictly confidential and accessible only to authorized persons if 
unblinding of individual subjects becomes necessary in cases of emergency or for expedited reporting. 
Only when the study has been completed and the study database locked will the randomization schedule 
be made available for analysis. 
4.4 Blinding 
Investigators, subjects, and all study staff with direct subject contact will be blinded to treatment 
assignment. 
The investigator will ensure that blinding is broken only in accordance with the protocol conditions for 
unblinding due to medical necessity or safety reasons. 
There is an IDMC for this study that reviews unblinded data approximately every 8 weeks with a focus 
towards monitoring subject safety (including pulmonary exacerbations) and study conduct. The IDMC will 
have access to unblinded safety and efficacy data to enable risk-benefit assessments but will be 
requested to avoid formal evaluations of efficacy for the purpose of discontinuing the trial early for benefit. 
This report to the IDMC will be prepared by the Sponsor's CRO/designee (i.e., an independent statistician 
who will be responsible for preparing the unblinded study results) and will include a summary of adverse 
event (AE) rates by treatment group. AEs will be tabulated by body system, severity, and their 
relationship to the trial drug. Serious adverse events (SAEs) will be similarly presented. This report will 
also include tabulation of pulmonary exacerbations and their severity, and their relationship to the trial 
drug. Additionally, data will be provided on subject weight, neutrophil counts, other safety labs and 
sputum microbiology, as the data become available. 
4.5 Determination of Sample Size 
The sample size calculation was performed with the following assumptions: 
 
Page 8 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
• 
1: 1: 1 ratio of 50 mg CTX-4430, 100 mg CTX-4430, and placebo (2: 1 ratio of CTX-4430 to 
placebo) 
• 
Difference between average treatment effect (change from baseline) of 50 mg/100 mg CTX-4430 
versus placebo of 3.5 percentage points in FEV1 percent predicted at 48 weeks with a Common 
standard deviation (SD) of 7 percentage points 
• 
Power of at least 90% 
• 
One-sided alpha = 0.05. 
Using a two-sample t-test for the mean difference with the above assumptions, a sample size of 156 
subjects (52:52:52) is required for the primary, overall comparison of CTX-4430 versus placebo. Although 
the primary analysis will be based upon the Full Analysis Population (FAP), it is also of interest to be able 
to have a sufficient number of subjects to support analyses in the Per-protocol Population (PP). It is 
expected that approximately 80% of randomized subjects will be included in the PP. As such, the number 
of randomized subjects is increased to 195 (65:65:65). 
5. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
5.1 Changes in the Conduct of the Study 
There were no changes in the conduct of the study at the time of preparing this statistical analysis plan. 
5.2 Changes from the Analyses Planned in the Protocol 
In the event that a subject does not have data for Week 48, the primary analysis will use the last recorded 
data from Week 32 to Week 48 rather than basing the primary analysis solely on values from Week 48 
(i.e., the analysis window has been expanded from that described in Section 6.2). 
Sensitivity analyses of the primary analysis are being added to: 
• 
Exclude any subject that experienced a pulmonary exacerbation between Week 32 and Week 48 
inclusive 
• 
Include a mixed model repeated measures analysis of absolute change from baseline in FEV1 
percent predicted 
• 
Exclude any data collected more than 1 week after discontinuing study treatment. 
The primary endpoint will be summarized within groups formed by the number of pulmonary 
exacerbations recorded during the course of the study: 0 exacerbations, 1 exacerbation or more than 1 
pulmonary exacerbation during the study. 
For simplicity, the repeated measures analysis for the primary endpoint will not include terms for the 
randomization strata. The protocol indicates that data will be collected for subjects who discontinue 
treatment early and remain in the study after study treatment discontinuation. The analysis of the rate of 
exacerbation and the time to first exacerbation will be repeated after excluding data collected more than 
one week after study treatment discontinuation. If a CFTR modulator is started during the course of the 
study, that subject will be excluded from the Per-Protocol population. 
Change from Baseline in body mass index (BMI) at Week 48 is being added as a secondary analysis. 
 
Page 9 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
6. BASELINE, EFFICACY AND SAFETY EVALUATIONS 
6.1 Schedule of Evaluations 
Table 3: Assessments Conducted at each Scheduled Visit 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Visit Name/Week• Screeni Baseli 
na 
ne 
4 
6 
8 
12 
16 
20 
24 28 
32 
36 
40 
44 48 
52 
Informed consent (study ICF 
X 
 
Demographics & disease 
X 
characteristics 
Medical history 
X 
X 
Physical exam c 
xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xc 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, calculation of BMI 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CFQ-Re 
X 
X 
X 
X 
Spirometrv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary exacerbation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
checklist 
Sputum sample 1 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hs-CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 9 
X 
HIV & HCV antibodies, 
X 
HBsAg 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine alcohol and drug screen 
X 
Randomization 
X 
  
Xh 
Xh 
Xh 
IP dispensing 
X 
X 
X 
X 
X 
X 
Xi 
Xi 
Xi 
IP collection and capsule 
X 
X 
X 
X 
X 
X 
X 
X 
X 
count 
AE & concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
recording 
AE = adverse event; BMI = body mass index, CFQ-R = Cystic Fibrosis Questionnaire - Revised; ECG= electrocardiogram; HBsAg 
= hepatitis B surface antigen; HCV = hepatitis C virus; HIV= human immunodeficiency virus, hs-CRP = high-sensitivity C-reactive 
protein: ICF = informed consent form; IP= investigational product; 
 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV= human immunodeficiency virus, 
 
a 
Baseline visit within 21 days of Screening, window for other visits: ±5 days 
b 
Visits 10, 12, and 14 will be conducted via phone call. 
c 
Complete physical exam at Screening and Week 48, focused physical exam at all other visits 
d 
Pre-dose and before discharge 
e 
To be administered before spirometry and sample collection 
f 
After spirometry 
g 
For women of childbearing potential 
 
 
 
 
2 bottles of IP must be dispensed 
 
Page 10 of 33 
 
 
Early 
Term 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Celtaxsys 
Protocol CTX-4430-CF-201 
6.2 Time Point Algorithms 
6.2.1. Relative Study Day 
Statistical Analysis Plan 
The date of first dose of study drug will be considered relative Day 1, and the day before the first dose 
of study drug will be relative Day -1. Relative days will be calculated as follows only when the full 
assessment date is known (i.e., partial dates will have missing relative days): 
For days on or after the first dose of study drug: 
Date of Assessment - Date of First Dose of Study Drug + 1. 
For days before the first dose of study drug: 
Date of Assessment - Date of First Dose of Study Drug. 
6.2.2. Analysis Visit Windows 
For the purpose of analysis, the visit numbers will be recalculated according to the parameter's 
scheduled assessments to be analyzed and the relative study day as defined above. All efficacy data 
collected at scheduled visits, unless otherwise noted, will be used in the analyses, including data 
collected after a subject discontinued study medication. For safety analyses, data collected up to 28 
days post-treatment will be used. Baseline is defined as the latest assessment obtained prior to first 
dose of study medication. The lower bound of the window for the first post-baseline assessment will 
be set to relative study Day 2. The window for the last scheduled post-baseline assessment will be 
defined with only a lower bound. All other lower and upper bounds are determined by the following 
algorithm: 
Let Xi = scheduled day for assessment i. 
Let Xi+1 = scheduled day for assessment i+1. 
The lower bound for assessment i+1 is defined as: 
LBi+1 = Xi - round ([Xi+1 - Xi]/2) 
The upper bound for assessment i for Week 4 through Week 40 is defined as: 
UBi = LBi+1 - 1 
For Week 48 the upper bound will be the maximum of the treatment stop day + 7 days or study day 
350, which is the value determined by the upper bound formula for this visit. For Week 52, the lower 
bound will be the maximum of (the treatment stop day+ 7 or study day 350) + 1 day. 
For example, spirometry is scheduled to be collected at Screening, Baseline, Weeks 4, 8, 12, 16, 24, 
32, 40, 48, 52 and, if applicable, early termination. The analysis windows for spirometry assessments 
is given below. 
 
Page 11 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
Table 4: Analysis Windows for Spirometry 
Scheduled Visit 
Scheduled Study Day 
Visit Window for Analysis 
(Days) 
Baseline 
1 
::;; 1 
Week4 
29 
2-42 
Week8 
57 
43-70 
Week 12 
85 
71 - 98 
Week 16 
113 
99 -140 
Week 24 
169 
141 - 196 
Week 32 
225 
197 - 252 
Week 40 
281 
253 - 308 
Week 48 
337 
309 - maximum of treatment end 
day + 7 or study day 350 
Week 52 
365 
maximum of (treatment end day 
+ 7 or study day 350) + 1 
For analyses conducted by analysis visit window, if 2 visits have the same distance from the 
scheduled study day, the data of the visit labeled as the scheduled visit will be used and data from 
the visit labeled Unscheduled will not be used. 
Descriptive analysis visits for other parameters are defined similarly. The only exception to this rule is 
for vital signs at the Baseline visit. When both are collected on relative study Day 1, the pre-dose 
assessment will be assigned as baseline and the assessment prior to discharge will be summarized 
as a separate time point. 
6.3 Baseline Assessments 
Baseline is defined as the latest assessment obtained prior to first dose of study drug. 
The following baseline assessments will be conducted: 
• 
Demographics (age [years], gender, race, ethnicity) 
• 
Medical history 
• 
Physical examination 
• 
12-lead ECG 
• 
Assessment of CFQ-R 
• 
Vital signs (heart rate, systolic/diastolic blood pressure, respiratory rate) 
• 
Pulse oximetry 
• 
Height, weight and BMI 
• 
Laboratory tests (hematology, chemistry, urinalysis) 
• 
Spirometry (FEV1 [absolute value and percent predicted], FVC percent predicted, FEF2s-75% 
percent predicted) 
• 
Biomarkers (sputum DNA concentration, sputum elastase concentration, serum hs-CRP) 
• 
Disease characteristics 
6.4 Efficacy Variables 
6.4.1.Primary Efficacy Variable 
 
Page 12 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
The primary efficacy variable is FEV1 percent predicted and is collected at Screening, Baseline, and 
Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52, and, if applicable, early termination. In addition to visit values, 
absolute change in FEV1 percent predicted from baseline will be calculated for each post-baseline 
assessment, according to windowing rules specified in Section 6.2.2. 
Absolute change from baseline is defined as the Week 48 (using the visit window defined previously) 
visit value minus the Baseline visit value. The percent predicted value for all spirometry measures 
will be determined with the NHANES Ill database using the equations of Hankinson et al. 19998. 
6.4.2. Secondary Efficacy Variables 
6.4.2.1. Spirometry 
Spirometry variables FEV1 percent predicted, FVC percent predicted and FEF2s-75% percent predicted 
which will be collected at Screening, Baseline, and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 52, and, if 
applicable, early termination. Visit values are assigned using the windowing method specified in 
Section 6.2.2. Absolute and relative or percent change from baseline will also be calculated at each 
post-baseline assessment. Relative or percent change from baseline is defined as 100 times the 
absolute change from baseline divided by the Baseline visit value. 
6.4.2.2. Pulmonary exacerbations 
The time to first protocol defined pulmonary exacerbation and number of protocol defined pulmonary 
exacerbations are determined by the pulmonary exacerbation checklist. The pulmonary exacerbation 
checklist is collected at every post-Screening visit except at Week 6. Any pulmonary exacerbation 
that occurs after first dose of study medication will be included in the analysis. 
Pulmonary exacerbations are defined as treatment with oral, inhaled, or intravenous antibiotic(s) for 
2:4 of symptoms/signs listed below per the modified Fuchs criteria6. The onset date is defined as the 
date that antibiotics were initiated and as reflected on the pulmonary exacerbation checklist. If the 
same pulmonary exacerbation spans 2 or more study visits, it will be considered as one exacerbation. 
The pulmonary exacerbation checklist will capture the date of onset, the signs/symptoms listed below 
as well as the treatment with oral, inhaled, or intravenous antibiotics: 
• 
Change in sputum 
• 
New or increased hemoptysis 
• 
Increased cough 
• 
Increased dyspnea 
• 
Malaise, fatigue, or lethargy 
• 
Temperature >38°C 
• 
Anorexia or weight loss 
• 
Sinus pain or tenderness 
• 
Change in sinus discharge 
• 
Change in physical examination of the chest 
• 
10% or more absolute decrease in FEV1 percent predicted from the previously recorded 
value 
• 
Radiographic changes indicative of pulmonary infection. 
 
Page 13 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
6.4.2.3. Biomarkers 
Biomarker variables sputum DNA, elastase, and serum hs-CRP. Sputum DNA and elastase will be 
collected at Baseline and Weeks 8, 24, 48, and, if applicable, early termination. Serum hs-CRP will 
be collected at Baseline and Weeks 4, 8, 12, 24, 32, 40, 48, 52, and, if applicable, early termination. 
Visit values are assigned using the windowing method specified in Section 6.2.2. Absolute change 
from baseline will be calculated for all biomarkers at each collected study week. For sputum elastase 
and sputum DNA, change from baseline will be calculated using 10910 transformed absolute values at 
baseline and Week 48. If there are any values below the limit of detection, they will be imputed using 
a value half of the lower limit of detection (LOO). For elastase the LOO is 0.25 mcg/mL and for DNA 
the LOD is 0.625 mcg/ml. 
6.4.2.4. BMI 
BMI will be recorded at Screening and will be calculated for data analysis at Baseline and Weeks 4, 
8, 12, 20, 24, 32, 40, 48, 52, and, if applicable, early termination. BMI will be calculated as: 
Weight in kilograms collected at each visit/ (height in meters)2 collected at screening 
Visit values are assigned using the windowing method specified in Section 6.2.2. Absolute change 
from baseline will be calculated. 
6.4.3. Additional Variables 
The exploratory variables are sputum bacterial density and quality of life as assessed by the CFQ-R 
instrument. Sputum bacterial density will be collected at Baseline and Weeks 8, 24, 48, and, if 
applicable, early termination. Sputum bacterial density is measured by the presence (including, if 
present, number of colony forming units [CFUs] per gram of sputum) or absence of Pseudomonas 
aeruginosa, Burkholderia cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas 
maltophilia, and Staphylococcus aureus (including methicillin-resistant S. aureus and small colony 
variants of S. aureus). Presence of a pathogen is assessed by the number of subjects with a viable 
sample testing positive for the given pathogen at each collection point. Absence of a pathogen is 
determined by taking the difference of the total number of subjects with a viable sample and the 
number of subjects with a viable sample testing positive for the given pathogen at each collection 
point. CFU counts will be transformed using the 10910 transformation and summarized using the 
arithmetic mean. 
The CFQ-R consists of 9 quality of life domains (physical, role/school, vitality, emotion, social, body 
image, eating, treatment burden, health perceptions) and 3 symptom domains (weight, respiratory, 
and digestion). A standardized score for each domain is computed based on the individual 
components with a range of Oto 100 (higher scores indicating better health). The standardized 
domain score is only computed when at least 50% of the individual components are not missing. See 
Appendix 1 in Section 11.1 for more details on the derivation. 
Visit values are assigned using the windowing method specified in Section 6.2.2. Absolute change 
from baseline will be calculated for each domain of the CFQ-R and CFUs for bacterial density. 
 
 
 
 
Page 14 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
6.6 Safety Assessments 
6.6.1. Extent of Exposure and Compliance to Study Treatment 
The expected number of study medication doses will be calculated as: 
For subjects who complete treatment, the number of expected doses = date of last study medication 
dose - date of first dose of study medication + 1. For subjects who discontinue treatment, the number 
of expected doses = the earliest of date of Week 48 visit or date of study drug discontinuation - date 
of first dose of study medication + 1. 
The number of bottles dispensed, each containing 36 capsules, will be recorded. An investigational 
site staff member will count the capsules returned by each subject. Subjects will be questioned in 
relation to any capsules which may have been lost or destroyed to gain a full understanding of the 
number of capsules taken during the treatment period. The number of capsules taken is calculated 
as: 
Doses taken = number of capsules dispensed - number of capsules returned. 
Percent compliance will be calculated as: 
Percent compliance= (doses taken/ expected doses) * 100%. The expected number of doses is the 
number of capsules that should have been taken as discussed above. Subjects will be considered 
compliant with study medication if they take at least 80% of expected doses. 
If a bottle is dispensed but the bottle is not returned, then the doses taken for the unreturned bottle 
will be imputed as follows: 
1. 
Percent compliance for each subject will be calculated as above using only bottles with return 
information. 
2. 
For unreturned bottles, the number of doses taken will be set to the integer value of 36 x 
(percent compliance from step 1 / 100). 
Percent compliance will then be calculated as above using the imputed doses taken for unreturned 
bottles. 
6.6.2. Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and 
does not necessarily have a causal relationship with this product. For purposes of this trial, AEs will 
be reported from the signing of the study ICF through study completion or early termination. A 
treatment emergent AE (TEAE) is an AE that occurs after the first dose of study medication through 
28 days after the last dose, whether this occurs at the final dosing visit at Week 48, or earlier in the 
study if study drug was permanently discontinued. 
AEs will be attributed to treatments according to the following algorithm: 
• 
If the start date of an AE is known, then: 
o 
If the AE starts at any time prior to Day 1 then the AE will not be summarized and 
hence will not be attributed to any treatment. 
 
Page 15 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
o 
For AE's starting on Day 1 (day of first dose), the AE will be classified as treatment 
emergent for the purposes of reporting. These will be captured in a separate listing, 
o 
If the AE starts after Day 1 and on or prior to 28 days after the last dose of study 
medication, then the AE is considered treatment emergent and assigned to the actual 
treatment received. 
• 
If the start day of an AE is unknown but the month and year are known, then: 
o 
If the month and year are the same or later than the month and year of 
randomization, the AE will be considered treatment emergent and assigned to the 
actual treatment received. 
• 
If year is present, but month and day are missing 
o 
If the year is the same or later than the year of randomization, the AE will be 
considered treatment emergent and assigned to the actual treatment received. 
• 
Any other type of partial missing AE start date is considered to be treatment emergent. 
The investigator's verbatim term of each AE will be mapped to system organ class and preferred term 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) adverse event 
dictionary. 
The Investigator will assess the severity of each AE as either mild, moderate, or severe. If severity is 
missing, the AE severity will not be imputed (i.e., will be not be included in AE summaries requiring 
severity but the relevant AE will appear in all other summaries). 
The Investigator will assess the relationship of each AE to the study medication as either not related, 
unlikely related, possibly related, probably related, or definitely related. If relationship is missing, the 
attribution will not be imputed. 
6.6.3.Clinical Laboratory Evaluations 
Safety blood and urine specimens (see Table 5) will be collected from all subjects at Screening, 
Baseline, and Weeks 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 52, and, if applicable, early termination. 
Visit values are assigned using the windowing method specified in Section 6.2.2. Absolute change 
from baseline will be calculated for continuous lab parameters. Laboratory values will also be 
classified as normal (if the value is within normal reference range) or abnormal (if the value is either 
below or above the normal reference range). Values that are three times below the normal lower 
reference range or three times above the normal upper reference range will be summarized. 
 
Page 16 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
Table 5 
Hematology, Chemistry, and Urinalysis Tests 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell (WBC) count 
WBC differential (absolute 
count and%) 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
6.6.4.Vital Signs 
Chemistry 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total and direct) 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Gamma glutamyl transferase 
Glucose 
Phosphorus 
Potassium 
Sodium 
Uric acid 
Total protein 
hs-CRP 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrites 
pH 
Protein 
Specific gravity 
Temperature, heart rate, systolic and diastolic blood pressure, and respiratory rate will be measured 
after the subject has been seated for 10 minutes at Screening, Baseline (pre-dose and prior to 
discharge), and Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 52, and, if applicable, early termination. Visit 
values are assigned using the windowing method specified in Section 6.2.2. Absolute change from 
baseline will be calculated. 
 
Page 17 of 33 
 
 


Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
6.6.5.Weight and Pulse Oximetry 
Weight and pulse oximetry will be measured at Screening, Baseline, and Weeks 4, 8, 12, 16, 20, 24, 
32, 40, 48, 52 and, if applicable, early termination. Visit values are assigned using the windowing 
method specified in Section 6.2.2. Absolute change from baseline will be calculated. 
6.6.6.Electrocardiogram 
An ECG will be performed at Screening, Baseline, and Weeks 4, 8, 12, 24, 32, 40, 48 and, if 
applicable, early termination. ECG parameters include mean RR duration, mean heart rate, mean PR 
duration, mean QRS duration, mean QT Duration, mean QTcB - Bazett's Correction Formula, and 
mean QTcF - Fridericia's Correction Formula. Visit values are assigned using the windowing method 
specified in Section 6.2.2. Absolute change from baseline will be calculated. The overall interpretation 
of the ECG will be classified as normal or abnormal. 
6.6.7.Physical Examination 
A complete physical exam will be performed at Screening and at Week 48. A physical exam focused 
on any medical complaints will be performed as required at Baseline, Weeks 4, 8, 12, 16, 20, 24, 32, 
40, and 52, and, if applicable, early termination. 
Any physical exam abnormality deemed clinically significant by the Investigator at Screening or 
Baseline (before dosing) will be reported as medical history. Any physical exam abnormality 
emergent after the administration of study medication, or abnormality that has worsened since 
Screening or Baseline reporting, that is deemed clinically significant by the Investigator, will be 
reported as an AE. 
7. STATISTICAL METHODS 
7 .1 General Methodology 
Standard statistical methods will be employed to analyze all data. Data collected in this study will be 
reported using summary tables and subject data listings. For categorical variables, frequencies, and 
percentages will be presented. For continuous variables, the number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum will be presented. Unless otherwise indicated, 
confidence intervals (Cls) will be 95% 2-sided intervals. 
Complete listings of all clinical data will be provided to supplement further investigation of tabulated 
values. Version 9.2 or later of the SAS® statistical software package will be used to provide all 
statistical analyses. 
7.2 Adjustments for Covariates 
Other than the adjustment for the randomization stratification factors for the analysis of the primary 
endpoint calculated using the 48-week analysis window, no adjustment for covariates is planned in 
this study. 
 
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7.3 Handling of Dropouts or Missing Data 
Subjects who terminate the study prematurely after randomization may not be replaced, regardless of 
the reason for withdrawal. The handling of missing data will be discussed throughout Section 8, 
where relevant. A number of imputation strategies will be investigated for the primary endpoint. 
Secondary endpoint analyses will be based upon the observed data. 
7.4 Pooling of Strata 
For the purpose of data analysis, randomization strata (FEV1 percent predicted at the Screening visit 
(50 to 75% and > 75%), number of pulmonary exacerbations in the 12 months before Screening (1 or 
>1), and use of cystic fibrosis transmembrane regulator (CFTR) modulating therapy such as ivacaftor 
or ivacaftor + lumacaftor (yes/no)) will be combined with smaller strata to have at least 10 subjects 
total within a stratum. This is a multi-center study with approximately 78 sites planned. Therefore, it is 
expected to have approximately only 2.5 subjects per site (195 subjects/ 78 sites). Subjects were not 
stratified by site for the purpose of randomization. Due to the expected small number of subjects at 
each site, the treatments will not be formally compared within site. 
7.5 Multiple Comparisons/Multiplicity 
The primary analysis will be based upon an analysis of variance (ANOVA) in which the average of the 
Week 48 change from Baseline in FEV1 percent predicted for the 2 CTX-4430 doses is compared to 
that in the placebo group using a 1-sided 0.05 level of significance. If the primary analysis (aggregate 
CTX-4430 effect vs. placebo) reaches the 0.05 level of significance (1-sided), the individual CTX-
4430 doses will be compared to the placebo arm using Dunnett's procedure at the 0.05 (2-sided) 
alpha level. This procedure maintains the type I error at the usual 0.05 (2-sided) level for the 
individual dose comparisons with placebo while allowing a proof of concept test for the pooled 
comparison at the 0.05 (1-sided). This approach is consistent with the Fleming and Richardson7 
approach to Phase 2 screening trials in which a screening trial, if positive at the more stringent 0.05 
2-sided level after preliminary testing, can be treated as providing a more definitive statistical test and 
may reduce the amount of additional confirmatory trial data that is needed. No other adjustments for 
multiplicity will be used and other statistical analyses will be viewed as supportive. 
The IDMC for the study will be requested to avoid formal evaluations of efficacy for the purpose of 
discontinuing the trial early for benefit. As such, no adjustment for multiple testing will be required. 
8. STATISTICAL ANALYSIS 
8.1 Disposition of Subjects 
The number of screened subjects, randomized subjects, treated subjects, subjects who completed 
the study, and subjects who discontinued the study drug early will be summarized by treatment 
group. For subjects who discontinue study drug, the subjects who discontinue study drug and the 
study, and those who discontinue study drug but stay in the study will be separately summarized. 
Reasons for discontinuation will also be summarized. 
The number of randomized subjects in each subject analysis population and the reasons for inclusion 
in the FAP but not in the PP will be summarized by treatment group. Additionally, a summary of the 
 
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concordance between the randomization strata as recorded in the IVRS system and the clinical 
database will be provided. 
8.2 Protocol Violations 
Protocol violations will be summarized. 
8.3 Analysis Populations 
8.3.1. Randomized Population 
All subjects randomized to an active treatment or placebo will be included in the Randomized 
Population. Subjects in the Randomized Population will be analyzed according to their randomized 
treatment group. 
8.3.2. Full Analysis Population 
All subjects randomized to and receiving at least 1 dose of assigned treatment will be included in the 
FAP. Subjects in the FAP will be analyzed according to their randomized treatment group. 
8.3.3. Safety Population 
All subjects randomized to and receiving at least 1 dose of assigned treatment will be included in the 
Safety Population. All safety analyses will be performed using the Safety Population according to the 
actual treatment received. 
8.3.4. Per-Protocol Population 
Subjects in the FAP who meet all study inclusion/exclusion criteria, are assessed at the Week 48 
visit, receive at least 80% of assigned treatment doses at the time of their Week 48 assessment, and 
do not start a CFTR modulator during the course of the study will be included in the PP. All subjects 
in the PP will be analyzed according to the actual treatment received. 
8.4 Demographic and Other Baseline Characteristics 
Sex, race, and ethnicity will be summarized using counts and percentages. Age, height (cm), weight 
(kg), and BMI will be summarized with descriptive statistics (number of subjects, mean, SD, median, 
minimum, and maximum) overall and by treatment group. 
The investigator's verbatim term of each medical history item will be mapped to system organ class 
and preferred term using the latest version of MedDRA. Medical history will be summarized by 
system organ class and preferred term; a subject will only be counted once per system organ class 
and once per preferred term within a treatment. 
8.5 Prior and Concomitant Therapy 
 
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The World Health Organization (WHO) Drug Dictionary will be used to classify medications by 
preferred term and WHO Anatomical Therapeutic Chemical (ATC) classification of ingredients. 
The following applies to all data collected on the prior and concomitant electronic case report form 
(eCRF) page and will be reported by each category separately. 
Where a medication start date is missing, this medication will be assumed to be concomitant for 
reporting purposes, unless the end date is prior to the first administration of study treatment. Partial 
dates will not be imputed. 
Descriptive statistics, such as frequency counts and percentages will be provided to summarize the 
use of medications other than the study drug reported throughout the study. The number and percent 
of subjects who took other therapy will be shown by WHO ATC classification of ingredients and by 
preferred term. 
8.6 Analysis of Efficacy Parameters 
8.6.1. Analysis of Primary Efficacy Variable 
The primary efficacy analysis of change from Baseline to Week 48 in FEV1 percent predicted will be 
performed on the FAP. The primary efficacy evaluation will compare the combined, average absolute 
change from Baseline in FEV1 percent predicted of the 50 mg and 100 mg CTX-4430 treatment 
groups versus the placebo group. 
For the primary efficacy analysis, the last data point (including early termination visit) recorded 
between Week 32 and Week 48 will be used in calculating the change from baseline. Subjects with 
no recorded data between Week 32 and Week 48 will be treated as missing the primary endpoint. 
Missing primary endpoint values will be imputed using the average placebo (according to the 
randomized treatment assignment) change from baseline to Week 48. 
The primary analysis will be based upon an analysis of variance (ANOVA) in which the average of the 
Week 48 absolute change from Baseline in FEV1 percent predicted for the 2 CTX-4430 doses is 
compared to that in the placebo group using a 1-sided test with a 0.05 level of significance. The 
ANOVA model will contain a separate term for each dose group with the average over the 2 CTX-
4430 doses created by averaging the parameters estimates within the ANOVA model (i.e., through 
the use of the LSMESTIMATE statement in SAS PROC MIXED with terms proportionate to [0.5, 0.5 
and -1], for the active arms and placebo, respectively). Weighting for these averages will be based on 
the number of subjects with a non-missing response in each randomization stratum for the FAP 
(using the OM option in PROC MIXED). In addition to terms for treatment group, the ANOVA will 
include a term for the stratification factors used for randomization (pooled strata based upon Section 
7.4) and a term for the interaction between treatment group and pooled strata. Simple descriptive 
statistics will be presented by treatment group and averaged CTX-4430 dose. 
If the 1-sided null hypothesis (comparison of CTX-4430 combined active doses vs placebo) is 
rejected, the individual CTX-4430 doses will be compared to the placebo arm using Dunnett's 
procedure at the 0.05 (2-sided) alpha level. This procedure maintains the type I error at the usual 
0.05 (2-sided) level for the individual dose comparisons with placebo while allowing a proof of 
concept test for the pooled comparison at the 0.05 (1-sided). This approach is consistent with the 
Fleming and Richardson7 approach to Phase 2 screening trials in which a screening trial, if positive at 
the more stringent 0.05 2-sided level after preliminary testing, can be treated as providing a more 
definitive statistical test and may reduce the amount of additional confirmatory trial data that is 
 
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needed.7 If the combined active dose comparison to placebo does not reject the null hypothesis at the 
1-sided 5% level, the pairwise comparisons (100 mg CTX-4430 vs placebo and 50 mg CTX-4430 vs 
placebo) will be treated as descriptive analyses for the purpose exploring the dose response 
relationship for CTX-4330. No other adjustments for multiplicity will be used and other statistical 
analyses will be viewed as supportive. 
The following sensitivity analyses for the primary analysis will be conducted: 
1.) The primary analysis will be repeated on the PP population. 
2.) The primary analysis will be repeated with missing values for FEV1 percent predicted imputed 
using last observation carried forward (LOCF; i.e., values for Weeks 4-28 will be used in the 
primary analysis if the primary endpoint is missing before the Week 32 visit). 
3.) The primary analysis will be repeated with missing values excluded from the analysis (i.e., 
observed data analysis) 
4.) The primary analysis will be repeated using a rank based transformation where missing 
values are imputed as the worst rank (Lachin, 1999).9 In this procedure, subjects are pooled 
over treatment and then ranks are assigned from 1-N where N is the number of subjects in 
the full analysis population. Ranks 1-K will be assigned a value of (K+1)/2. 
5.) A mixed model repeated measures analysis of absolute change from Baseline in FEV1 
percent predicted using all post-baseline data to explore the consistency of the treatment 
effect over time. The model will include treatment (2 doses and placebo), visit, and treatment-
by-visit interaction. The comparison between treatments will be made using means 
estimated by this model for the 48-week analysis window. 
6.) The primary analysis will be repeated excluding any subject who experienced a protocol 
defined pulmonary exacerbation that began between the Week 32 and Week 48 visits, 
inclusive. 
7.) The primary analysis will be repeated excluding any data collected more than 1 week after 
discontinuing study treatment. 
8.6.2.Analysis of Secondary Efficacy Variables 
The absolute change from baseline at Week 48 in the spirometric measures FVC percent predicted 
and FEF2s-75% percent predicted and percent change (relative change) from baseline in FEV1 percent 
predicted, will be analyzed using ANOVA as described above for the primary efficacy variable. The 
overall comparison of the combined active doses vs. placebo as well as the comparisons between 
each active dose and placebo will be made. These analyses will be limited to the observed data on 
the FAP. 
The time to first protocol defined pulmonary exacerbation will be analyzed using a Cox proportional 
hazards model (SAS PROC PH REG). The model will contain terms for treatment. For simplicity, an 
unstratified analysis will be performed. The two active doses will be compared to placebo individually 
as well as pooled together using a contrast statement similar to that used for the primary analysis. 
Time in study will be defined as the date of the Week 48 or Early Termination visit - treatment start 
date + 1. Plots of the distribution of time to first exacerbation will be produced using Kaplan-Meier 
(KM) methodology. In these analyses, subjects will be censored as of their last assessment for 
pulmonary exacerbations. The estimated hazard ratios with 95% 2-sided Cls will be summarized in a 
forest plot. These analyses will be limited to the observed data on the FAP and PP population. 
The number of protocol-defined pulmonary exacerbations reported through the Week 48/Early 
Termination visit will be annualized where a year is defined by 52 weeks and will be analyzed using a 
 
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negative binomial regression (SAS PROC GENMOD). The two active doses will be compared to 
placebo individually as well as pooled together using a contrast statement similar to that used for the 
primary analysis. The model will include factors for treatment group and the natural log of time in 
study as an offset variable. Time in study will be defined as the date of the Week 48 or Early 
Termination visit - treatment start date + 1. Point estimates, standard errors, and 95% Cls for the 
mean of number of pulmonary exacerbations will be presented. The difference in means between 
each CTX-4430 group from placebo will be presented along with standard errors and 95% Cls. The 
estimated treatment effect along with standard errors and 95% Cls will also be calculated for the 
combined active doses. In these analysis, subjects will be censored as of their last assessment for 
pulmonary exacerbations. The estimated differences between the arms with 95% 2-sided Cls will be 
summarized in a forest plot. These analyses will be limited to the observed data on the FAP and PP 
population. 
To examine the impact of early treatment discontinuation on the treatment effect, the overall analyses 
of the time to first exacerbation and the rate of exacerbations will be repeated censoring more than 1 
week after treatment discontinuation. For this analysis, the same negative binomial model will be 
used, but time in study will be defined as the treatment end date - treatment start date+ 7. 
Additionally, the number of protocol-defined pulmonary exacerbations leading to hospitalizations and 
those necessitating the administration of intravenous antibiotics will be annualized where a year is 
defined as 52 weeks and assessed between the combined active doses and placebo arms and 
between each active dose and placebo. The analysis will be done using negative binomial regression 
as described for the analysis of all protocol-defined pulmonary exacerbations. 
Descriptive statistics for the spirometric measures will also be presented on observed data for the 
visit values, percent and absolute change from baseline for each scheduled visit. The 95% Cls for the 
mean differences between the CTX-4430 groups and placebo will also be presented on the absolute 
and percent changes from baseline. 
The change from baseline at Week 48 in serum hs-CRP will be summarized using ANOVA to 
estimate the means and 95% Cls for each individual treatment group and the pooled CTX-4430 
treatment groups and the mean differences between the CTX-4430 groups (individual and pooled) 
and placebo. The model will contain a term for treatment, a term for the stratification factors used for 
randomization (pooled strata based upon Section 7.4), and a term for the interaction between 
treatment group and pooled strata. Weighting for the means will be based on the number of subjects 
with a non-missing response in each randomization stratum for the FAP (using the OM option in 
PROC MIXED). Additionally, serum hs-CRP will be summarized using descriptive statistics by 
treatment group (individual and pooled) for each scheduled visit (per Table 5). The summary will be 
done on the FAP using observed data with no imputation for missing data. 
Sputum DNA and elastase data will be transformed using the 10910 transformation and summarized 
using the same methods as serum hs-CRP. 
The change from baseline at Week 48 in BMI will be summarized using ANOVA to estimate 
the means and 95% Cls for each individual treatment group and the pooled CTX-4430 
treatment groups and the mean differences between the CTX-4430 groups (individual and 
pooled) and placebo. The model will contain a term for treatment, a term for the stratification 
factors used for randomization (pooled strata based upon Section 7.4), and a term for the 
interaction between treatment group and pooled strata. The summary will be done on the 
F AP. In case of missing data, the last data recorded starting from the Week 3 2 to the Week 
48/Early Termination visit, inclusive, will be used. 
 
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8.6.3. Subgroup Analyses 
The primary endpoint (both by individual dose and combined active doses) will be examined for 
subgroups formed by the following variables: 
Stratification factors at randomization: 
• 
Baseline FEV1 percent predicted (:::;;?5% and >75%) 
• 
Number of pulmonary exacerbations in the 12 months before Screening (1 or >1) 
• 
Use of CFTR-modulating therapy, such as ivacaftor or ivacaftor + lumacaftor (yes/no) 
Additional factors: 
• 
Baseline FEV1 percent predicted (:::;pooled median, >pooled median) 
• 
Age (:::;pooled median, >pooled median) 
• 
Number of pulmonary exacerbations in the 12 months before Screening ~2 or >2) 
• 
Use of azithromycin (yes/no) 
• 
Number of protocol defined pulmonary exacerbations experienced during the study (0, 1, or 
>1) 
The time to first exacerbation and the rate of pulmonary exacerbations will be examined (both by 
individual dose and combined active doses) within subgroups formed on the basis of the following 
variables: 
• 
Baseline FEV1 percent predicted of:::;; 75% and > 75% 
• 
Pulmonary Exacerbations in the past 12 months prior to screening categorized as 1 or >1 
exacerbation 
• 
Use of CFTR-modulating therapy such as ivacaftor or ivacaftor + lumacaftor (yes/no) 
• 
Number of pulmonary exacerbations in the 12 months before Screening ~2 or >2) 
• 
Use of azithromycin in the past 12 months (yes/no) 
Subgroup analyses will be based upon observed data (without imputation) by the presentation of 
simple, descriptive statistics and Cls within the subgroups. 
Additionally, for the secondary endpoint of time to first protocol defined pulmonary exacerbation, The 
Cox proportion hazards model as described in section 8.6.2 will be used to estimate the hazard rate 
and the corresponding 95% Cls within the subgroups. For the secondary endpoint of number of 
protocol-defined pulmonary exacerbations, negative binomial regression will be used as described in 
Section 8.6.2 to estimate the annualized rate of exacerbations and the corresponding 95% Cls within 
the subgroups. 
Forest plots will be used to graphically display the means and Cls for each subgroup for the primary 
endpoint and the secondary endpoint of number of protocol-defined pulmonary exacerbations. 
8.6.4. Exploratory Analyses 
CFUs for sputum bacterial density and change from baseline in CFU will be analyzed descriptively by 
treatment group at Weeks 8, 24 and 48. CFUs will be transformed using the 10910 transformation and 
summaries of the transformed CFU counts will be provided at each visit for total CFU counts and 
 
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Statistical Analysis Plan 
CFU counts for each pathogen (P aeruginosa, Burkholderia cepacia complex, Achromobacter 
xylosoxidans, Stenotrophomonas maltophilia, and Staphylococcus aureus (including methicillin-
resistant S aureus and small colony variants of S aureus)). In addition to the basic descriptive 
statistics, 95% Cls for the mean differences between the CTX-4430 groups and placebo for the 
absolute change from baseline for both total bacterial load and organism will be presented. 
CFQ-R domain scores will be analyzed descriptively by treatment group. In addition to the basic 
descriptive statistics, 95% Cls for the mean differences between the CTX-4430 groups and placebo 
for the absolute change from baseline will be presented 
8. 7 Analysis of Safety 
All safety analyses will be performed on the Safety Population. 
8.7.1.Extent of Exposure and Compliance to Study Treatment 
• Extent of Exposure 
The extent of subject exposure to study medication will be quantified using the parameters expected 
doses and taken doses, which will be summarized using descriptive statistics (N, mean, SD, median, 
minimum, maximum) by treatment group. 
• Measurements of Treatment Compliance 
Percent compliance will be summarized using descriptive statistics (N, mean, SD, median, minimum, 
maximum) by treatment group. Percent compliance will also be summarized in the categories of 
<80% and 2:80%. 
8. 7.2. Adverse Events 
The investigator's verbatim term of each AE will be mapped to system organ class and preferred term 
using the latest version of the MedDRA dictionary. 
TEAEs will be summarized by system organ class and preferred term; a subject will only be counted 
once per system organ class and once per preferred term within a treatment. Subject counts and 
percentages will be presented for each treatment group and totaled for all treatment groups for the 
following: 
• 
All TEAEs 
• 
All TEAEs by severity 
• 
All TEAE by relationship 
• 
All treatment emergent SAEs 
• 
TEAEs leading to discontinuation of study participation 
Listings will be presented by subject for all TEAEs, all treatment-emergent SAEs, TEAEs with death 
as the outcome, and TEAEs leading to discontinuation from the study. 
AEs recorded between the screening and baseline visit will be listed separately. In addition, AEs 
occurring on Day 1 (baseline visit) will be listed separately. 
 
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For the summary of AEs by severity, if a subject has multiple events occurring in the same body 
system or same preferred term, then the event with the highest severity will be counted. For AEs by 
relationship to study drug, if a subject has multiple events occurring in the same body system or same 
preferred term, the event with the highest association to study drug will be summarized. AEs 
potentially related to study drug are defined as a subset of adverse events with a relationship to study 
drug of either possible, probable, definite, or unknown. 
No statistical inference between the treatments will be performed on adverse events. 
8.7.3.Clinical Laboratory Evaluations 
Clinical laboratory results at each time point and change from Baseline will be summarized 
using summary statistics (n, mean, SD, median, minimum and maximum values) by 
treatment group to each scheduled assessment. In addition, shift tables of specified clinical 
laboratory evaluations will be presented to display the shift in the normal range categories 
(low, normal, high) from Baseline to each scheduled assessment. For hematology, WBC, 
hematocrit, hemoglobin, platelet count, and absolute neutrophil count will be summarized. 
For chemistry, alkaline phosphatase; alanine aminotransferase, aspartate aminotransferase, 
gamma glutamyl transferase, bilirubin (total and direct), blood urea nitrogen, creatinine, 
glucose, and uric acid 
Listings of laboratory data will also be presented for all tests. Within each listing, laboratory values 
outside the normal ranges will be flagged as either high or low. 
8.7.4.Vital Signs 
Values at each time point and absolute change from Baseline for vital sign measurements (systolic 
and diastolic blood pressure, pulse, respiration rate, and temperature), will be summarized with 
descriptive statistics (n, mean, SD, median, minimum, and maximum) at each scheduled visit by 
treatment group. Listings of these data will also be presented. 
8.7.5.Weight, BMI, and Pulse Oximetry 
Values at each time point and absolute change from Baseline for weight, BMI, and pulse oximetry 
measurements, will be summarized with descriptive statistics (n, mean, SD, median, minimum, and 
maximum) at each scheduled visit by treatment group. Listings of these data will also be presented. 
8.7.6.Physical Examination Findings 
Any physical examination abnormality deemed clinically significant by the Investigator at Screening or 
Baseline will be reported as medical history. Any physical exam abnormality emergent after the 
administration of study medication, or abnormality that has worsened since Screening or Baseline 
reporting, that is deemed clinically significant by the Investigator, will be reported as an AE. Listings of 
these data will be presented. 
8. 7. 7. Electrocardiogram 
Values at each time point and absolute change from Baseline for ECG measurements (mean RR 
duration, mean heart rate, mean PR duration, mean QRS duration, mean QT duration, QTcB, and 
QTcF), will be summarized with descriptive statistics (n, mean, SD, median, minimum, and maximum) 
at each scheduled visit by treatment group. In addition, shift tables will be presented to display the 
 
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shift in the overall interpretation categories (normal or abnormal) from Baseline to each scheduled 
assessment. Listings of these data will also be presented. 
9. 
Amendment History 
Prior to unblinding, the windowing convention for Week 48 was updated to include subjects that had a 
valid Week 48 visit but were being excluded from the Week 48 window. 
• 
In Version 1, the Week 48 window was defined as any assessment occurring between study 
days 309 and 350 inclusive. 
• 
In Version 2, the upper bound for the Week 48 visit was changed to the maximum of study 
day 350 or the treatment end day + 7 days. The lower bound for the Week 52 visit was also 
adjusted accordingly. 
10. Computer Software 
 
 
 
For continuous variables, descriptive statistics (number of subjects, mean, SD, median, minimum, 
and maximum) will be generated. For categorical variables, the number and proportion of subjects will 
be displayed. 
 
 
11. REFERENCES 
1. 
Cystic Fibrosis Foundation. About CF: causes, signs & symptoms. http://www.cff.org/AboutCF/. 
Accessed March 16, 2015. 
2. 
O'Driscoll BR, Cromwell 0, Kay AB. Sputum leukotrienes in obstructive airways diseases. Clin 
Exp lmmunol. 1984;55:397-404. 
3. 
Carpagnano GE, Barnes PJ, Geddes DM, et al. Increased leukotriene B4 and interleukin-6 in 
exhaled breath condensate in cystic fibrosis. Am J Respir Crit Care Med. 2003;167:1109-1112 .. 
4. 
Woolhouse IS, Bayley DL, Stockley RA. Sputum chemotactic activity in chronic obstructive 
pulmonary disease: effect of a1-antitrypsin deficiency and the role of leukotriene B4 and 
interleukin 8. Thorax. 2002;57:709-714. 
5. 
Tirouvanziam R. Neutrophilic inflammation as a major determinant in the progression of cystic 
fibrosis. Drug News Perspect. 2006; 19:609-614. 
6. 
Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase 
on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic 
fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331 :637-642. 
7. 
Fleming TR, Richardson BA. Some design issues in trials of microbicides for the prevention of 
HIV infection. J Infect Dis. 2004;190:666-674. 
8. 
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 Jan;159(1):179-87. 
9. 
Lachin JM. Worst-rank score analysis with informatively missing observations in clinical trials. 
Control Clin Trials. 1999;20:408-422. 
 
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12. APPENDICES 
12.1 
APPENDIX 1: VARIABLE DEFINITIONS 
Weight will be displayed in kilograms (kg), height will be displayed in centimeters (cm), and 
temperature will be displayed in Celsius (C). Weights, heights, or temperatures recorded in alternate 
units will be converted to the units being displayed using standard conversion formulas. 
• 
CFQ-R 
The CFQ-R is comprised of 50 individual questions contributing to 12 domains. The 50 
questions are classified to domains as follows: 
Question 1 = phys1 
Question 2 = phys2 
Question 3 = phys3 
Question 4 = phys4 
Question 5 = phys5 
Question 6 = vital6 
Question 7 = emot7 
Question 8 = emot8 
Question 9 = vital9 
Question 10 = vital10 
Question 11 = vital11 
Question 12 = emot12 
Question 13 = phys13 
Question 14 = eat14 
Question 15 = treat15 
Question 16 = treat16 
Question 17 = treat17 
Question 18 = health18 
Question 19 = phys19 
Question 20 = phys20 
Question 21 = eat21 
Question 22 = social22 
Question 23 = social23 
Question 24 = body24 
Question 25 = body25 
Question 26 = body26 
Question 27 = social27 
Question 28 = social28 
Question 29 = social29 
Question 30 = social30 
Question 31 = emot31 
Question 32 = health32 
Question 33 = emot33 
Question 34 = health34 
Question 35 = role35 
Question 36 = role36 
Question 37 = role37 
 
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Question 38 = role38 
Question 39 = weight39 
Question 40 = resp40 
Question 41 = resp41 
Question 42 = resp42 
Question 43 = resp43 
Question 44 = resp44 
Question 45 = resp45 
Question 46 = resp46 
Question 47 = digest47 
Question 48 = digest48 
Question 49 = digest49 
Question 50 = eat50 
Statistical Analysis Plan 
Each response to an individual question is on an ordinal scale from 1 to 4. However, due to the 
phrasing of responses to certain questions, some responses need to be reversed ordered (1 recoded 
to 4, 2 recoded to 3, 3 recoded to 2, and 4 recoded to 1). This can be done via the following code: 
vital6 
= 
5-vital6; 
vital10 = 
5-vital1 0; 
phys13 = 
5-phys13; 
treat15 = 
5-treat15; 
treat17 = 
5-treat17; 
health18 
= 
5-health18; 
social23 
= 
5-social23; 
social28 
= 
5-social28; 
social30 
= 
5-social30; 
health32 
= 
5-health32; 
health34 
= 
5-health34; 
role35 = 
5-role35; 
resp43 
= 
5-resp43; 
The domain scores can then be calculated using the following code: 
if nmiss (phys1, phys2, phys3, phys4, phys5, phys13, phys19, phys20) <= 4 then 
physical= (mean (phys1, phys2, phys3, phys4, phys5, phys13, phys19, phys20)-1)/3*100; 
if nmiss (role35, role36, role37, role38) <= 2 then 
role= (mean (role35, role36, role37, role38)-1)/3*100; 
if nmiss (vital6, vital9, vital10, vital11) <= 2 then 
vitality= (mean (vital6, vital9, vital10, vital11)-1)/3*100; 
if nmiss (emot7, emot8, emot12, emot31, emot33) <= 2 then 
emotion= (mean (emot7, emot8, emot12, emot31, emot33)-1)/3*100; 
if nmiss (social22, social23, social27, social28, social29, social30) <= 3 then 
social= (mean (social22, social23, social27, social28, social29, social30)-1)/3*100; 
if nmiss (body24, body25, body26) <= 1 then 
body= (mean (body24, body25, body26)-1)/3*100; 
if nmiss (eat14, eat21, eat50) <= 1 then 
 
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Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
eat= (mean (eat14, eat21, eat50)-1)/3*100; 
if nmiss (treat15, treat16, treat17) <= 1 then 
treat = (mean (treat15, treat16, treat17)-1 )/3*100; 
if nmiss (health18, health32, health34) <= 1 then 
health= (mean (health18, health32, health34)-1)/3*100; 
if nmiss (weight39) = 0 then 
weight= (mean (weight39)-1)/3*100; 
if nmiss (resp40, resp41, resp42, resp44, resp45, resp46) <= 3 then 
respirat = (mean (resp40, resp41, resp42, resp44, resp45, resp46)-1)/3*100; 
if nmiss (digest47, digest48, digest49) <= 1 then 
digest= (mean (digest47, digest48, digest49)-1)/3*100; 
12.2 
APPENDIX 2: STATISTICAL ANALYSIS AND PROGRAMMING DETAILS 
ANOVA Analysis 
The SAS procedure MIXED will be used in the ANOVA analysis for change from baseline at Week 
48. 
proc summary data=ADEF nway; 
Where xxx; 
class STRATA TRT01P; 
varxxx; 
output out=cells (keep=STRATA TRT01 P) n=n; 
run; 
proc summary data=ADEF nway; 
class STRATA; 
var; 
output out=STRATA (keep=STRATA n) n=n; 
run; 
*find unique strata/treatment combinations; 
*where conditions provided by table shell; 
*xxx is numeric variable being summarized; 
*n being output is not used, forces creation of 1 
record per stratum; 
*find count of nonmissing within stratum; 
*n used as weight; 
data om; 
* make dataset with strata/treatment combinations each having 
* number of records as stratum size ; 
*there will be 2 times the number of records as in the original 
* dataset; 
merge cells strata; 
by strata; 
do i=1 to n; 
output; 
end; 
keep STRATA TRT01 Pt; 
run; 
ods output DIFFS=outstat; 
 
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Celtaxsys 
Protocol CTX-4430-CF-201 
proc mixed data=ADEF; 
class TRTPN STRATA; 
Statistical Analysis Plan 
model <RESP>= TRTPN STRATA TRTPN *STRATA; 
lsmeans TRTPN / pdifftdiff cl om=om diff=control('xxx'); 
lsmestimate TRTPN 'Placebo' O O 1 / om=om cl; 
lsmestimate TRTPN 'Combined' 0.5 0.5 I om=om cl; 
lsmestimate TRTPN 'Combined vs. Placebo' 0.5 0.5 -1 / om=om cl; 
run; 
Where the ordering of TRTPN is 1 = 50 mg CTX-4430, 2 = 100 mg CTX-4430, and 3 = Placebo. 
<RESP> corresponds to absolute change, percent change or rank of absolute change. 
Mixed Model Repeated Measures Analysis 
The SAS procedure MIXED will be used in the repeated measures analysis. 
PROC MIXED DATA=ADSP; 
WHERE PARAMCD = <VALUE>; 
CLASS TRTPN AVISITN USUBJID; 
MODEL <RESP>= TRTPN AVISITN AVISITN*TRTPN; 
LSMEANS TRTPN / CL DIFF=CONTROL('3') ADJUST=DUNNETT; 
LSMEANS TRTP*AVISITN / CL diff; 
LSMEANS TRTP*AVISITN / CL diff=control('3' '48') adjust=dunnett; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 4' .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 8' 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 12' 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 16' 0 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 24' 0 0 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 32' 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 40' 0 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined at Week 48' 0 0 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 / CL; 
lsmESTIMATE TRTPN 'Combined' .5 .5 0 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 4' .5 0 0 0 0 0 0 0 .5 0 0 0 0 0 0 0 -
1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 8' 0 .5 0 0 0 0 0 0 0 .5 0 0 0 0 0 0 
0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 12' 0 0 .5 0 0 0 0 0 0 0 .5 0 0 0 0 0 
0 0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 16' 0 0 0 .5 0 0 0 0 0 0 0 .5 0 0 0 0 
0 0 0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 24' 0 0 0 0 .5 0 0 0 0 0 0 0 .5 0 0 0 
0 0 0 0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 32' 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 0 0 
0 0 0 0 0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 40' 0 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 0 
0 0 0 0 0 0 -1 / CL; 
lsmESTIMATE TRTPN*AVISITN 'Combined vs Placebo at Week 48' 0 0 0 0 0 0 0 .5 0 0 0 0 0 0 0 .5 
0 0 0 0 0 0 0 -1 / CL; 
lsmESTIMATE TRTPN 'Combined vs. Placebo' 0.5 0.5 -1 / CL; 
REPEATED AVISITN / SUBJECT=USUBJID TYPE=UN; 
RUN; 
 
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Celtaxsys 
Protocol CTX-4430-CF-201 
Statistical Analysis Plan 
Cox Proportional Hazards Analysis 
The SAS procedure PHREG will be used in the Cox proportional hazards analysis. The following 
code will be used for the time to first pulmonary exacerbation. 
proc phreg data=ADTTE; 
WHERE PARAMCD = <value); 
class TRTPN(param=effect); 
model AVAL*CNSR(1) = TRTPN; 
lsmeans TRTPN; 
contrast '50 mg vs Placebo' TRTPN 
2 1 / estimate=exp; 
contrast '100 mb vs Placebo' TRTPN 1 2 / estimate=exp; 
contrast 'Combined vs Placebo' TRTPN 3 3 / estimate=exp; 
run; 
Negative Binomial Regression Analysis 
The SAS procedure GENMOD will be used in the negative binomial regression analysis. The 
following code will be used for the number of pulmonary exacerbations. 
PROC GENMOD DATA=ADSP; 
WHERE PARAMCD = <VALUE>; 
CLASS TRTPN; 
MODEL <RESP>= TRTPN/ DIST=NEGBIN LINK=LOG OFFSET=OFFSET; 
estimate '50mg' intercept 1 TRTPN 1 0 0 / exp; 
estimate '100mg' intercept 1 TRTPN O 1 0 / exp; 
estimate 'Combined' intercept 1 TRTPN .5 .5 0 / exp; 
estimate 'Placebo' intercept 1 TRTPN O O 1 / exp; 
RUN; 
Where RESP is the count of exacerbations and lnyear is the natural log of years of follow-up for each 
subject. Estimates of the differences from placebo will be obtained using the SAS macros NLMeans 
and NLEstimate 
Kaplan Meier Analysis 
The SAS procedure LIFETEST will be used in the Kaplan-Meier analysis. The following code will be 
used for the time to first pulmonary exacerbation. 
PROC LIFETEST DATA=ADTTE METHOD=KM CONFTYPE=LOGLOG; 
STRATA TPTPN; 
TIME AVAL*CNSR(1); 
RUN; 
Where CNSR = 0 for subjects with a pulmonary exacerbation and CNSR = 1 for subjects without a 
pulmonary exacerbation. 
 
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