A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study Investigating the Optimal Dose Regimen, Efficacy, and Safety of Adding Oral Cysteamine in Adult Patients Being Treated for an Exacerbation of CF-associated Lung Disease
Phase: PHASE2
Conditions: Cystic Fibrosis
Sponsor: NovaBiotics Ltd.

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CLINICAL RESEARCH PROTOCOL 
DRUG: 
Cysteamine 
STUDY NUMBER(S): 
NBTCS02 
PROTOCOL(S) TITLE: 
A Randomized, Double-Blind, Parallel Group, 
Placebo-Controlled Study Investigating the 
Optimal Dose Regimen, Efficacy, and Safety of 
Adding Oral Cysteamine in Adult Patients with 
Cystic Fibrosis (CF) Being Treated for an 
Exacerbation of CF-associated Lung Disease 
IND NUMBER: 
127409 
EudraCT NUMBER: 
2015-004986-99 
SPONSOR: 
NovaBiotics, Ltd. 
Cruickshank Building 
Craibstone, Aberdeen AB21 9TR 
United Kingdom 
ORIGINAL PROTOCOL DATE: 
AMENDMENT 1: 
AMENDMENT 2: 
AMENDMENT 2-UK: 
AMENDMENT 2-IT: 
AMENDMENT 3: 
16 November 2015 
07 March 2016 
21 July 2016 
05 October 2016 
02 November 2016  
18 October 2017 
 
 
 

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NBTCS02 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study 
Investigating the Optimal Dose Regimen, Efficacy, and Safety of Adding 
Oral Cysteamine in Adult Patients with Cystic Fibrosis (CF) Being Treated 
for an Exacerbation of CF-associated Lung Disease 
Confidentiality and Investigator Statement 
The information contained in this protocol and all other information relevant to protocol 
NBTCS02 are the confidential and proprietary information of NovaBiotics, Ltd, and except as 
may be required by federal, state or local laws or regulation, may not be disclosed to others 
without prior written permission of NovaBiotics, Ltd. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described.  I will conduct 
this study as outlined herein, in accordance with the regulations stated in the International 
Conference on Harmonisation (ICH) guidelines, as well as local regulations, and will make a 
reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision with copies of the protocol and any 
amendments, and access to all information provided by NovaBiotics, Ltd or specified 
designees.  I will discuss the material with them to ensure that they are fully informed about 
cysteamine and the study. 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name  
 
 
 
 
Site Number 
 
 

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Study Personnel & Contacts 
Sponsor: 
 
NovaBiotics, Ltd 
Cruickshank Building 
Craibstone, Aberdeen  AB21 9TR 
United Kingdom  
Primary Contact:  Deborah O’Neil 
email:  deborah@novabiotics.co.uk 
Telephone: +44 1224 711 377 
Coordinating 
Investigator 
 
Prof. Graham Devereux 
Professor of Respiratory Medicine 
Chest Clinic C 
Aberdeen Royal Infirmary 
Foresterhill, Aberdeen  AB25 2ZN 
United Kingdom 
Telephone:  +44 1224 438 476  
Global Project 
Management, Project 
Management & 
Monitoring for 
European Union 
 
PSR Group B.V. 
Crown Business Center Schiphol 
Planetenweg 5 
2132 HN Hoofddorp 
The Netherlands 
Telephone:  +31 23 55 63 220 
 
Data Management 
 
PSR Group B.V. 
Crown Business Center Schiphol 
Planetenweg 5 
2132 HN Hoofddorp 
The Netherlands 
Telephone:  +31 23 55 63 220 
Project Management & 
Monitoring for United 
States of America 
Agility Clinical, Inc. 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
United States of America 
Telephone: +1 760 268 8200 
Biostatistics 
Agility Clinical, Inc. 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
United States of America 
Telephone: +1 760 268 8200 

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Medical Monitor & 
SAE Reporting 
 
 
 
Product Life Group. 
St. John’s Innovation Park 
Cambridge CB4 0WS 
United Kingdom 
Telephone:  +44 1223 40 2660 
 
 
 
 
 

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Study Synopsis 
Name of 
Study 
Compound 
Cysteamine 
Protocol 
Number 
NBTCS02 
Protocol Title 
 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled 
Study Investigating the Optimal Dose Regimen, Efficacy, and Safety 
of Adding Oral Cysteamine in Adult Patients with Cystic Fibrosis 
(CF) Being Treated for an Exacerbation of CF-associated Lung 
Disease 
Phase of 
Development 
2 
Primary 
Study 
Objectives 
• To determine the optimal dose and regimen of cysteamine in 
comparison with placebo in patients with exacerbations of CF-
associated lung disease  
• To further evaluate the safety and tolerability of cysteamine in 
patients with exacerbations of CF-associated lung disease  
Secondary 
Study 
Objectives 
• To characterize clinical benefit arising from use of cysteamine in 
exacerbations of CF-associated lung disease in the Cystic 
Fibrosis Respiratory Symptom Diary (CFRSD)–Chronic 
Respiratory Infection Symptom Score (CRISS), Jarad and 
Sequerios Symptom Score, Cystic Fibrosis Questionnaire-
Revised (CFQ-R) questionnaires, and Patient Global Assessment 
of Exacerbation 
• Determine the effects of treatment with cysteamine on an 
exacerbation of CF-associated lung disease for each of the 
following: 
o Sputum IL8 and neutrophil elastase levels 
o Forced expiratory volume in the first second (FEV1) 
o Weight and body mass index (BMI) 
o C-reactive protein (CRP) 
o Blood leukocyte count 
o Assessment of blood and sputum cysteamine levels  
 

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Study Design 
 
This is a multicenter, double-blind, randomized, placebo-controlled, 
6-arm study to investigate the optimal dose regimen, efficacy, and 
safety of cysteamine in the treatment of adult patients with CF who 
are experiencing an exacerbation of CF-associated lung disease. 
Patients will be screened for the study and eligible patients will be 
randomized to receive either cysteamine or placebo as add-on therapy 
to their standard of care treatment for CF-associated lung disease.  
Approximately 120 patients with CF will be randomized in a 
1:1:1:1:1:1 ratio to the following total daily dose groups of cysteamine 
or placebo:  450 mg as one dose (20 patients): 450 mg as 3 doses of 
150 mg (20 patients): 900 mg as 2 doses of 450 mg (20 patients): 900 
mg as 3 doses of 300 mg (20 patients): 1,350 mg as 3 doses of 450 mg 
(20 patients): placebo (20 patients). 
During the treatment period, patients will take study drug daily for 
14 days, in accordance with their treatment assignment, and will be 
evaluated for the study on Days 7, 14, and 21.  Patients who 
discontinue prior to Day 21 will be requested to complete the 
procedures for Day 21/End of Study.  During the study, patients will 
be evaluated for the following efficacy parameters:  sputum microbial 
load, sputum IL8 and neutrophil elastase levels, FEV1, weight, CRP, 
blood leukocyte count, assessment of blood and sputum cysteamine 
levels, and the following health-related questionnaires/patient-reported 
outcome measurements (PROMs):  Cystic Fibrosis Respiratory 
Symptom Diary – Chronic Respiratory Infection Symptom Scale 
(CFRSD-CRISS), Jarad and Sequeiros Symptom Score Questionnaire, 
Cystic Fibrosis Questionnaire – Revised (CFQ-R), and Patient Global 
Assessment of Exacerbation. 
Patient safety will be evaluated by adverse events (AEs), laboratory 
assessments (chemistry, hematology, and urinalysis), physical 
examinations, and vital signs.  Additionally, a Data Safety Monitoring 
Board (DSMB) will review the study at periodic intervals, as specified 
in the DSMB Charter. 
Study Schematic 
 
 
 
Number of 
Patients 
Approximately 120 patients will be randomized in the study.   
Study 
Population 
Adult patients with CF-associated lung disease infected with a 
Gram-negative organism(s) (e.g., Pseudomonas, Burkholderia, 
Stenotrophomonas) who experience an exacerbation of their lung 
disease. 
Follow-up/ 
End of Study 
(Day 21) 
Treatment Period 
(Day 1 to Day 14) 
Screening followed by 
Baseline/ 
Randomization (Day 0) 

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Number of 
Study Sites 
Up to 20 study centers located in Europe and up to 20 study centers 
located in the United States of America (USA) will participate in this 
study. 
Treatments 
Cysteamine (as mercaptamine bitartrate) will be provided as 150 mg 
hard capsules for oral administration.  Placebo will be provided as 
matching hard capsules. 
Patients will be randomly assigned to one of the following treatment 
groups: 
Treatment 
Group 
Total Daily 
Dose 
Dosing Regimen 
Morning 
Mid-Day 
Evening 
A 
cysteamine  
450 mg 
3 cysteamine 
150 mg 
capsules 
3 placebo 
capsules 
3 placebo 
capsules 
B 
cysteamine  
900 mg 
3 cysteamine 
150 mg 
capsules 
3 placebo 
capsules 
3 cysteamine 
150 mg 
capsules  
C 
cysteamine 
1,350 mg 
3 cysteamine 
150 mg 
capsules 
3 cysteamine 
150 mg 
capsules 
3 cysteamine 
150 mg 
capsules 
D 
Placebo 
3 placebo 
capsules 
3 placebo 
capsules 
3 placebo 
capsules 
E 
cysteamine 
450 mg 
1 cysteamine 
150 mg 
capsule 
2 placebo 
capsules 
1 cysteamine 
150 mg 
capsule 
2 placebo 
capsules 
1 cysteamine 
150 mg 
capsule 
2 placebo 
capsules 
F 
cysteamine 
900 mg 
2 cysteamine 
150 mg 
capsules 
1 placebo 
capsule 
2 cysteamine 
150 mg 
capsules 
1 placebo 
capsule 
2 cysteamine 
150 mg 
capsules 
1 placebo 
capsule 
Duration of 
Participation 
Following randomization, each eligible patient will participate in the 
study for 3 weeks, including 2 weeks of treatment and 1 week of 
follow-up. 
Inclusion 
Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study: 
1) CF-associated lung disease with documented history of chronic 
infection with Gram-negative organism(s) 
2) Established patient of the Principal Investigator’s CF 
Multi-Disciplinary Team (MDT) 
3) Age ≥18 years 
4) Weight >40 kg 
5) FEV1 >30% of predicted within the 6 months prior to study 
exacerbation 

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6) At the baseline visit: experiencing a new exacerbation of CF-
associated lung disease (based on Investigator assessment of ≥4 
symptoms present on the Fuchs’ criteria) requiring treatment that 
includes an aminoglycoside antibiotic (see Section 6.4)  
7) Females of childbearing potential will be included if they are 
either sexually inactive (sexually abstinent for 14 days prior to the 
first study drug dose continuing through 28 days after the last 
study drug dose, or using one of the following highly effective  
contraceptive (i.e. results in <1% failure rate when used 
consistently and correctly) methods in this trial: 
a. intrauterine device (IUD); 
b. surgical sterilization of the partner (vasectomy for 6 months 
minimum); 
c. combined (estrogen or progestogen containing) hormonal 
contraception associated with the inhibition of ovulation 
(either oral, intravaginal, or transdermal); 
d. progestogen only hormonal contraception associated with the 
inhibition 
of 
ovulation 
(either 
oral, 
injectable, 
or 
implantable); 
e. intrauterine hormone releasing system (IUS);  
f. bilateral tubal occlusion. 
8) Females of childbearing potential agree to remain sexually 
inactive or to keep the same birth control method for at least 28 
days following the last dose. 
 
9) A female of non-childbearing potential must have undergone one 
of the following sterilization procedures at least 6 months prior to 
the first study drug dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior 
to the first study drug dose and follicle stimulating hormone 
(FSH) serum levels consistent with postmenopausal status. 
10) A non-vasectomized male subject agrees to use a condom with 
spermicide or abstain from sexual intercourse during the study 
until 90 days beyond the last dose of study medication and the 
female partner agrees to comply with inclusion 7 or 9.  For a 
vasectomized male who has had his vasectomy 6 months or more 
prior to study start, it is required that they use a condom during 
sexual intercourse. A male who has been vasectomized less than 6 
months prior to study start must follow the same restrictions as a 
non-vasectomized male. 
11) If male, agrees not to donate sperm from the first study drug dose 
until 90 days after dosing. 

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12) Willing and able to comply with all protocol requirements and 
procedures, including induction of sputum, if necessary 
 
13) Willing and able to provide signed and dated informed consent 
Exclusion 
Criteria 
Patients who meet any of the following criteria will be excluded from 
participation in the study:  
1) Hypersensitive to cysteamine or to any of the excipients 
2) Hypersensitive to penicillamine 
3) Transplant recipient 
4) Participation in any other interventional clinical research study 
(participation in observational studies is not exclusionary) within 
30 days of Baseline (Day 0), and any planned participation in an 
interventional clinical research study for the duration of this study 
5) If female, pregnancy, planned pregnancy, or breast-feeding  
6) Any other significant disease/disorder which, in the Investigator’s 
opinion, either puts the patient at risk due to study participation, or 
may influence the results of the study or the patient's ability to 
participate in the study 
Efficacy 
Assessments 
Efficacy parameters collected include the following: sputum microbial 
load, sputum IL8 and neutrophil elastase levels, FEV1, weight, CRP, 
blood leukocyte count, assessment of blood and sputum cysteamine 
levels, and the following health-related questionnaires/PROMs:  
CFRSD–CRISS, Jarad and Sequeiros Symptom Score Questionnaire, 
CFQ-R, and Patient Global Assessment of Exacerbation. 
Safety 
Assessments 
Safety parameters collected include: AEs, serious adverse events 
(SAEs), vital signs, physical examinations, and laboratory parameters 
(chemistry, hematology, and urinalysis). 
Sample Size 
Justification 
A total of approximately 120 patients with CF being treated for an 
exacerbation of CF-associated lung disease will be enrolled in the 
study: 20 patients in each group. The sample size of 120 patients was 
selected empirically without a formal statistical assumption. The 
sample size selection is considered to be appropriate to determine the 
optimal dose and regimen based on evidence of efficacy and 
acceptable safety and tolerability profile as well as establish point 
estimates and variability for efficacy endpoints for future evaluation. 
A sample size of 20 patients in each group will have approximately 
80% power to detect a 1.2 log reduction over placebo, assuming a 
standard deviation of 1.31 in the reduction of sputum bacterial load, 
based on a two-sided, two-sample t-test at the 5% level of 
significance. This estimated standard deviation is that reported for a 2-
week study of CF patients with Pseudomonas aeruginosa who were 
treated during exacerbations with 2 weeks of intravenous tobramycin 
(Al-Aloul et al, 2014).  

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Statistical 
Methods and 
Types of 
Analyses 
The primary objective of this study, to determine the optimal dose and 
regimen of cysteamine in patients with exacerbations of CF-associated 
lung disease, will be investigated through a combination of safety, 
efficacy, and microbiology endpoints. Though statistical comparisons 
between treatment groups with respect to efficacy and microbiology 
will be performed to help inform the selection of the final dose for 
further development, safety and tolerability will also be paramount in 
the selection of the optimal dose. 
The primary efficacy endpoint for the study is: 
• Change from baseline (Day 0) in log-transformed sputum bacterial 
load of gram negative CFU per ml and per mg following a CF 
exacerbation 
The secondary efficacy endpoints for the study are: 
• Change from baseline (Day 0) in patient health-related 
questionnaires/PROMs (CFRSD-CRISS, Jarad and Sequeiros 
Symptom Score Questionnaire, and CFQ-R)  
• Patient Global Assessment of Exacerbation questionnaire 
• Change from baseline (Day 0) in sputum IL8 and neutrophil 
elastase levels following a CF exacerbation 
• Change from baseline (Day 0) in the following: 
o FEV1  
o Weight and BMI 
o CRP 
o Blood leukocyte count 
• Assessment of blood and sputum cysteamine levels at Day 14 
 
The efficacy comparisons of interest at Day 14 will be conducted 
using a linear mixed model for repeated measures, analysis of 
variance (ANOVA), and chi-square tests as appropriate. Change from 
baseline (Day 0) to Day 7 and Day 21 will also be assessed where 
applicable. All analyses will be conducted using two-sided tests at the 
alpha=0.05 level of significance. There will be no adjustments for 
multiple comparisons in the efficacy analyses for this study.  
The data for change from baseline (Day 0) measures will be 
summarized with descriptive statistics and confidence intervals and 
will be analyzed via contrast statements from the mixed model for all 
pairwise and pooled total daily dose (TDD) group comparisons, each 
at the alpha=0.05 level of significance.  Analyses of subgroups and 
other exploratory linear mixed models may be explored. 
Continuous variables will be summarized descriptively by the number 
of patients with non-missing data, mean and standard deviation, 
median, minimum, and maximum values.  Categorical variables will 
be summarized descriptively by their counts and associated 
percentages. 

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Safety analyses will involve the examination of the descriptive 
statistics and individual patient listings for any effects of study 
treatment on clinical safety.  Summaries will be prepared by treatment 
group and TDD group. 
Treatment-emergent adverse event (TEAE) summaries will include 
the overall incidence (by system organ class and preferred term), 
events by maximum intensity, events by relationship to study 
treatment, events leading to discontinuation of study drug, and SAEs. 
Vital signs and laboratory parameters (hematology, chemistry, and 
urinalysis) will be summarized descriptively by treatment.  Actual and 
change from baseline (Day 0) data will be calculated and summarized. 
Each potentially efficacious dose will also be assessed from a safety 
and tolerability perspective based on assessment of AEs, laboratory 
values, and vital signs.  Potential doses for future development will 
consist of one or more doses that are both potentially efficacious and 
have demonstrated an adequate safety profile. 
 
 

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TABLE OF CONTENTS 
CONTENTS 
Study Personnel & Contacts ............................................................................................. 4 
1 
INTRODUCTION AND RATIONALE ................................................................. 18 
1.1 
Background .......................................................................................................... 18 
1.1.1 
Cystic Fibrosis (CF) ...................................................................................... 18 
1.1.2 
Cysteamine ..................................................................................................... 19 
1.1.3 
Rationale for Using Cysteamine in CF ........................................................ 19 
1.1.4 
Clinical Experience with Cysteamine in Patients with CF ........................ 19 
2 
STUDY OBJECTIVES ............................................................................................ 21 
2.1 
Main Objectives ................................................................................................... 21 
2.2 
Additional Objectives .......................................................................................... 21 
3 
STUDY ENDPOINTS .............................................................................................. 21 
4 
STUDY PLAN .......................................................................................................... 22 
4.1 
Study Design ........................................................................................................ 22 
4.2 
Study Schematic .................................................................................................. 22 
4.3 
Schedule of Assessments ..................................................................................... 23 
5 
RANDOMIZATION AND BLINDING ................................................................. 24 
5.1 
Randomization and Blinding .............................................................................. 24 
5.2 
Emergency Unblinding ....................................................................................... 24 
6 
POPULATION ......................................................................................................... 25 
6.1 
Number of Patients and Study Centers ............................................................. 25 
6.2 
Inclusion Criteria ................................................................................................ 25 
6.3 
Exclusion Criteria ............................................................................................... 26 
6.4 
Fuchs’ Criteria ..................................................................................................... 27 
6.5 
Deviation from Inclusion/Exclusion Criteria .................................................... 28 
7 
STUDY CONDUCT ................................................................................................. 28 
7.1 
General Instructions ........................................................................................... 28 
7.2 
Study Procedures by Time Point ....................................................................... 28 
7.2.1 
Screening ........................................................................................................ 28 
7.2.2 
Treatment Period .......................................................................................... 29 
7.2.3 
Follow-Up ....................................................................................................... 30 
7.2.4 
Unscheduled Visits ........................................................................................ 31 
7.3 
Premature Discontinuation ................................................................................ 31 
8 
STUDY DRUG ......................................................................................................... 32 
8.1 
Cysteamine & Placebo Descriptions .................................................................. 32 
8.2 
Packaging, Shipment, and Storage .................................................................... 32 
8.3 
Dose and Administration .................................................................................... 32 
8.4 
Accountability and Compliance ......................................................................... 33 
9 
DESCRIPTION OF STUDY PROCEDURES ...................................................... 33 
9.1 
Sputum Analysis .................................................................................................. 33 
9.2 
FEV1 ..................................................................................................................... 34 
9.3 
Health-related Questionnaires/Patient-Reported Outcome Measures 
(PROMs) .............................................................................................................. 34 

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9.3.1 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD)–Chronic 
Respiratory Infection Symptom Scale (CRISS) ......................................... 34 
9.3.2 
Jarad and Sequeiros Symptom Score Questionnaire ................................. 34 
9.3.3 
Cystic Fibrosis Questionnaire – Revised (CFQ-R) ..................................... 34 
9.3.4 
Patient Global Assessment of Exacerbation ............................................... 35 
9.4 
Physical Examinations ........................................................................................ 35 
9.5 
Vital Signs, Height, and Weight ......................................................................... 35 
9.6 
Laboratory Testing ............................................................................................. 35 
9.6.1 
Clinical Laboratory Tests ............................................................................. 36 
9.6.2 
Cysteamine plasma and sputum level sampling ......................................... 36 
10 Concomitant Medications, Non-Medication Therapies, and Study 
Restrictions ............................................................................................................... 36 
10.1 
Prohibited Foods and Medications .................................................................... 37 
10.1.1 
Restricted Foods ............................................................................................ 37 
10.1.2 
Restricted Medications ................................................................................. 37 
11 ADVERSE EVENTS ................................................................................................ 37 
11.1 
Definition of Adverse Events .............................................................................. 37 
11.2 
Documenting Adverse Events ............................................................................ 38 
11.3 
Assessment of Severity ........................................................................................ 38 
11.4 
Assessment of Causality ...................................................................................... 39 
11.5 
Adverse Event Outcome ..................................................................................... 39 
11.5.1 
Withdrawal Due to Adverse Event .............................................................. 40 
12 SERIOUS ADVERSE EVENT ............................................................................... 40 
12.1 
Definition of Serious Adverse Event .................................................................. 40 
12.2 
SAE Expectedness ............................................................................................... 41 
12.3 
Reporting Serious Adverse Events .................................................................... 41 
12.3.1 
Overdose ......................................................................................................... 42 
12.3.2 
Pregnancy ....................................................................................................... 42 
13 STATISTICS ............................................................................................................ 42 
13.1 
Analysis Populations ........................................................................................... 42 
13.2 
General Procedures ............................................................................................. 43 
13.3 
Sample Size .......................................................................................................... 43 
13.4 
Statistical Methods .............................................................................................. 43 
13.4.1 
Demographic and Baseline Characteristics ................................................ 43 
13.4.2 
Efficacy Analyses ........................................................................................... 43 
13.4.3 
Safety Analyses .............................................................................................. 43 
13.5 
Interim Analysis .................................................................................................. 45 
14 ETHICS AND RESPONSIBILITIES .................................................................... 45 
14.1 
Good Clinical Practice ........................................................................................ 45 
14.2 
Data Safety Monitoring Board (DSMB) ............................................................ 45 
14.3 
Institutional Review Board (IRB)/Ethics Committee (EC) ............................. 45 
14.4 
Informed Consent ................................................................................................ 46 
14.5 
Records Management and Study Monitoring .................................................. 46 
14.6 
Source Documentation and Data Collection ..................................................... 47 
14.7 
Study Files and Record Retention ..................................................................... 47 
14.8 
Declaration of End of Clinical Study ................................................................. 47 
14.9 
Registration of Clinical Study ............................................................................ 47 
15 AUDITING ............................................................................................................... 47 
16 AMENDMENTS ...................................................................................................... 48 

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17 FINANCING AND INSURANCE .......................................................................... 48 
18 STUDY REPORT AND PUBLICATIONS ........................................................... 48 
19 STUDY DISCONTINUATION .............................................................................. 48 
20 CONFIDENTIALITY ............................................................................................. 49 
21 REFERENCES ......................................................................................................... 50 
22 APPENDICES .......................................................................................................... 52 
22.1 
APPENDIX A – Cystic Fibrosis Respiratory Symptom Diary (CFRSD) – 
Chronic Respiratory Infection Symptom Scale (CRISS) ................................ 52 
22.2 
APPENDIX B – Jarad and Sequeiros Symptom Score Questionnaire .......... 58 
22.3 
APPENDIX C – Cystic Fibrosis Questionnaire – Revised (CFQ-R) .............. 59 
22.4 
APPENDIX D – Patient Global Assessment of Exacerbation ......................... 62 
22.5 
APPENDIX E – Declaration of Helsinki ........................................................... 63 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
ATS 
American Thoracic Society 
BMI 
Body Mass Index 
°C 
Celsius 
CF 
Cystic Fibrosis 
CFQ-R 
Cystic Fibrosis Questionnaire – Revised 
CFR 
Code of Federal Regulations 
CFRSD 
Cystic Fibrosis Respiratory Symptom Diary 
CFTR 
Cystic Fibrosis Transmembrane Regulator 
CFU 
Colony-Forming Unit 
CI 
Confidence Interval 
CL/F 
Oral Clearance 
Cmax 
Maximum Serum Concentration 
eCRF 
Electronic Case Report Form  
CRISS 
Chronic Respiratory Infection Symptom Scale 
CRP 
C-reactive Protein 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ERS 
European Respiratory Society 
EU 
European Union 
eudraCT 
European Union Drug Regulating Authorities Clinical Trials 
°F 
Fahrenheit 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in the First Second 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IL8 
Interleukin 8 
IRB 
Institutional Review Board 
IQR 
Interquartile Range 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
kg 
Kilogram(s) 
L 
Liter(s) 
MBC 
Minimum Bacterial Concentration 
MDT 
Multi-Disciplinary Team 

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mg 
Milligram(s) 
MIC 
Minimum Inhibitory Concentration 
MMRM 
Mixed Model for Repeated Measures 
PP 
Per Protocol 
PROM 
Patient-Reported Outcome Measure 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedures 
TEAE 
Treatment-Emergent Adverse Event 
TDD 
Total Daily Dose 
T1/2 
Half-Life 
Tmax 
Time to Maximum Concentration 
USA 
United States of America 
UK 
United Kingdom 
Vd/F 
Volume of Distribution 

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1 
INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Cystic Fibrosis (CF) 
Cystic Fibrosis (CF) is the most common fatal inherited disease in Caucasian populations of 
European origin.  In the United Kingdom (UK), the carrier rate for this autosomal recessive 
condition is 1 in 25 and disease prevalence is approximately 1 in 2,500.  CF affects over 9,000 
people in the UK and about 70,000 people globally (UK CF Registry, 2014).  CF is associated 
with reduced life expectancy, with the current median age of death at 26 to 29 years in the 
UK.  CF results from >1,000 mutations in the CF transmembrane regulator (CFTR) gene that 
codes for a chloride ion channel located in the apical membrane of epithelial cells; the CFTR 
has also been identified in non-epithelial cells.  Although CF affects the pancreas, 
hepatobiliary tree, and the intestinal and reproductive tracts, by far the most important aspect 
of the disease is respiratory, with 90% of the morbidity and mortality associated with CF 
resulting from chronic suppurative lung disease and ultimately respiratory failure (Goss and 
Quittner, 2007).  CFTR mutations result in airway surface liquid dehydration, consequent 
impairment of mucociliary clearance, bacterial colonization of the airways, and chronic 
suppurative lung disease.  The chronic infection and inflammation of CF lung disease results 
in daily symptoms such as dyspnea, cough, and sputum production.  A characteristic feature 
of CF is intermittent episodes of acute worsening of symptoms, commonly known as 
exacerbations.  Exacerbations are characterized by increased cough, increased sputum 
production, increased dyspnea, loss of appetite, weight loss, and lung function decline (Goss 
and Burns, 2007).  Such exacerbations have an adverse impact on patients’ quality of life 
(Hegarty et al, 2009), incur significant healthcare costs (Britto et al, 2002), and are associated 
with a more rapid loss of lung function (Sanders et al, 2010; Sanders et al, 2011).  
Pseudomonas aeruginosa is the most common pathogen in CF (UK CF Registry, 2014), and 
infection with this organism is characterized by persistence of the bacteria, repeated 
exacerbations, and an accelerated rate of decline in lung function.  Other Gram-negative 
bacteria can also infect or colonize the lung, probably the most clinically significant of which 
is the Burkholderia cepacia complex.  The Gram-negative bacteria that infect patients with 
CF are intrinsically resistant to many antibiotics, and the prevalence of bacteria with newly 
acquired resistance has increased with improved life expectancy.  Resistance rates in P. 
aeruginosa in the UK have increased dramatically with approximately 40% of patients 
resistant to two or more antibiotics in one study (Pitt et al, 2003).  The development of 
antibiotic resistance in CF is most likely due to the intensive selective pressure provided by 
the large amounts of antibiotics used in these patients and the high frequency of 
hypermutatable P. aeruginosa found in CF lung infection (Oliver et al, 2000; Giwercman et 
al, 1990).  In CF, P. aeruginosa and the B. cepacia complex grow in biofilms and, as such, are 
much more resistant to antibiotics compared with planktonic-growing cells of the same 
isolate: minimum inhibitory concentration (MIC) and minimum bacterial concentration 
(MBC) can be 100- to 1,000- fold greater in biofilms (Stewart and Costerton, 2007).  The 
issue of bacterial antibiotic resistance in CF is compounded by the relatively high incidence of 
adverse reactions (ARs) to antibiotics that has been reported in 9.5% of CF children and up to 
25% in CF adults (Wills et al, 1998; Pleasants and Samuelson, 1994).  The incidence of ARs 
increases with the number of courses of antibiotics administered (Koch et al, 1991). 

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The aggressive use of antibiotics to suppress chronic infection and to treat acute exacerbations 
is one of the mainstays of treatment in CF that has contributed to the increased survival of CF 
patients.  However, the problems of multiple drug resistance and ARs are major clinical 
issues.  This has led to calls for research into new antibiotics and new antibiotic strategies to 
target the biofilm and to increase the effectiveness of currently available antibiotics (Bals et 
al, 2011; Hoiby, 2002).  Preclinical work indicates that cysteamine, a drug already licensed 
for another indication, has potentially beneficial actions on biofilms and micro-organisms, and 
is the basis for the current study.  
1.1.2 
Cysteamine  
Cysteamine is an amino thiol (HSCH2CH2NH2) that is found endogenously in very low 
plasma levels as a consequence of coenzyme A metabolism (Besouw et al, 2013).  Since 
1976, cysteamine has been used to treat the lysosomal storage disorder, cystinosis.  An 
immediate release formulation (Cystagon) was licensed for the treatment of cystinosis in the 
United States of America (USA) in 1994 and in the European Union (EU) in 1997.  Adequate 
treatment of cystinosis with cysteamine reduces the rate of progression to end-stage renal 
failure, reduces extra renal manifestations, and improves growth.  
1.1.3 
Rationale for Using Cysteamine in CF 
The mucolytic and antimicrobial properties of cysteamine were identified by the study 
Sponsor (NovaBiotics Ltd).  Data obtained in the laboratory and from a clinical pilot study, in 
which the impact of cysteamine on the in vitro rheology and microbial burden of sputum from 
CF patients was assessed, highlights the therapeutic potential in CF.  Cysteamine is a potent 
mucolytic that is able to break down the sputum produced within the airways of CF patients 
(Charrier et al, 2014; Devereux et al, 2015).  This has the potential to aid sputum 
expectoration, improve lung function, and reduce the microbial burden in the airways.  This 
mucolytic action may also provide better access for antimicrobial agents to the bacteria within 
the airways of CF patients.  Cysteamine also possesses three key antimicrobial (non-
antibiotic) attributes that potentiate the effects of existing antibiotic regimens for CF patients 
(Charrier et al, 2014; Devereux et al, 2015):  
1. Cysteamine kills bacteria commonly associated with CF-associated lung disease. 
2. Cysteamine synergizes with other antibiotic agents, broadens their spectrum of activity, 
delivers a post-antimicrobial effect, and reverses antibiotic resistance (even in multi-
drug resistant strains).  
3. Cysteamine disrupts the biofilms that bacteria colonize in the airways of CF.  
1.1.4 
Clinical Experience with Cysteamine in Patients with CF 
In a Phase 2 study, oral cysteamine was administered to patients with CF-associated lung 
disease when not exacerbating to determine whether oral cysteamine is absorbed in adult CF 
patients and enters the bronchial secretions. Tolerability and clinical outcomes were explored.  
Ten patients with stable CF associated lung disease were enrolled: median (interquartile ratio 
[IQR]) age 21.5 (19.8-31.8) years; median (IQR) forced expiratory volume in the first second 
(FEV1) percent predicted 32% (26-49) predicted; 80% of patients were F508del/F508del and 
80% of patients were infected with a Gram-negative organism. Oral cysteamine was 
commenced at 450 mg once daily, then increased weekly to 450 mg four times daily.  The 

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maximal dose was taken for 2 weeks.  Serial plasma cysteamine levels were measured for 24 
hours after the first dose.  Seven of the 10 participants reported ARs typical of cysteamine and 
two patients discontinued treatment intervention.  Following the first 450 mg dose, the mean 
(SD) maximum serum concentration (Cmax) was 2.86 (1.96) mg/L, the time to maximum 
concentration (Tmax) was 1.2 (0.7) hours, the half-life (T½) was 3.7 (1.7), oral clearance 
(CL/F) was 89.9 (30.5) L/hour and volume of distribution (Vd/F) was 427 L (129).  
Cysteamine appeared to accumulate in sputum with a median (IQR) sputum:plasma 
cysteamine ratio of 4.2 (0.98-8.84).  Cysteamine treatment reduced sputum microbial load 
(0.9 log reduction [95% CI -0.05 to 1.9, p=0.060]) and viscosity with the maximal reduction 
observed with cysteamine 450 mg three times daily.  There was evidence of reduced 
adherence with the four times daily dosing regimen.  Cysteamine therapy was associated with 
clinically significant reductions in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) quality 
of life domains of ‘Vitality’ (16 points, p=0.012), ‘Physical Functioning’ (10 points, 
p=0.058), ‘Eating Disturbance’ (11 points) and ‘Weight’ (10 points).  
This study confirmed that oral cysteamine is absorbed and enters the bronchial secretions in 
patients with CF.  The effects of cysteamine on sputum microbial load and sputum viscosity 
were in line with the preclinical ex vivo data (Charrier et al, 2014; Devereux et al, 2015).  The 
adverse effects on quality of life are potentially clinically important and reinforce the notion 
that oral cysteamine is likely more suited for use as an adjunct to treatment of exacerbations 
of CF-associated lung disease where the duration of treatment is relatively short, typically 2 
weeks. 
The current study builds on the preclinical and clinical data to date by investigating the 
potential for cysteamine to be used as an adjunct to treat acute exacerbations of CF-associated 
lung disease, specifically to identify the optimal dose of cysteamine based on effect on 
sputum microbial load.  Oral formulations of cysteamine are available for licensed use in 
cystinosis, and there are more than 20 years of clinical experience with cysteamine for this 
indication.   
Any future phase 3 trial of cysteamine in acute exacerbations of CF-associated lung disease 
will require a health-related questionnaire/PROM, and such an outcome measure is currently 
not available for acute exacerbations in CF.  The following four potential health-related 
questionnaires/PROMs have been identified:  
 
a) The Cystic Fibrosis Respiratory Symptom Diary (CFRSD)–Chronic Respiratory 
Infection Symptom Score (CRISS) is a patient-completed questionnaire designed to 
evaluate the effect of treatment on the severity of symptoms of respiratory infection in 
patients with CF and a chronic respiratory infection. 
 
b) The Jarad and Sequeiros Symptom Questionnaire (Jarad and Sequieros 2011) is a 
simple patient-completed questionnaire that assesses and evaluates change in patient 
symptoms related to different aspects of respiratory function during a CF 
exacerbation. 
 
c) The CFQ-R is a patient-completed questionnaire to assess the impact of CF and 
treatment on everyday life, however this may not be ideally suited to the dynamic 
nature of an acute exacerbation because the CFQ-R enquires about symptoms over 
previous 2 weeks. 
 

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d) The Patient Global Assessment of Exacerbation is a patient-completed questionnaire 
that assesses the current CF exacerbation in comparison to the previous exacerbation.   
 
Another major aim of this study is to identify health-related questionnaires/PROMs most 
suited for use in any future study of cysteamine in acute exacerbations of CF-associated lung 
disease.  
 
2 
STUDY OBJECTIVES 
2.1 
Primary Study Objectives 
• To determine the optimal dose and regimen of cysteamine in comparison with placebo in 
patients with exacerbations of CF-associated lung disease  
• To further evaluate the safety and tolerability of cysteamine in patients with 
exacerbations of CF-associated lung disease 
2.2 
Secondary Study Objectives 
• To characterize clinical benefit arising from use of cysteamine in exacerbations of CF-
associated lung disease in the Cystic Fibrosis Respiratory Symptom Diary (CFRSD)–
Chronic Respiratory Infection Symptom Score (CRISS), Jarad and Sequerios Symptom 
Score, Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaires, and Patient 
Global Assessment of Exacerbation 
• Determine the effects of treatment with cysteamine on an exacerbation of CF-associated 
lung disease for each of the following: 
o Sputum IL8 and neutrophil elastase levels 
o Forced expiratory volume in the first second (FEV1) 
o Weight and body mass index (BMI) 
o C-reactive protein (CRP) 
o Blood leukocyte count 
o Assessment of blood and sputum cysteamine levels  
 
3 
STUDY ENDPOINTS  
The primary efficacy endpoint for the study is: 
• Change from baseline (Day 0) in log-transformed sputum bacterial load of gram negative 
CFU per ml and per mg following a CF exacerbation 
The secondary efficacy endpoints for the study are: 
• Change from baseline (Day 0) in patient health-related questionnaires/PROMs (CFRSD-
CRISS, Jarad and Sequeiros Symptom Score Questionnaire, and CFQ-R)  
• Patient Global Assessment of Exacerbation questionnaire 
• Change from baseline (Day 0) in sputum IL8 and neutrophil elastase levels following a 
CF exacerbation 

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• Change from baseline (Day 0) in the following: 
o FEV1  
o Weight and BMI 
o CRP 
o Blood leukocyte count 
• Assessment of blood and sputum cysteamine levels at Day 14 
 
4 
STUDY PLAN 
4.1 
Study Design 
This is a multicenter, double-blind, randomized, placebo-controlled, 6-arm study to 
investigate the optimal dose regimen, efficacy, and safety of cysteamine in the treatment of 
adult patients with CF who are experiencing an exacerbation of CF-associated lung disease. 
Patients will be screened for the study and eligible patients will be randomized to receive 
either cysteamine or placebo as add-on therapy to their standard of care treatment for CF-
associated lung disease.  Approximately 120 patients with CF will be randomized in a 
1:1:1:1:1:1 ratio to the following total daily dose groups of cysteamine or placebo:  450 mg as 
one dose (20 patients): 450 mg as 3 doses of 150 mg (20 patients): 900 mg as 2 doses of 450 
mg (20 patients): 900 mg as 3 doses of 300 mg (20 patients): 1,350 mg as 3 doses of 450 mg 
(20 patients): placebo (20 patients). 
During the treatment period, patients will take study drug daily for 14 days, in accordance 
with their treatment assignment, and will be evaluated for the study on Days 7, 14, and 21.  
Patients who discontinue prior to Day 21 will be requested to complete the procedures for 
Day 21/End of Study.  
During the study, patients will be evaluated for the following efficacy parameters:  sputum 
microbial load, IL8 and neutrophil elastase levels, FEV1, weight, CRP, blood leukocyte 
count, assessment of blood and sputum cysteamine levels, and the following health-related 
questionnaires/PROMs:  CFRSD-CRISS, Jarad and Sequeiros Symptom Score Questionnaire, 
CFQ-R, and Patient Global Assessment of Exacerbation. 
Patient safety will be evaluated by AEs, laboratory assessments (chemistry, hematology, and 
urinalysis), physical examinations, and vital signs.  Additionally, a Data Safety Monitoring 
Board (DSMB) will review the study at periodic intervals, as specified in the DSMB Charter. 
4.2 
Study Schematic 
 
 
 
 
 
Follow-up/ 
End of Study 
(Day 21) 
Treatment Period 
(Day 1 to Day 14) 
Screening followed by 
Baseline/ 
Randomization (Day 0) 

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4.3 
Schedule of Assessments 
Assessment 
 
Screeninga 
Baseline a 
(Day 0) 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21 
(±1 day) 
Follow-Up/  
End of Study 
Written informed consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Relevant medical/surgical history 
X 
 
 
 
 
Physical examination 
 
X 
 
 
X 
Evaluate Fuchs’ criteria 
 
X 
 
 
 
Assessment of eligibility criteria 
X 
X 
 
 
 
Randomization 
 
X 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
FEV1 
 
X 
X 
X 
X 
CFRSD–CRISS 
 
X 
X 
X 
X 
Jarad and Sequeiros Symptom Score 
Questionnaire 
 
X 
X 
X 
X 
CFQ-R 
 
X 
X 
X 
X 
Patient Global Assessment of Exacerbation 
 
 
 
X 
 
Sputum sampleb 
 
X 
X 
X 
X 
Laboratory samples  
 
X 
X 
X 
X 
Cysteamine plasma and sputumb level 
sampling 
 
 
 
X 
 
Pregnancy testc 
 
X 
 
 
X 
Dispense study drugd 
 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
 
Concomitant medications 
 
X------------------------------------------X 
Non-medication therapies 
 
X------------------------------------------X 
Adverse eventse 
 
 X---------------------------------X 
a  Screening may occur prior to the start of a CF-associated lung disease exacerbation.  Screening and Baseline (Day 0) may 
be performed as separate visits or as a combined visit.  If performed as a combined visit, procedures noted at both visits will 
only be performed once (i.e., assessment of eligibility criteria, weight, and vital signs).  If performed as separate visits, the 
procedures noted at both visits will be performed at each required visit.  Upon determination of eligibility by the Investigator, 
the patient may be randomized. 
b  Sites may collect separate samples for each required sputum assessment or may collect one sputum sample and split it into 
either 2 or 3 parts (depending on sample requirements for the visit).  The sample will either be split into 2 parts for Day 0, 
Day 7 and Day 21, and 3 parts for Day 14 or 2 samples will be collected for Day 0, Day 7 and Day 21, or 3 samples will be 
collected for Day 14. Each part or sample will be placed into a separate container for shipping and analyses, details are 
included in the Laboratory Manual. 
c  A urine pregnancy test will be performed on all females of childbearing potential.  If the urine pregnancy test is positive, a 
serum pregnancy test will be performed. 
d  Study drug will be dispensed to the patient for self-administration if the patient will be seen on an outpatient basis or at 
another preferred location (at visits Day 7 and Day 14 only).  If the patient will be seen on an inpatient basis, study drug will 
be administered to the patient daily by qualified site personnel. 
e  AE recording begins at the first dose.  Events occurring prior to the first dose will be recorded as medical history. 
 

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5 
RANDOMIZATION AND BLINDING 
5.1 
Randomization and Blinding 
Cysteamine (as mercaptamine bitartrate) will be provided as 150 mg hard capsules for oral 
administration. 
Patients will be randomly assigned to one of the following treatment groups noted in Table 1. 
Table 1: 
Treatment Groups 
Treatment 
Group 
Total Daily 
Dose 
Dosing Regimen 
Morning 
Mid-Day 
Evening 
A 
cysteamine  
450 mg 
3 cysteamine 150 mg 
capsules 
3 placebo capsules 
3 placebo capsules 
B 
cysteamine  
900 mg 
3 cysteamine 150 mg 
capsules 
3 placebo capsules 
3 cysteamine 
150 mg capsules  
C 
cysteamine 
1,350 mg 
3 cysteamine 150 mg 
capsules 
3 cysteamine 150 mg 
capsules 
3 cysteamine 
150 mg capsules 
D 
Placebo 
3 placebo capsules 
3 placebo capsules 
3 placebo capsules 
E 
cysteamine 
450 mg 
1 cysteamine 
150 mg capsule 
2 placebo capsules 
1 cysteamine 
150 mg capsule 
2 placebo capsules 
1 cysteamine 
150 mg capsule 
2 placebo capsules 
F 
cysteamine 
900 mg 
2 cysteamine 
150 mg capsules 
1 placebo capsule 
2 cysteamine 150 mg 
capsules 
1 placebo capsule 
2 cysteamine 150 
mg capsules 
1 placebo capsule 
 
In order to maintain the study blind, placebo capsules will be taken so that each patient takes 
3 capsules 3 times per day (i.e., morning, mid-day, and evening doses). 
The randomization schedule will be generated using a computer program and verified for 
accuracy using strict quality control procedures.  Randomization will be centralized. 
The investigational site will maintain an inventory of study drug supplied by the Sponsor.  
Eligible patients will receive a blinded treatment assignment with a unique randomization 
code based on the randomization list.  The assigned randomization code will be captured in 
the electronic Case Report Form (eCRF). 
5.2 
Emergency Unblinding 
The Study Handbook details the procedures for emergency unblinding.  In the event a 
patient’s treatment assignment is unblinded, this treatment assignment will be kept 
confidential and shared only as required for patient safety and/or regulatory reporting. 
Unblinding should only be performed if knowledge of the treatment assignment is considered 
relevant for medical care.  

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6 
POPULATION 
The patient population will consist of adult patients with CF-associated lung disease infected 
with a Gram-negative organism(s) (e.g., Pseudomonas, Burkholderia, Stenotrophomonas) 
who experience an exacerbation of their lung disease.  
6.1 
Number of Patients and Study Centers 
Approximately 120 patients will be randomized in the study.  
Patients will be enrolled from up to 20 study centers located in Europe and up to 20 study 
centers located in the USA. 
6.2 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study: 
1) CF-associated lung disease with documented history of chronic infection with Gram-
negative organism(s) 
2) Established patient of the Principal Investigator’s CF Multi-Disciplinary Team (MDT) 
3) Age ≥18 years 
4) Weight >40 kg 
5) FEV1 >30% of predicted within the 6 months prior to study exacerbation 
6) At the baseline visit: experiencing a new exacerbation of CF-associated lung disease 
(based on Investigator assessment of ≥4 symptoms present on the Fuchs’ criteria) 
requiring treatment that includes an aminoglycoside antibiotic (see Section 6.4)  
7) Females of childbearing potential will be included if they are either sexually inactive 
(sexually abstinent for 14 days prior to the first study drug dose continuing through 28 
days after the last study drug dose, or using one of the following highly effective  
contraceptive (i.e. results in <1% failure rate when used consistently and correctly) 
methods in this trial: 
g. intrauterine device (IUD)); 
h. surgical sterilization of the partner (vasectomy for 6 months minimum); 
i. combined (estrogen or progestogen containing) hormonal contraception associated 
with the inhibition of ovulation (either oral, intravaginal, or transdermal); 
j. progestogen only hormonal contraception associated with the inhibition of ovulation 
(either oral, injectable, or implantable); 
k. intrauterine hormone releasing system (IUS);  
l. bilateral tubal occlusion. 
 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 

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treatments. In this trial abstinence is only acceptable if in line with the subjects preferred 
and usual lifestyle. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception.  As well, female condom and male condom 
should not be used together. 
8) Females of childbearing potential agree to remain sexually inactive or to keep the same 
birth control method for at least 28 days following the last dose. 
9) A female of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first study drug dose: 
e. hysteroscopic sterilization; 
f. bilateral tubal ligation or bilateral salpingectomy; 
g. hysterectomy; 
h. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first study drug 
dose and follicle stimulating hormone (FSH) serum levels consistent with 
postmenopausal status. 
10) A non-vasectomized male subject agrees to use a condom with spermicide or abstain from 
sexual intercourse during the study until 90 days beyond the last dose of study medication 
and the female partner agrees to comply with inclusion 7 or 9.  For a vasectomized male 
who has had his vasectomy 6 months or more prior to study start, it is required that they 
use a condom during sexual intercourse. A male who has been vasectomized less than 6 
months prior to study start must follow the same restrictions as a non-vasectomized male. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not 
acceptable methods of contraception.  As well, female condom and male condom should 
not be used together.      
11) If male, agrees not to donate sperm from the first study drug dose until 90 days after 
dosing. 
12) Willing and able to comply with all protocol requirements and procedures, including 
induction of sputum if necessary 
13) Willing and able to provide signed and dated informed consent 
6.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the 
study:  
1) Hypersensitive to cysteamine or to any of the excipients 

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2) Hypersensitive to penicillamine 
3) Transplant recipient 
4) Participation in any other interventional clinical research study (participation in 
observational studies is not exclusionary) within 30 days of Baseline (Day 0), and any 
planned participation in an interventional clinical research study for the duration of this 
study 
5) If female, pregnancy, planned pregnancy, or breast-feeding  
6) Any other significant disease/disorder which, in the Investigator’s opinion, either puts the 
patient at risk due to study participation, or may influence the results of the study or the 
patient's ability to participate in the study 
6.4 
Fuchs’ Criteria 
Fuchs’ Criteria is a standardized method for determining when a patient with CF is 
experiencing a CF exacerbation of respiratory symptoms (Fuchs et al, 1994).  Based on 
Fuchs’ Criteria an exacerbation will be deemed present if the patient requires treatment with 
parenteral antibiotics for any 4 or more of the following 12 signs or symptoms: 
• Change in sputum 
• New or increased hemoptysis 
• Increased cough 
• Increased dyspnea 
• Malaise, fatigue or lethargy 
• Temperature above 38°C/100.4°F 
• Anorexia or weight loss 
• Sinus pain or tenderness 
• Change in sinus discharge 
• Change in physical examination of the chest 
• Decrease in pulmonary function by 10% or more from a previously recorded value 
• Radiographic changes indicative of pulmonary infection 
Investigators will evaluate Fuchs’ criteria to determine study eligibility.  Patients must have 
≥4 symptoms at Baseline (Day 0) for randomization into the study. 

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6.5 
Deviation from Inclusion/Exclusion Criteria 
Deviations from the inclusion/exclusion criteria of the protocol will not be prospectively 
granted.  If the Investigator learns that a patient who did not meet protocol eligibility criteria 
was entered into the study, the Investigator must immediately inform the Medical Monitor of 
the protocol violation so a determination can be made regarding the patient’s continued 
participation in the study. 
 
7 
STUDY CONDUCT 
It is not allowed for patients to participate in the study more than once. Participation is in this 
case defined as having received at least 1 dose of study medication. 
7.1 
General Instructions 
All patients screened will be assigned a unique patient number after the informed consent 
form is signed.  The patient number and patient initials will identify each patient throughout 
the study.  Patient initials will comply with local requirements regarding patient 
confidentiality in applicable countries (e.g., AAA, BBB). 
7.2 
Study Procedures by Time Point 
7.2.1 
Screening 
Screening will begin with the signing of the informed consent form.  At Screening, patients 
will receive an explanation of the purpose and nature of the study, and will be asked to review 
and sign the informed consent form prior to any study-related procedures.  The Screening visit 
may be combined with the Baseline (Day 0) visit.  In the event the visits are performed on the 
same day, the following procedures will only be performed once:  assessment of eligibility 
criteria, weight, and vital signs. 
The following Screening procedures will be performed after signing of the informed consent: 
• Document relevant medical/surgical history, including the patient’s demographic 
information, CF diagnosis, and concurrent medical conditions. 
• Review all concomitant medications (i.e., prescription, over-the-counter, 
supplements) and any non-medication therapies used in the 30 days prior to 
signing the informed consent form. 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and temperature), 
including height and weight. 
• Review inclusion/exclusion criteria, with the exception of evaluating the Fuchs’ 
criteria if Screening and Baseline are not performed on the same day. 

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7.2.1.1 
Screening Failures 
Any patient who does not meet the entry criteria or withdraws consent prior to randomization 
on Day 0 will be considered a screening failure.  The reason for each screen failure will be 
documented.  Patients who screen fail may be re-screened with approval from the Medical 
Monitor. 
7.2.2 
Treatment Period 
During the treatment period, patient assessments may be performed as an inpatient, an 
outpatient, or a combination of inpatient and outpatient assessments or at another preferred 
location (at visits Day 7 and Day 14 only), in accordance with the Investigator’s standard of 
care procedures. 
7.2.2.1 
Baseline (Day 0) 
The procedures noted below will be performed at Baseline (Day 0).  In the event the 
Screening visit is performed on the same day as the Baseline (Day 0) visit, procedures 
performed for Screening do not need to be repeated. 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and temperature), 
including weight. 
• Perform a complete physical examination. 
• Review any changes in concomitant medications and non-medication therapies. 
• Perform spirometry to obtain the FEV1. 
• Evaluate Fuchs’ criteria. 
• Review inclusion/exclusion criteria.  If the patient continues to be eligible for study 
entry, randomize the patient to treatment by entering the assigned randomization 
number in the eCRF. 
• Obtain sputum sample(s).  
• Obtain blood and urine specimens for central laboratory assessments. 
• Perform a urine pregnancy test (females of childbearing potential only). 
• Complete the following health-related questionnaires/PROMs in the noted order:  
CFRSD–CRISS, Jarad and Sequeiros Symptom Score Questionnaire, and CFQ-R. 
• Instruct the patient in administration of study drug. Subjects should take their first 
dose of study drug as close together in time as possible with their first dose of 
aminoglycosides. The first dose of study drug should be administered within 24 hours 
of the first dose of aminoglycoside.  
• If the patient will continue in the study on an outpatient basis or at another preferred 
location (at visits Day 7 and Day 14 only), dispense study drug to the patient. 

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• Review AEs following administration of the first dose. 
7.2.2.2 
Day 7 and Day 14 
The following procedures to assess CF exacerbation will be performed on Day 7 (±1 day) and 
Day 14 (±1 day): 
• Obtain sputum sample(s). 
• Obtain blood and urine specimens for laboratory assessments. 
• Review any changes in concomitant medications, non-medication therapies, and 
document any AEs. 
• Perform spirometry to obtain the FEV1. 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and temperature) and 
weight. 
• Complete the following health-related questionnaires/PROMs in the noted order:  
CFRSD–CRISS, Jarad and Sequeiros Symptom Score Questionnaire., and CFQ-R.  
On Day 14, the Patient Global Assessment of Exacerbation will be completed 
following the CFQ-R. 
If the patient is seen on an outpatient basis or at another preferred location (at visits Day 7 and 
Day 14 only), study personnel will review returned study drug inventory and reconcile any 
dosing discrepancies with the patient.  If the patient is seen on an inpatient basis, dosing 
discrepancies will be assessed on a daily basis.  If the patient will continue in the study on an 
outpatient basis, unused study drug will be returned to the patient (Day 7 only). 
7.2.3 
Follow-Up 
7.2.3.1 
Day 21 (End of Study) 
The follow-up visit will be conducted at Day 21 (±1 day), or as the End of Study visit for 
patients who discontinue from the study prior to Day 21.  The following procedures to assess 
CF exacerbation will be performed: 
• Obtain sputum sample(s). 
• Obtain blood and urine specimens for central laboratory assessments. 
• Perform a urine pregnancy test (females of childbearing potential only). 
• Review any changes in concomitant medications, non-medication therapies, and 
document any AEs. 
• Perform spirometry to obtain the FEV1. 
• Obtain vital signs (blood pressure, heart rate, respiratory rate, and temperature), 
including weight. 

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• Perform a complete physical examination. 
• Complete the following health-related questionnaires/PROMs in the noted order:  
CFRSD–CRISS, Jarad and Sequeiros Symptom Score Questionnaire, and CFQ-R. 
7.2.4 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request, 
or as deemed necessary by the Investigator.  The date and reason for the unscheduled visit, as 
well as the procedures performed, will be documented. 
7.3 
Premature Discontinuation 
Patients may withdraw from the study at any time.  However, patients who wish to withdraw 
will be encouraged to undergo End of Study procedures (see Section 7.2.3.1) before 
withdrawing from the study.  The reasons for withdrawal from the study and reason for 
withdrawal from study drug will be documented.  Reasons for withdrawal from the study or 
the study drug may include, but are not limited to the following: 
A. Significant patient noncompliance, defined as inability or unwillingness to complete 
the procedures defined in the Schedule of Assessments (Section 4.3), missed/late study 
visits, and/or missing 6 or more consecutive doses of study drug; 
B. Patient lost to follow-up (i.e., staff unable to contact patient after several attempts); 
C. Request of the patient or Investigator; 
D. Laboratory test results; or 
E. Development of any AE, SAE, condition, intercurrent illness, injury, medical 
condition, or use of a medication that is likely to interfere with patient safety, the 
overall assessment, or the study procedures. 
If a patient withdraws from the study or study drug with a clinically significant laboratory 
abnormality or AE, every effort must be made to follow the event until satisfactory resolution, 
or until the Investigator feels the event is stable and chronic in nature.  
Patients who discontinue study drug prior to completing the full 14 day treatment period, if 
willing, should complete the remaining study visits through Day 21. 
Patients enrolled who are later determined not to have experienced an exacerbation of CF-
associated lung disease due to a Gram-negative organism(s) at baseline will not be 
discontinued from the study but will be replaced. Patients who discontinue from the study for 
any other reason will also be replaced. These patients will be excluded from the Per Protocol 
analysis.  
In addition, the Sponsor reserves the right to discontinue this clinical study at any time for any 
reason.  Such a termination must be implemented by the Investigator in a time frame that is 
compatible with patient well-being. 

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8 
STUDY DRUG 
Patients will be randomly assigned to one of the following treatment groups (total daily dose) 
in a 1:1:1:1:1:1 ratio: 
• Group A:  cysteamine 450 mg/day taken as one dose  
• Group B:  cysteamine 900 mg/day taken as two doses 
• Group C:  cysteamine 1,350 mg/day taken as three doses 
• Group D: placebo 
• Group E: cysteamine 450 mg/day taken as three doses 
• Group F: cysteamine 900 mg/day taken as three doses 
In order to maintain the study blind, placebo capsules will be taken so that each patient takes 
3 capsules 3 times per day (i.e., morning, mid-day, and evening doses); see Table 1. 
8.1 
Cysteamine & Placebo Descriptions 
Cysteamine (as mercaptamine bitartrate) will be provided as 150 mg hard capsules for oral 
administration. 
To fit the blindness requirement, placebo is manufactured with common bulking excipients 
for immediate release formulation. Placebo will be provided as matching hard capsules. 
8.2 
Packaging, Shipment, and Storage 
The study drug, provided by the Sponsor, will be packaged and labeled in accordance with the 
principles and the detailed guidelines of GMP for Medicinal Products. 
In order to maintain the blind, all study drug will be identified with the following limited 
information:  protocol number, dosing time, randomization code, administration instructions, 
storage requirements, and a cautionary statement according to local regulations. 
Study drug will be provided to the investigational sites as capsules in blister packs. For each 
randomized patient, each investigator will be provided with a kit containing 2 boxes, one for 
every week of treatment. Each box will contain 8 daily blisters for seven days of treatment 
plus one day as reserve. Each daily blister will contain 9 capsules of cysteamine 150 mg or 
placebo. Study drug must be stored in a locked, secured, and temperature controlled storage 
facility accessible only to those individuals authorized by the Investigator to dispense the 
study drug.  Study drug must be stored at room temperature (≤25°C ) and prevented from 
freezing.  Additionally, study drug must be protected from light and moisture.  Patients must 
also be instructed on the proper storage of the product. 
8.3 
Dose and Administration 
Administration of study drug will occur three times daily in approximately equally spaced 
doses (i.e., morning, mid-day, and evening); see Table 1.  Study drug should be swallowed.  

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Each dose should be taken with food or just after food, whenever possible.  If food cannot be 
taken, then the patient can take the study drug on an empty stomach.  In the event a dose is 
missed during the study day, the dose should be skipped (i.e., the patient should not make up 
the dose).  
In the event the patient experiences nausea possibly due to the study drug, the investigator 
may prescribe a proton pump inhibitor.  No dosing regimen changes will be allowed.  In the 
event a patient is unable to tolerate the assigned dose, the patient will be discontinued from 
the study drug and will be requested to remain in the study until the planned completion. 
8.4 
Accountability and Compliance 
Upon receipt of the study drug supplies, it is the responsibility of the Investigator to ensure 
that records of inventory and accountability are maintained.  Inventory and records must be 
readily available for inspection by the Sponsor or its representatives and regulatory authorities 
at any time.  For patients seen on an outpatient basis, study drug containers and any unused 
study drug must be returned to the investigational site by the patient at each visit for 
reconciliation by the Investigator, or designee. 
Compliance will be assessed by a review of the inventory returned from patients treated on an 
outpatient basis at each visit, and on a daily basis for patients treated on an inpatient basis.  
Patients will be questioned regarding any discrepancies from expected dosing. 
9 
DESCRIPTION OF STUDY PROCEDURES 
Specific study procedures are described below.  Assessment time points are provided in the 
Schedule of Assessments (Section 4.3).  Efficacy will be assessed by sputum microbial load, 
sputum IL8 and neutrophil elastase levels, FEV1, weight, CRP, blood leukocyte count, 
assessment of blood and sputum cysteamine levels, and the following health-related 
questionnaires/PROMs:  CFRSD-CRISS, Jarad and Sequeiros Symptom Score Questionnaire, 
CFQ-R, and Patient Global Assessment of Exacerbation.  Safety will be assessed by 
collection and review of AEs, physical examinations, vital signs, and laboratory parameters 
(chemistry, hematology, and urinalysis). 
9.1 
Sputum Analysis 
Quantitative and standard clinical microbiology will be performed on each sputum sample by 
the central lab.  Results will indicate (a) total CFU count per ml and per mg and (b) organisms 
as Gram-positive/negative per ml and per mg. 
Quantitative IL8 neutrophil and elastase assays will be performed on each sputum sample by 
the sponsor. 
Sites may collect separate samples for each required sputum assessment or may collect one 
sputum sample and split it into either 2 or 3 parts (depending on sample requirements for the 
visit).  The sample will either be split into 2 parts for Day 0, Day 7 and Day 21, and 3 parts 
for Day 14 or 2 samples will be collected for Day 0, Day 7 and Day 21, or 3 samples will be 
collected for Day 14. Each part or sample will be placed into a separate container for shipping 
and analyses, details.  Details on sample collection, preparation and shipping are included in 
the Laboratory Manual. 

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Because the results of these analyses are potentially unblinding, they will not be made 
available to the investigational sites prior to database lock.  
9.2 
FEV1 
FEV1 is the volume exhaled during the first second of a forced expiratory maneuver started 
from the level of total lung capacity.  Three satisfactory maneuvers will be performed and the 
largest value of the three maneuvers will be reported.  Each maneuver will be performed in 
accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) 
standards (Miller et al, 2005).  For consistency, patients should be tested using the same 
equipment at each visit.  Additionally, whenever possible, the same staff member should 
perform all testing for a given patient at each required visit.  Patients must have a documented 
history of FEV1>30% of predicted within the 6 months prior to the study exacerbation. 
9.3 
Health-related Questionnaires/Patient-Reported Outcome Measures (PROMs) 
Patients will complete the health-related questionnaires/PROMs.  The questionnaires may be 
updated/translated in accordance with local requirements.  In the event the patient is unable to 
complete the questionnaires without assistance, the questionnaires may be verbally answered 
and the patient’s responses recorded by site personnel or a chaperone. 
9.3.1 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD)–Chronic Respiratory 
Infection Symptom Scale (CRISS) 
The CFRSD is a 16-item PROM to evaluate the effect of treatment on the severity of CF 
symptoms (ie, CFRSD-CRISS) and to assess the emotional and activity impacts of these 
symptoms. The CFRSD-CRISS is a validated unidimensional scale based on a subset of 8 
items from the CFRSD questionnaire and is designed to evaluate the effect of treatment on the 
severity of symptoms of respiratory infection in patients with CF and a chronic respiratory 
infection. The 8 CFRSD-CRISS items are scored using a 5-point Likert scale ranging from 0 
(no symptom) to 4 (the highest magnitude of severity). A copy of the CFRSD is provided in 
Section 22.1. 
9.3.2 
Jarad and Sequeiros Symptom Score Questionnaire 
The Jarad and Sequeiros Symptom Questionnaire (Jarad and Sequieros 2011) is a simple 
patient-completed questionnaire that assesses and evaluates change in patient symptoms 
related to different aspects of respiratory function during a CF exacerbation. The 
questionnaire consists of 4 questions, each answered on a 4-point scale ranging from 1 (best) 
to 4 (worst).  Individual symptom scores are summed with a total score ranging from 4 to 16. 
A copy of the Jarad and Sequeiros Symptom Score Questionnaire is provided in Section 22.2. 
9.3.3 
Cystic Fibrosis Questionnaire – Revised (CFQ-R) 
The CFQ-R is a patient-completed questionnaire to assess the impact of CF and treatment on 
everyday life.  The questionnaire consists of the following four sections:  Demographics, 
Quality of Life, School, Work or Daily Activities, and Symptom Difficulties.  A copy of the 
CFQ-R is provided in Section 22.3. 

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9.3.4 
Patient Global Assessment of Exacerbation 
The Patient Global Assessment of Exacerbation is a patient-completed questionnaire that 
assesses the current CF exacerbation in comparison to the previous exacerbation.  The 
questionnaire consists of 6 questions, each answered on a 6-point scale, as well as 2 questions 
regarding the time to recovery.  A copy of the Patient Global Assessment of Exacerbation is 
provided in Section 22.4. 
9.4 
Physical Examinations 
A complete physical examination will be performed and will include an assessment of the 
following body systems:  general appearance; mental status; head, eyes, ears, nose, and throat; 
dermatologic; cardiovascular; respiratory; gastrointestinal; and neurological.  Additional body 
systems may be examined at the Investigator’s discretion.  After the Baseline (Day 0) physical 
examination, any physical examination finding, with the exception of CF progression, that is 
assessed by the Investigator to be a clinically significant change (worsening) compared to the 
Baseline (Day 0) assessment, will be considered an AE and reported as described in Section 
11. 
9.5 
Vital Signs, Height, and Weight 
Vital signs include temperature and blood pressure (systolic and diastolic), heart rate, and 
respiratory rate assessed after 5 minutes of rest in a supine position. Weight will be measured 
using a calibrated scale with the patient lightly clothed and shoes off.  Height may be obtained 
from the patient’s medical history, or measured using a calibrated wall mounted stadiometer.  
Any vital sign or weight measurement that is assessed by the Investigator as a clinically 
significant change (worsening) compared to the Baseline (Day 0) assessment will be 
considered an AE and reported as described in Section 11. 
9.6 
Laboratory Testing 
A central laboratory will perform all laboratory testing, with the exception of the urine 
pregnancy tests.  The urine pregnancy test will be performed by study personnel using a 
pregnancy testing kit provided by the central laboratory.  The procedures for laboratory 
collection and processing will be detailed in a separate laboratory manual. 

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9.6.1 
Clinical Laboratory Tests 
The clinical laboratory assessments to be conducted are the following: 
CHEMISTRY 
HEMATOLOGY 
URINALYSIS 
(dipstick) 
PREGNANCY 
Sputum 
analysis 
• CRP 
• alkaline 
phosphatase  
• aspartate 
aminotransferase 
• alanine 
aminotransferase 
• gamma-glutamyl 
transpeptidase 
• lactate 
dehydrogenase 
• total bilirubin 
• total protein 
• albumin 
• blood urea nitrogen  
• creatinine 
• sodium  
• phosphate 
• potassium  
• chloride  
• calcium 
• cysteamine*  
• hemoglobin 
• hematocrit 
• mean corpuscular 
hemoglobin 
• mean corpuscular 
hemoglobin 
concentration 
• mean corpuscular 
volume 
• red blood cell 
count 
• platelet count 
• white blood cell 
count and 
differential count 
o neutrophils 
o lymphocytes 
o eosinophils 
o monocytes 
o basophils 
o large unstained 
cells 
• protein 
• glucose 
• ketones 
• pH 
• specific gravity 
• Blood 
• Nitrite 
• Leukocytes 
• Bilirubin 
• Urobilinogen 
 
• Urine pregnancy 
testing will be 
performed on all 
females of 
childbearing 
potential.  In the 
event pregnancy 
is suspected, a 
serum 
pregnancy test 
will be 
performed. 
• microbiology 
• IL8 
neutrophil 
and 
elastase 
levels 
• cysteamine* 
*cysteamine level results will only be shared once the database is locked to ensure the study is not unblinded 
Reports containing laboratory safety test results will be generated by the central laboratory 
and transmitted to the investigational sites.  In the event any clinically significant abnormal 
laboratory test results are identified, follow-up laboratory tests may be conducted.   
Other clinical laboratory tests may be performed locally by the Investigator, as deemed 
necessary, to ensure patient safety. 
9.6.2 
Cysteamine plasma and sputum level sampling 
At Day 14, a blood sample will be taken for the analysis of cysteamine levels in plasma. The 
cysteamine sputum level will be measured in the sample that is collected for the microbial 
analysis and IL8 and neutrophil elastase levels analysis. The exact time of sampling will be 
recorded in the eCRF, as will the time and date of the last dose taken prior to the sampling.  
Because the results of these analyses are potentially unblinding, they will not be made 
available to the investigational sites prior to database lock. 
10 CONCOMITANT MEDICATIONS, NON-MEDICATION THERAPIES, AND 
STUDY RESTRICTIONS 
All medications (i.e., prescription, over-the-counter, supplements) taken by the patient from 
30 days prior to the Screening visit and throughout the study will be documented.  
Documentation will include new medications, existing medications, and dose changes to 

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existing medications.  The following will be collected for all concomitant medications:  
medication name, start/stop dates, total daily dose, route of administration, and indication for 
use. 
In addition, any non-medication therapies used by the patient from 30 days prior to the 
Screening visit and throughout the study will be documented.  Documentation will include 
new therapies, existing therapies, and changes to existing therapies.  The following will be 
collected for all non-medication therapies:  therapy name, start/stop dates, frequency of use, 
and indication for use. 
10.1 
Prohibited Foods and Medications 
10.1.1 
Restricted Foods 
There are no food and beverage restrictions in this study. 
10.1.2 
Restricted Medications 
Patients will be permitted to take all of their normal medications required as part of their 
management of CF.   
 
11 ADVERSE EVENTS 
11.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a patient in a clinical investigation 
who is administered a pharmaceutical product.  The AE does not necessarily have to have a 
causal relationship with this product.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the investigational product, whether or not related to the 
investigational product. 
An AE includes:  
• Any symptom not previously reported in the patient’s medical history; 
• A worsening of a pre-existing condition; 
• A significant increase in frequency or intensity of a pre-existing condition; and 
• A condition first detected or diagnosed after study drug administration, even though 
the condition may have been present before the start of the trial.  
An AE does not include:  
• Symptoms of the underlying disease (CF) that might be reasonably anticipated to 
come and go, or progress, given the nature and severity of the condition.  However, if 
the progression of the disease results in hospitalization for reasons other than the 

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exacerbation under the current study, is life-threatening, or is fatal, then progression of 
the disease should be reported as an SAE (see Section 12.1); 
• Expected variations in severity of disease signs and symptoms that have previously 
been reported in the patient’s medical history; 
• Pre-planned medical or surgical procedures (e.g., surgery, tooth extraction, or 
transfusion) [Note: The condition that leads to the procedure may be an AE];  
• Overdose of study drug without any clinical signs or symptoms; or 
• Clinically significant laboratory values.  If abnormal laboratory values are 
accompanied by abnormal signs or symptoms, the signs or symptoms are considered 
an AE and should be recorded as such.  Abnormal laboratory values associated with 
the current CF exacerbation are not an AE.  Abnormal laboratory values will be 
recorded in the study database.  
It is the responsibility of the Investigator to document all AEs that occur after the first dose of 
study drug is administered, regardless of whether or not they are considered to be related to 
the study drug.  
11.2 
Documenting Adverse Events 
AEs will be elicited by asking each patient a general, non-directed question such as “How 
have you been feeling since the last visit?”  Directed questioning and examination will then be 
done, as appropriate.  All reported AEs will be documented. 
Whenever feasible, AEs should be documented as medical diagnoses (highest possible level 
of integration).  When this is not possible, the AE should be documented in terms of the signs 
and/or symptoms observed by the Investigator or reported by the patient. 
Information documented will include the description of the AE, the date of onset and 
resolution (if applicable), severity, seriousness, relationship to study procedures, action taken, 
and the outcome.  The Investigator must follow AEs until the Day 21/End of Study visit, the 
event resolves, or until the condition stabilizes and the Investigator feels no further medical 
follow-up is warranted.  
11.3 
Assessment of Severity 
The Investigator will categorize the severity of each AE according to the definitions listed 
below: 
Mild: 
An event that is easily tolerated by the patient, causing minimal 
discomfort, and not interfering with everyday activities. 
Moderate: 
An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
Severe: 
An event that prevents normal everyday activities. 

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Note: the term ‘severe’, used to describe the intensity, should not be confused with ‘serious’ 
which is a regulatory definition based on patient/event outcome or action criteria.  For example, 
a headache may be severe but not serious, while a minor stroke is serious but may not be severe. 
11.4 
Assessment of Causality 
After careful medical consideration, the Investigator will assess the relationship of the AE to 
the study drug according to the following categories:  
Unrelated: 
The event is not considered to be related to the study drug. 
Possibly Related: 
Although a relationship to the study drug cannot be completely 
ruled out, the nature of the event, the underlying disease, 
concomitant medication or temporal relationship make other 
explanations possible. 
Probably Related: 
The temporal relationship and absence of a more likely 
explanation suggest the event could be related to the study drug.  
Definitely Related: The known effects of the study drug or its therapeutic class, or 
based on challenge testing, suggest that study drug is the most 
likely cause. 
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. possibly, 
probably, definitely) to the study drug will be considered as ARs/serious adverse reactions 
(SARs).   
Alternative causes such as natural history of the underlying disease, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the treatment should be 
considered.  
11.5 
Adverse Event Outcome 
The Investigator will categorize the outcome of each AE according to the following 
definitions: 
Resolved: 
The patient recovered from the AE.  Record the AE stop 
date. 
Resolved with Sequelae 
The patient recovered from the AE with sequelae.  Record 
the AE stop date as the date the patient recovered with 
sequelae. 
Ongoing: 
At the time of the last assessment, the event is ongoing, 
with an undetermined outcome.  Note: ongoing AEs are not 
considered resolved as a result of death.  No AE stop date 
should be recorded when an AE is ongoing. 
Chronic/Stable: 
At the time of last assessment, the event is ongoing and 
stabilized, with no change to the event outcome 
anticipated.  Record the AE stop date. 

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Death: 
The AE directly caused death.  Record the date of death as 
the AE stop date. 
Unknown: 
There is an inability to access the patient or the patient’s 
records to determine the outcome (e.g., patient withdraws 
consent or is lost to follow up).  No AE stop date should be 
recorded. 
The Investigator must follow AEs until the Day 21/End of Study visit, the event resolves, or 
until the condition stabilizes and the Investigator feels no further medical follow-up is 
warranted. 
11.5.1 
Withdrawal Due to Adverse Event 
If a patient is withdrawn from the study by the Investigator wholly or in part due to an AE, the 
patient will be monitored at the discretion of the Investigator (e.g., until the event has resolved 
or stabilized, until the patient is referred to the care of a health care professional, or until a 
determination of a cause unrelated to the study drug is determined). 
12 SERIOUS ADVERSE EVENT 
12.1 
Definition of Serious Adverse Event 
A SAE is any event that meets any of the following criteria: 
• Death; 
• Life-threatening; 
• Inpatient hospitalization or prolongation of existing hospitalization; Hospitalizations 
scheduled for an elective procedure or for treatment of a pre-existing condition that 
has not worsened during participation in the study will not be considered an SAE; 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a patient; and/or 
• Other:  Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm; 
o Blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; and/or 
o Development of drug dependency or drug abuse. 

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An AE that does not meet any of the criteria for seriousness listed above will be regarded as a 
non-serious AE. 
Definition of Terms 
Life threatening:  An AE is life threatening if the patient was at immediate risk of death from 
the event as it occurred; i.e., it does not include a reaction that if it had occurred in a more 
serious form might have caused death.  For example, drug induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life threatening, even though 
drug induced hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of an AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) need not be considered AEs or 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'non-serious' according to the defined criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or in the emergency department for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient setting. 
As noted in Section 11.1, if progression of the symptoms of the underlying disease (CF) result 
in hospitalization for reasons other than the exacerbation under the current study, if it is 
life-threatening, or is fatal, then progression of the disease will be reported as an SAE.  If the 
event does not meet these criteria, then the hospitalization for the CF exacerbation under 
study will not be reported as an SAE. 
Disability/incapacitating:  An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient's ability to carry out normal life 
functions. 
12.2 
SAE Expectedness 
An SAE that is not included in the Investigator’s Brochures by its specificity, severity, 
outcome, or frequency is considered an unexpected AE.  If a serious unexpected AE is 
believed to be related to the study drug or study procedures, the Sponsor will take appropriate 
steps to notify all Investigators participating in sponsored clinical studies of cysteamine, as 
well as the appropriate regulatory authorities. 
12.3 
Reporting Serious Adverse Events 
Any SAE that occurs at any time following the first dose of study drug or within 4 weeks 
following the last dose of study drug, whether or not related to the study drug, must be 
reported by the Investigator to the Medical Monitor within 24 hours of knowledge of the 
event.  The Investigator should not wait to receive additional information to fully document 
the event before completing the initial SAE form. 
Where applicable, information from relevant hospital records and autopsy reports should be 
obtained.  In the event of a fatal or life-threatening SAE, any required follow-up must be 
provided within seven calendar days of the initial report.  The Investigator will follow all 

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SAEs until resolved or deemed stable and chronic in nature.  Any follow-up information 
relevant to the SAE must be reported to the Medical Monitor. 
Instances of death, cancer, or congenital abnormality, if brought to the attention of the 
Investigator AT ANY TIME after study drug administration AND considered by the 
Principal Investigator to be RELATED TO THE STUDY DRUG, must be reported to the 
Medical Monitor.  
SAEs will be reported to the Sponsor according to the procedures outlined in the Study 
Handbook.  Where required by local regulations, the Institutional Review Board/Ethics 
Committee (IRB/EC) and/or regulatory authorities will be informed of SAEs in accordance 
with local regulation timeframes and reporting requirements (as specified in the Study 
Handbook). 
No protocol-defined AEs for expedited reporting are identified for this study. 
12.3.1 
Overdose 
Any instance of overdose (suspected or confirmed and irrespective of whether or not the study 
drug was involved) must be communicated to the Sponsor in accordance with the procedures 
outlined in the Study Handbook. 
12.3.2 
Pregnancy 
Pregnancy is not considered an AE or SAE; however, the Investigator must collect pregnancy 
information for female patients or female partners of male patients who become pregnant 
while participating in a study.  The Investigator should report the pregnancy to the Sponsor in 
accordance with the procedures outlined in the Study Handbook. 
Any pregnancy that occurs in a patient or patient’s partner during a study should be followed 
to outcome.  In some circumstances, it may be necessary to monitor the development of the 
newborn for an appropriate period post-delivery.   
Should the patient or patient’s partner not wish for the pregnancy to be followed to outcome 
or beyond, this should be documented. 
Female patients who become pregnant will be advised to discontinue study drug immediately, 
and will not be administered further study drug. 
13 STATISTICS 
A comprehensive statistical analysis plan (SAP) will be developed for this study and finalized 
prior to locking the database. The SAP will provide additional details about the specific 
planned analyses and hypothesis tests.   
13.1 
Analysis Populations 
.The analysis population for all efficacy and safety analyses will include all patients who 
received at least one dose of study drug, which will be referred to as the Safety Population. 

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The Per Protocol (PP) population will include all randomized patients who complete the 
Treatment Period without experiencing a significant protocol violation that would impact 
critical safety and efficacy interpretation (eg, missing 6 or more consecutive doses, 
determined not to have experienced an exacerbation of CF-associated lung disease due to a 
Gram-negative organism(s) at baseline). 
 
13.2 
General Procedures 
All analyses will be performed and all tables, figures and data listings will be prepared using 
SAS, Version 9.4 or higher.  
Continuous variables will be summarized descriptively by the number of patients with non-
missing data, mean and standard deviation, median, minimum, and maximum values.   
Categorical variables will be summarized descriptively by their counts and associated 
percentages. 
 
13.3 
Sample Size 
A total of approximately 120 patients with CF being treated for an exacerbation of CF-
associated lung disease will be enrolled in the study: 20 patients in each group. The sample 
size of 120 patients was selected empirically without a formal statistical assumption. The 
sample size selection is considered to be appropriate to determine the optimal dose and 
regimen based on evidence of efficacy and acceptable safety and tolerability profile as well as 
establish point estimates and variability for efficacy endpoints for future evaluation. 
A sample size of 20 patients in each group will have approximately 80% power to detect a 1.2 
log reduction over placebo, assuming a standard deviation of 1.31 in the reduction of sputum 
bacterial load, based on a two-sided, two-sample t-test at the 5% level of significance. This 
estimated standard deviation is that reported for a 2-week study of CF patients with 
Pseudomonas aeruginosa who were treated during exacerbations with 2 weeks of intravenous 
tobramycin (Al-Aloul et al, 2014).  
13.4 
Statistical Methods 
13.4.1 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics.  
13.4.2 
Efficacy Analyses 
The primary objective of this study, to determine the optimal dose and regimen of cysteamine 
in patients with exacerbations of CF-associated lung disease, will be investigated through a 
combination of safety, efficacy, and microbiology endpoints. Though statistical comparisons 
between treatment groups with respect to efficacy and microbiology will be performed to help 
inform the selection of the final dose for further development, safety and tolerability will also 
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The primary efficacy endpoint for the study is: 
• Change from baseline (Day 0) in log-transformed sputum bacterial load of gram negative 
CFU per ml and per mg following a CF exacerbation 
The secondary efficacy endpoints for the study are: 
• Change from baseline (Day 0) in patient health-related questionnaires/PROMs (CFRSD-
CRISS, Jarad and Sequeiros Symptom Score Questionnaire, and CFQ-R)  
• Patient Global Assessment of Exacerbation questionnaire 
• Change from baseline (Day 0) in sputum IL8 and neutrophil elastase levels following a 
CF exacerbation 
• Change from baseline (Day 0) in the following: 
o FEV1  
o Weight and BMI 
o CRP 
o Blood leukocyte count 
• Assessment of blood and sputum cysteamine levels at Day 14 
 
The efficacy comparisons of interest at Day 14 will be conducted using a linear mixed model 
for repeated measures, analysis of variance (ANOVA), and chi-square tests as appropriate. 
Change from baseline (Day 0) to Day 7 and Day 21 will also be assessed where applicable. 
All analyses will be conducted using two-sided tests at the alpha=0.05 level of significance. 
There will be no adjustments for multiple comparisons in the efficacy analyses for this study.  
The data for change from baseline (Day 0) measures will be summarized with descriptive 
statistics and confidence intervals and will be analyzed via contrast statements from the mixed 
model for all pairwise and pooled total daily dose (TDD) group comparisons, each at the 
alpha=0.05 level of significance.  Analyses of subgroups and other exploratory linear mixed 
models may be explored. 
 
Continuous variables will be summarized descriptively by the number of patients with non-
missing data, mean and standard deviation, median, minimum, and maximum values.  
Categorical variables will be summarized descriptively by their counts and associated 
percentages. 
 
13.4.3 
Safety Analyses 
Safety analyses will involve the examination of the descriptive statistics and individual patient 
listings for any effects of study treatment on clinical safety.  Summaries will be prepared by 
treatment group and TDD group. 
 
Treatment-emergent adverse event (TEAE) summaries will include the overall incidence (by 
system organ class and preferred term), events by maximum intensity, events by relationship 
to study treatment, events leading to discontinuation of study drug, and SAEs. 
 
Vital signs and laboratory parameters (hematology, chemistry, and urinalysis) will be 
summarized descriptively by treatment.  Actual and change from baseline (Day 0) data will be 
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Each potentially efficacious dose will also be assessed from a safety and tolerability 
perspective based on assessment of AEs, laboratory values, and vital signs.  Potential doses 
for future development will consist of one or more doses that are both potentially efficacious 
and have demonstrated an adequate safety profile. 
AEs and concomitant medications will be coded using standardized medical dictionaries. 
13.5 
Interim Analysis 
There will be no interim analysis for this study. 
14 ETHICS AND RESPONSIBILITIES 
14.1 
Good Clinical Practice 
This study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any 
applicable national and local laws and regulations (e.g., Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, EU Directive 20/EC and 28/EC).  Any episode of 
noncompliance will be documented. 
The Investigator is responsible for performing the study in accordance with this protocol and 
the applicable GCP guidelines referenced above for collecting, recording, and accurately 
reporting the data. 
The Investigator is responsible for ensuring the privacy, health, and welfare of the patients 
during and after the study, and must ensure that trained personnel are immediately available in 
the event of a medical emergency.  The Investigator and the applicable study staff must be 
familiar with the requirements of the study and with the properties of the study drug described 
in the Investigator’s Brochure. 
The Investigator at each investigational site has the overall responsibility for the conduct and 
administration of the study at that site and for contacts with study management, the IRB/EC, 
and with local authorities. 
14.2 
Data Safety Monitoring Board (DSMB) 
The DSMB will review safety data periodically throughout the study with special attention to 
all AEs, SAEs, and other measures of safety in order to monitor the emerging safety profile, 
and recommend modification or premature termination of the study, if necessary.  The DSMB 
will be composed of independent physicians with expertise in the relevant therapeutic field, as 
well as other relevant experts, such as a statistician.  The DSMB Charter will outline the data 
to be reviewed by the DSMB and the frequency of the meetings. 
14.3 
Institutional Review Board (IRB)/Ethics Committee (EC) 
Before initiation of the study, the Investigator must submit the protocol, Investigator’s 
Brochure, informed consent form, advertisements, and any written materials that will be made 
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guidelines for approval.  Written IRB/EC approval of the noted documents must be obtained 
prior to initiation of the study. 
The Investigator and/or Sponsor are responsible for reporting the following to the IRB/EC, if 
applicable, in accordance with local and IRB/EC regulations: 
• All SAEs regardless of cause and whether anticipated or unanticipated (reported per 
IRB/EC regulations)  
• Significant findings that become known during the course of the study that might 
affect the willingness of patients to continue to participate  
• Protocol or consent amendments prior to the implementation of the change 
• Study progress reports at least once a year, if applicable 
• Notification of study completion or termination 
Details of reporting requirements are provided in the Study Handbook. 
14.4 
Informed Consent 
The Investigator, or designee, will thoroughly explain to the patient the purpose of the study, 
the associated procedures, as well as any expected effects and ARs before any study-specific 
screening procedures are conducted.   
The Investigator will explain that the patient is completely free to refuse participation in the 
study or to withdraw from the study at any time and for any reason.  Similarly, the 
Investigator and/or Sponsor will be free to withdraw the patient at any time for safety or 
administrative reasons.  Any other requirements necessary for the protection of the human 
rights of the patient will also be explained according to current ICH GCP guidelines (ICH E6 
1997) and the Declaration of Helsinki, 1964 (as amended in 2013); see Section 22.5.   
The patient will be provided with an informed consent form and will be given sufficient time 
and opportunity to inquire about the details of the study and to decide whether or not to allow 
the patient to participate.  The patient and the study personnel with whom he/she discusses the 
informed consent, will sign and date the consent form. 
14.5 
Records Management and Study Monitoring 
Representatives of the Sponsor may request access to all study records for inspection 
throughout the study or after study completion.  Such access must be stated in the informed 
consent form signed by the patient. 
The Sponsor is responsible for ensuring the protocol conduct of the study with regard to 
ethics, protocol adherence and site procedures, integrity of the data, and applicable laws 
and/or regulations.  Study monitoring will be conducted at regular intervals during the study 
and following completion of the study.  Study monitors will contact the investigational site 
via visits to the site, telephone calls, and other communication methods in order to review the 
progress of the study.  During the monitoring visits, the following aspects of the study 
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compliance with study procedures, source data verification, AE and SAE documentation and 
reporting, and quality of the data.  The Investigators must make all study data accessible to 
the clinical monitor, to other authorized representatives of the Sponsor, members of the 
IRB/EC, and regulatory inspectors.  The informed consent form signed by the patient must 
indicate the possibility for review of the data by these authorized individuals/entities. 
14.6 
Source Documentation and Data Collection 
All patient-related data will be documented in case report forms (CRFs) in a confidential 
fashion, with the patient identified by patient number and initials only.  Study data will be 
collected using an electronic data capture (EDC) system.  
All the information required by the protocol must be documented and any omissions 
explained.  The Investigator must review all CRF entries for completeness and accuracy. 
Source documents, including all demographic and medical information, CRFs, and informed 
consent form for each patient in the study must be maintained by the Investigator.  All 
information in the CRFs must be traceable to the original source documents.  Examples of 
source documents include hospital records, outpatient visit records, physician notes, 
consulting physician notes, laboratory reports, study drug inventory records, and patient 
dosing data.  Records may be written in hard copy or in an electronic medical records system.  
The Investigator must maintain the original source document records for each patient for the 
length of time required by the Sponsor. 
14.7 
Study Files and Record Retention 
All data relating to the study, including the contents of the Investigator’s Site Files, patient 
CRFs, financial records, and other source data will be stored by the Investigator until written 
notification is received from the Sponsor indicating that records no longer require storage. 
If the Investigator cannot guarantee this archiving requirement at the study site, arrangements 
must be made between the Investigator and the Sponsor to store the documents in an 
alternative secure facility.  Study documents should not be destroyed without written approval 
from the Sponsor. 
14.8 
Declaration of End of Clinical Study 
For investigational sites located in the EU, a declaration of the end of the clinical study will 
be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); for 
other countries, local regulations will be followed. 
14.9 
Registration of Clinical Study 
This clinical study will be registered on clinical trial registry websites, according to the 
Sponsor’s standard procedures. 
15 AUDITING 
Sponsor representatives may audit some investigational sites to evaluate study conduct and 
compliance with protocols, Standard Operating Procedures (SOPs), GCPs, and applicable 
regulatory requirements.  Additionally, regulatory authorities and IRB/EC representatives 

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may also perform audits to verify compliance with GCP guidelines.  The Investigator must 
permit these inspections as part of the study conduct. 
16 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may 
only be made by the Sponsor.  A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/EC is 
notified in accordance with their procedures. 
Any permanent change to the protocol must be handled as a protocol amendment.  The 
written amendment must be submitted to the IRB/EC, and the Investigator must receive 
approval before implementing the change(s). 
If in the judgment of the IRB/EC, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the 
patient and/or has an impact on the patient's involvement as a study participant, the currently 
approved written informed consent form will require similar modification.  In such cases, 
informed consent will be renewed for patients enrolled in the study before continued 
participation. 
17 FINANCING AND INSURANCE 
A separate financial agreement will be made between the Investigator and the Sponsor before 
study drug is shipped to the investigational site.  The Investigator will provide the Sponsor 
with financial information required to complete USA Food and Drug Administration (FDA) 
Form FDA 3454, as well as any additional information required for local regulatory 
authorities.  Each Investigator will notify the Sponsor of any relevant changes in this financial 
information during the conduct of the study, and for 1 year after study completion. 
This clinical study is insured in accordance with the corresponding local legal provisions.  
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions.  
Excluded from the insurance coverage are damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study.  The policy regarding clinical trials insurance will be provided to the 
investigational sites by the Sponsor.   
18 STUDY REPORT AND PUBLICATIONS 
The Sponsor is responsible for preparing a clinical study report based on the results of this 
study.  The Sponsor’s publication policy is discussed in the Investigator's Clinical Research 
Agreement. 
19 STUDY DISCONTINUATION  
Both the Sponsor and the Investigator reserve the right to terminate the study at the 
Investigator’s site at any time.  Should this be necessary, the Investigator will inform the 
IRB/EC of the same.  In terminating the study, the Sponsor and the Investigator will assure 
that adequate consideration is given to the protection of the patients’ interests. 

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20 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from the Sponsor.  However, authorized regulatory officials, IRB/EC 
personnel, the Sponsor and its authorized representatives are allowed full access to the 
records. 
Identification of patients in CRFs shall be by initials and screening numbers only.  If required 
by local agencies, initials will be coded per local regulations (e.g., AAA, BBB).  Additionally, 
if required, the patient's full name may be made known to an authorized regulatory agency or 
other authorized official. 
 
 

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21 REFERENCES 
Al-Aloul, M., Nazareth, D., Walshaw, M. Nebulized tobramycin in the treatment of adult CF 
pulmonary exacerbations. J. Aerosol Med and Pulmonary Drug Del 2014. 27 (4): 299-305. 
Bals R, Hubert D, Tümmler B. Antibiotic treatment of CF lung disease: From bench to 
bedside. J Cystic Fibrosis 2011; 10 Suppl 2: S146–S151. 
Besouw M, Masereeuw R, van den Heuvel L, Levtchenko E. Cysteamine: an old drug with 
new potential. Drug Discovery Today 2013, 18; 15/16: 785-92. 
Britto MT, Kotagal UR, Hornung RW, et al. Impact of recent pulmonary exacerbations on 
quality of life in patients with cystic fibrosis. Chest 2002; 121:64–72. 
Charrier C, Rodger C, Robertson J, Kowalczuk A, Shand N, Fraser-Pitt D, Mercer D, O’Neil 
D. Cysteamine (Lynovex®), a novel mucoactive antimicrobial & antibiofilm agent for the 
treatment of cystic fibrosis. Orphanet Journal of Rare Diseases 2014 9:189. 
Devereux G, Fraser-Pittb, D, Robertsonb, J, Devlina, E, Mercerb, D, O’Neil, D. Cysteamine 
as a Future Intervention in Cystic Fibrosis Against Current and Emerging Pathogens: A 
Patient-based ex vivo Study Confirming its Antimicrobial and Mucoactive Potential in 
Sputum. EBIOM-00245 Article in Press August 2015. 
Fuchs HJ, Borowitz, DS, Christiansen, DH. 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. 
Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis. 
Thorax 2007; 62:360–367. 
Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc 
2007; 4:378–386. 
Giwercman B, Lambert PA, Rosdahl VT, Shand GH, Hoiby N. Rapid emergence of resistance 
in Pseudomonas aeruginosa in cystic fibrosis patients due tot in vivo selection of stable 
partially derepressed B-lactamase producing strains. J Antimicrobial Chemo 1990; 26: 247-
59. 
Hegarty M, MacDonald J, Watter P, Wilson C. Quality of life in young people with cystic 
fibrosis: effects of hospitalization, age and gender, and differences in parent/child perceptions. 
Child: Care, Health Develop 2009; 35:462–468. 
Hoiby N. New antimicrobials in the management of cystic fibrosis. J Antimicrobial Chem, 
2002; 49:235-238. 
Jarad, NA and Sequeiros, IM. A novel respiratory symptom scoring system for CF pulmonary 
exacerbations. Q J Med 2012; 105:137–143.  
Koch C, Pedersen S, Jensen E, et al. Retrospective clinical study of hypersensitivity reactions 
to aztreonam and six other beta-lactam antibiotics in cystic fibrosis patients receiving multiple 
treatment courses. Rev Infect Dis 1991;13:S608–11. 

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Miller MR et al.  Standardisation of spirometry.  Eur Resp J 2005;26:319-38.  
Oliver A, Canton R, Campo P, Baquero F, Blazquez J. High frequency of hypermutatable 
Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 2000; 288:1251-3.  
Pitt TL, Sparrow M, Warner M, Stefanidou M. Survey of resistance of Pseudomonas 
aeruginosa from UK patients with cystic fibrosis to six commonly prescribed antimicrobial 
agents. Thorax 2003;58:794–6. 
Pleasants R, Samuelson W. Allergic reactions to parenteral beta-lactam antibiotics in patients 
with cystic fibrosis. Chest 1994;106:1124–8. 
Sanders DB, Bittner RCL, Rosenfeld M, et al. Failure to recover to baseline pulmonary 
function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010; 
182:627–632. 
Sanders DB, Bittner RCL, Rosenfeld M, et al. Pulmonary exacerbations are associated with 
subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol 
2011; 46:393–400. 
Stewart PS, Costerton JW. Antibiotic resistance of bacteria in biofilms. Lancet 2007; 
358:135-8. 
Ting, Naitee(2009) 'Practical and Statistical Considerations in Designing an Early Phase II. 
Osteoarthritis Clinical Trial: A Case Study', Communications in Statistics - Theory and 
Methods, 38: 18, 3282 — 3296 
UK CF Registry,  Annual Data Report 2014 
http://www.cysticfibrosis.org.uk/media/598466/annual-data-report-2013-jul14.pdf 
Wills R, Henry RL, J Francis. Antibiotic hypersensitivity reactions in cystic fibrosis. J 
Paediatr Child Health 1998;43:325–9. 
 
 
 

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22 APPENDICES 
22.1 
APPENDIX A – Cystic Fibrosis Respiratory Symptom Diary (CFRSD) – Chronic 
Respiratory Infection Symptom Scale (CRISS) 
 
 
 

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22.2 
APPENDIX B – Jarad and Sequeiros Symptom Score Questionnaire 
 
 
 

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22.3 
APPENDIX C – Cystic Fibrosis Questionnaire – Revised (CFQ-R) 

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22.4 
APPENDIX D – Patient Global Assessment of Exacerbation 
 

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22.5 
APPENDIX E – Declaration of Helsinki 
 
 
 

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