Clinical trial NCT03979638
Conditions: Chronic Refractory Cough
Keywords: Unexplained or refractory chronic cough, P2X3 antagonists
Sponsor: Bellus Health Inc. - a GSK company
Start date: 2019-07-10; Completion date: 2020-04-23
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multi-center, randomized, double-blind, placebo-controlled, crossover, dose escalation study of BLU-5937 in subjects with unexplained or refractory chronic cough

Detailed description:
This study will have two 16-day treatment periods (four escalating doses or matching placebo at four days interval) separated by a 10 to 14-day washout period. There will be a 14-day follow-up period.

Arms: arm 1: Randomized crossover design of 4 different doses (25, 50, 100, 200 mg BID) of BLU-5937 tablets to be administered orally BID arm 2: Randomized crossover design of matching placebo tablets to be administered orally BID
Interventions: intervention 1: BLU-5937 intervention 2: Placebo
Intervention descriptions: intervention 1: Four escalating doses of BLU-5937 administered BID over the course of the study intervention 2: Matching placebo for BLU-5937

Protocol documents:
Prot_SAP_000.pdf: 




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A Randomized, Double-blind, Placebo-Controlled, Crossover, Dose Escalation Study of 
BLU-5937 in Subjects with Unexplained or Refractory Chronic Cough. 
 
 
I have carefully read this study protocol and agree it contains all necessary information required to 
conduct this study. I agree to conduct the study according to this protocol and in accordance with GCP 
and the applicable regulatory requirements. 




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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................ 5 
LIST OF IN-TEXT TABLES ..................................................................................................................................... 9 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................................................. 10 
STUDY SYNOPSIS ................................................................................................................................................... 12 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE ................................................................ 21 
1. INTRODUCTION .............................................................................................................................................. 24 
1.1. Cough Reflex Mechanism ............................................................................................................................. 24 
1.2. BLU-5937 Pharmacology .............................................................................................................................. 25 
1.3. Clinical Indication ......................................................................................................................................... 25 
1.4. Nonclinical Experience ................................................................................................................................. 26 
1.5. Nonclinical Pharmacokinetics ....................................................................................................................... 26 
1.6. Toxicology .................................................................................................................................................... 27 
1.7. Clinical Experience ....................................................................................................................................... 28 
1.8. Study Rationale ............................................................................................................................................. 29 
1.9. Risk/Benefit Assessment ............................................................................................................................... 30 
1.9.1 Known Potential Risks ........................................................................................................................... 30 
1.9.2. Known Potential Benefits....................................................................................................................... 30 
2. STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 30 
2.1. Primary Objective ......................................................................................................................................... 30 
2.2. Secondary Objective ..................................................................................................................................... 30 
2.3. Primary Efficacy Endpoint ............................................................................................................................ 30 
2.4. Secondary Efficacy Endpoints ...................................................................................................................... 30 
2.5. Exploratory Efficacy Endpoints .................................................................................................................... 31 
2.6. Safety Endpoints ........................................................................................................................................... 31 
2.7. Pharmacokinetics .......................................................................................................................................... 31 
3. STUDY DESIGN ................................................................................................................................................ 31 
3.1. Discussion of Study Design .......................................................................................................................... 32 
4. SUBJECT POPULATION ................................................................................................................................ 32 
4.1. Inclusion Criteria ........................................................................................................................................... 32 
4.2. Exclusion Criteria .......................................................................................................................................... 33 
4.3. Withdrawal Criteria ....................................................................................................................................... 34 
4.3.1. Before First Treatment Administration .................................................................................................. 34 
4.3.2. After First Treatment Administration..................................................................................................... 35 
4.3.3. Individual Subject Stopping Rules ......................................................................................................... 35 
4.3.4. Liver Function Stopping Criteria ........................................................................................................... 35 


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4.4. Prohibited Medications and non-pharmacological Therapies / Washout ...................................................... 36 
5. STUDY TREATMENTS .................................................................................................................................... 37 
5.1. Investigational Product and Placebo ............................................................................................................. 37 
5.1.1. BLU-5937 tablets ................................................................................................................................... 37 
5.1.2. Placebo ................................................................................................................................................... 37 
5.2. Investigational Product Management ............................................................................................................ 37 
5.2.1. Packaging, Labelling and Dispensing .................................................................................................... 37 
5.2.2. Storage and Handling ............................................................................................................................. 38 
5.2.3. Method of Assigning Subjects to Treatment Groups ............................................................................. 38 
5.2.4. Blinding .................................................................................................................................................. 39 
5.2.5. Study Drug Accountability..................................................................................................................... 39 
5.2.6. Treatment compliance ............................................................................................................................ 39 
6. STUDY PROCEDURES .................................................................................................................................... 39 
6.1. Safety Assessments ....................................................................................................................................... 40 
6.1.1. Medical History ...................................................................................................................................... 40 
6.1.2. Physical Examination ............................................................................................................................. 40 
6.1.3. Vital Signs .............................................................................................................................................. 40 
6.1.4. 12-Lead Electrocardiogram .................................................................................................................... 40 
6.1.5. Laboratory Evaluations .......................................................................................................................... 40 
6.2. Blood Volume Collected ............................................................................................................................... 41 
6.3. Pharmacokinetic Assessments ....................................................................................................................... 42 
6.4. Evaluation of Taste Disturbance ................................................................................................................... 42 
6.5. Efficacy Parameters ....................................................................................................................................... 42 
6.6. Study Visits ................................................................................................................................................... 42 
6.6.1. Screening Period Procedures (Visit 1/Day -14 to Day -1) in Clinic ....................................................... 42 
6.6.2. Randomization (Day -4 to Day 1) .......................................................................................................... 43 
6.6.3. Baseline Visit Procedures Period 1 (Visit 2/Day 0) in clinic or at home ............................................... 43 
6.6.4. Treatment Visit Procedures (Visit 3/Day 1) ........................................................................................... 43 
6.6.5. Treatment Visit Procedures (Visit 4/Day 4) in clinic or at home ........................................................... 44 
6.6.6. Treatment Visit Procedures (Visit 5/Day 8) in clinic or at home ........................................................... 45 
6.6.7. Treatment Visit Procedures (Visit 6/Day 12) in clinic or at home ......................................................... 45 
6.6.8. Treatment Visit Procedures (Visit 7/Day 16) in clinic ........................................................................... 46 
6.6.9. Washout Period (Days 17-30) ................................................................................................................ 47 
6.6.10. Baseline Visit Procedures Period 2 (Visit 8/Day 30) in clinic or at home ............................................. 47 
6.6.11. Treatment Visit Procedures (Visit 9/Day 31) in clinic ........................................................................... 47 
6.6.12. Treatment Visit Procedures (Visit 10/Day 34) in clinic or at home ....................................................... 48 
6.6.13. Treatment Visit Procedures (Visit 11/Day 38) in clinic or at home ....................................................... 49 


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6.6.14. Treatment Visit Procedures (Visit 12/Day 42) in clinic or at home ....................................................... 49 
6.6.15. Treatment Visit Procedures (Visit 13/Day 46/Early Termination Visit) in clinic .................................. 50 
6.6.16. Follow-Up Visit Procedures (Visit 14/Day 60) in clinic ........................................................................ 51 
6.6.17. Early Termination .................................................................................................................................. 51 
7. ADVERSE EVENTS DOCUMENTATION .................................................................................................... 51 
7.1. Definitions ..................................................................................................................................................... 51 
7.2. Severity Assessment ...................................................................................................................................... 52 
7.3. Causality Assessment .................................................................................................................................... 53 
7.4. Adverse Event Monitoring ............................................................................................................................ 53 
7.5. Reporting of Pregnancy ................................................................................................................................. 54 
7.6. Serious Adverse Event Reporting ................................................................................................................. 54 
7.7. Serious Adverse Event Reporting to Regulatory Authorities and study Investigators .................................. 55 
8. DATA ANALYSIS AND STATISTICAL METHODS ................................................................................... 55 
8.1. Analysis Sets ................................................................................................................................................. 55 
8.2. General Approach ......................................................................................................................................... 56 
8.3. Demographic Data and Other Baseline Characteristics ................................................................................. 56 
8.4. Efficacy Analysis .......................................................................................................................................... 56 
8.4.1. Primary Endpoint – Awake Cough Count .............................................................................................. 56 
8.4.2. Secondary Endpoints .............................................................................................................................. 57 
8.4.3. Exploratory Efficacy Endpoints ............................................................................................................. 58 
8.5. Multiplicity .................................................................................................................................................... 58 
8.6. Extent of Exposure ........................................................................................................................................ 58 
8.7. Safety Analysis .............................................................................................................................................. 58 
8.8. Laboratory Values ......................................................................................................................................... 58 
8.9. Vital Signs ..................................................................................................................................................... 59 
8.10. ECG ............................................................................................................................................................... 59 
8.11. PK Analysis ................................................................................................................................................... 59 
8.12. PK/PD Relationship ...................................................................................................................................... 59 
8.13. Planned Interim Analyses .............................................................................................................................. 59 
8.14. Determination of Sample Size ....................................................................................................................... 59 
9. ETHICS ............................................................................................................................................................... 59 
9.1. Independent Ethics Committee / Institutional Review Board ....................................................................... 59 
9.2. Ethical Conduct of the Study ......................................................................................................................... 60 
9.3. Subject Information and Consent .................................................................................................................. 60 
9.4. Subject Confidentiality .................................................................................................................................. 60 
10. DATA COLLECTION, RETENTION, AND MONITORING ...................................................................... 60 
10.1. Case Report Forms ........................................................................................................................................ 60 


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10.2. Data Management and Processing ................................................................................................................. 61 
10.3. Record Retention ........................................................................................................................................... 61 
10.4. Monitoring of the Study ................................................................................................................................ 61 
11. ADMINISTRATIVE PROCEDURES .............................................................................................................. 61 
11.1. Adherence to Protocol ................................................................................................................................... 61 
11.2. Statement of Investigator ............................................................................................................................... 61 
11.3. Delegation of Investigator Duties .................................................................................................................. 61 
11.4. Clinical Trial Application .............................................................................................................................. 61 
11.5. Exemption Application for Controlled Substances ....................................................................................... 62 
11.6. Disclosure & Confidentiality ......................................................................................................................... 62 
12. REFERENCES ................................................................................................................................................... 63 
13. APPENDIX 1: ACCP/BTS Guidelines ............................................................................................................. 65 
14. APPENDIX 2: 
 .................................................................................................... 66 
15. APPENDIX 3: GLOBAL RATING of CHANGE SCALE ............................................................................. 67 
 


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LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities  ................................................................................................................................. 19 
Table 2.  Prohibited Medications and non-pharmacological Therapies / Washout Period ................................. 36 
Table 3. Treatment Kit Dispensing .......................................................................................................................... 38 
Table 4. Clinical Laboratory Evaluations ............................................................................................................... 40 
Table 5. Adverse Event Relationship to Study Drug .............................................................................................. 53 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ACCP 
American College of Chest Physicians 
ACE 
Angiotensin-converting-enzyme  
AE 
ALP 
Adverse Event 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine triphosphate 
BID 
bis in die (twice per day) 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BTS 
British Thoracic Society 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
COPD 
Chronic Obstructive Pulmonary Disease 
CT 
Computed Tomography 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
ET 
Early Termination 
EOS 
End of Study 
EU 
European Union 
DBP 
Diastolic Blood Pressure 
FDA 
Food and Drug Administration 
FEV1/FVC 
Tiffeneau – Pinelli Index 
GCP 
Good Clinical Practice 
GERD 
Gastroesophageal Reflux Disease 
GGT 
Gamma-glutamyl transferase 
gm/dL 
Grams per deciliter 
GMP 
Good Manufacturing Practice 
h 
Hour 
HDPE 
High-density polyethylene 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
IUD 
Intrauterine Device 
kg 
Kilogram 
L 
Liter 
LCQ 
Leicester Cough Questionnaire 
LFT 
Liver Function Tests 
ln 
Neperian log transformation 


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MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 
min 
Minute 
mL 
Milliliters 
mmHg 
Millimetre of Mercury 
NASH 
Non-alcoholic Steatohepatitis 
NOAEL 
No Observed Adverse Effect Level 
OTC 
Over-the-counter 
pH 
The Logarithm, On The Base 10, of The Reciprocal of The Hydrogen Ion 
Concentration 
PI 
Principal Investigator 
PIL 
Participant Information Leaflet 
PK 
Pharmacokinetic 
PR 
Time between P and R wave 
PT 
Preferred Term 
QC 
Quality Control 
QTc 
QT Interval Corrected for Heart Rate 
QTcF 
QT Interval Corrected for Heart Rate – Friderica’s Correction Formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SoA 
Schedule of Activities 
SGOT 
Aspartate Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee  
ST 
ST segment of the Electrocardiogram 
SUSAR 
Suspected Unexpected Serious Adverse Event 
T 
T wave of the Electrocardiogram 
UCAS 
Upper Airway Cough Syndrome 
ULN 
Upper Limit of Normal 
USA 
United States of America 
UK 
United Kingdom 
VAS 
Visual Analogue Scale 
 
 






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• Cough Severity Visual Analogue Scale (VAS): scored on a 100 mm visual 
analogue scale at Screening (Day -14 to -1) subject to record cough severity 
over past 2 weeks, Baseline (Day 0) and on Days 4, 8, 12, 16, 30 (Baseline 
Period 2), 34, 38, 42, 46 and 60 (Follow Up) subject to record cough severity 
over past 24 hours 
• Leicester Cough Questionnaire (LCQ): completed on Days 1, 16, 31, and 
46.  
• Global Rating of Change Scale: scored at Days 4, 8, 12, 16, 34, 38, 42, 46 
and 60 (Follow Up) 
 
Subjects will return 10-14 days after completing the second Treatment Period 
(Day 46/Early Withdrawal) for a Follow-Up Visit (Day 60) to assess cough count 
and AEs 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject) up to 74 days: 
Screening – 1 to 14 days 
Treatment Period 1 – 16 days  
Wash out – 10 to 14 days 
Treatment Period 2 – 16 days  
Follow up – 10 to 14 Days  
Safety 
Assessments: 
Safety will be assessed through monitoring of adverse events (AEs), physical 
examination, vital signs, electrocardiograms (ECGs), and laboratory 
assessments. Frequency of assessments is detailed in the Schedule of Activities 
(Table 1) 
Study Population: 
Male and female patients (18-80 years of age inclusive) with unexplained or 
refractory chronic cough 
Planned Number of 
Subjects: 
Approximately 68 subjects may be randomized in the study in order to achieve 
62 completers 
Inclusion Criteria: 
Subjects who meet all of the following criteria will be included in the study: 
1. Have provided written consent and are willing and able to comply with all 
aspects of the protocol. 
2. Women and Men between 18 and 80 years of age inclusive. 
3. Chest radiograph or CT thorax within the last 5 years from screening not 
demonstrating any abnormality considered to be significantly contributing 
to the chronic cough in the opinion of the Principal Investigator and 
Medical Monitor. 
4. Have unexplained or refractory chronic cough for at least one year: a cough 
that is unresponsive to at least 8 weeks of targeted treatment for identified 
underlying triggers including reflux disease, asthma and post-nasal drip or 
unexplained cough; or a cough for which no objective evidence of an 
underlying trigger can be determined after investigation (see Appendix 1). 
5. Awake Cough Count of ≥ 10 per hour (Cough Count at Screening). 
6. A score of ≥ 40mm on the Cough Severity VAS at Screening. 
7. Women of child-bearing potential must have a negative serum pregnancy 
test at Screening. 
8. Women of child-bearing potential must use a highly effective contraception 
method from Screening through to the Follow-Up Visit. Acceptable birth 




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gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection). 
13. Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood 
pressure (DBP) >100 mm Hg. 
14. Clinically significant abnormal electrocardiogram (ECG) at Screening, 
including any of the following: 
a. QTcF interval > 450 milliseconds  
b. Atrial fibrillation or atrial flutter  
c. Heart rate <40 beats per minute >110 bpm 
d. Second degree or third degree (complete) AV block 
e. Left bundle branch block (including hemiblock)  
f. Wolff-Parkinson-White Syndrome 
Personal or family history of congenital long QT syndrome or 
family history of sudden death  
 
15. Clinically significant abnormal laboratory tests at Screening, including: 
a. Alkaline phosphatase (ALP), alanine aminotransferase (ALT, 
SGPT), aspartate aminotransferase (AST, SGOT) >150% of the 
upper limit of normal (ULN), gamma-glutamyl transferase (GGT) 
>200% of the upper limit of normal (ULN), or Total bilirubin 
above the upper limit of normal (ULN) 
b. Creatinine >200% of the upper limit of normal (ULN) 
c. Unexplained creatine kinase concentration >3 x ULN 
d. haemoglobin < 10 g/dL, WBC count <2500 mm3, neutrophil count 
<1500 mm3, platelet count <100 × 103/mm3 
e. Positive screen for drugs of abuse (certain drugs of abuse are 
acceptable for non-cough indications see section 4.4) 
 
16. Significant coagulopathy as defined by a known hereditary deficiency of 
coagulation factors or platelet function or an unexplained elevation of the 
prothrombin time (PT) or international normalized ratio (INR) of ≥1.5. 
17. Criteria No.17 removed from here in protocol v5.0. See 15c above for 
details. 
18. Breastfeeding. 
19. Criteria No.19 removed from here in protocol v5.0. See Table 2 section 4.4 
for details.  
20. Blood donation within 56 days or plasma donation within 7 days prior to 
dosing. 
21. Other severe, acute, or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with trial 
participation or investigational product administration or may interfere with 
the interpretation of trial results and, in the judgment of the Investigator or 


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Sponsor, would make the subject inappropriate for entry into this trial. 
Prohibited 
Medications or 
non-
pharmacological 
Therapies 
Refer to Table 2 in Section 4.4.  
Statistical Analysis: 
Efficacy Analyses 
Primary Endpoint 
A repeated measures mixed model analysis of variance will be used to evaluate 
the primary endpoint. The log transformed awake cough frequency measured at 
assessment visits within periods will be the repeated measure. The model will 
include fixed effect terms for treatment sequence,  treatment,  period as well as 
assessment visit within period and the treatment by assessment visit interaction. 
Average log baseline awake cough count and period specific log baseline 
awake cough frequencies will be included as covariates. Subject will be classed 
as a random effect.  Model contrasts will be constructed to compare active 
treatment to placebo for each dose level. 
Secondary Endpoints 
Statistical approaches for analysis of the secondary endpoints will be similar in 
approach to that of the primary endpoint. 
Safety Endpoints 
Safety endpoints will be summarized by treatment group and, where 
appropriate, by dose and timepoint. 


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Figure 1. Schedule of Visits 
 
 
 
 


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Table 1. Schedule of Activities  
Procedure 
Visit 1 
ScreeningA, B 
Day -14 to -1 
Day -4 to Day 1 
Randomization in 
 
Visit 2 & 8 
Day 0D & Day 30D 
(Baseline) 
Visit 3 & 9 
Day 1 & 
Day 31C 
Visit 4 & 10 
Day 4D &  
Day 34D 
Visit 5 &11 
Day 8D &  
Day 38D 
Visit 6 & 12 
Day 12D &  
Day 42D 
Visit 7 & 13 
Day 16 &  
Day 46 / Early 
Termination 
Visit 14 
Follow Up 
Day 60 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
XI 
 
 
 
 
 
Randomization 
 
 
X* 
 
    (X)** 
 
 
 
 
 
Allocate treatment period 2 kit (in 
 
 
 
 
XP 
 
 
 
 
 
Demographics, Medical History & 
Medication History 
X 
 
 
 
 
 
 
 
 
Review of Chest Radiograph/CT 
Thorax from the past 12 monthsE 
X 
 
 
 
 
 
 
 
 
VASN 
X 
 
X 
 
X 
X 
X 
X 
X 
Height, & Weight & BMI 
X 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, 
Temperature) 
X 
 
 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
 
 
 
 
 
 
X 
 
Brief Physical ExamN 
 
 
 
X 
 
 
 
 
X 
12-lead ECG (at screening & pre-
dose) 
X 
 
 
X 
X 
X 
X 
X 
 
12-lead ECG (1-hour post morning 
dose) 
 
 
 
X 
X 
X 
X 
X 
 
Spirometry 
X 
 
 
 
 
 
 
 
 
Clinical Laboratory (Biochem/Haemo) 
X 
 
 
X 
 
 
 
X 
 
LFT Panel (bilirubin total, bilirubin 
direct and indirect, ALP, AST, ALT, 
GGT) only)  
X 
 
 
X 
X 
X 
X 
X 
 
Lipids (TC, HDL-C, LDL-C, TGs) 
 
 
 
X 
 
 
 
X 
 
Coagulation (PT,INR,aPTT) 
X 
 
 
X 
X 
X 
X 
X 
 
Serum Pregnancy TestK 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy TestK, N 
 
 
 
X 
 
 
 
X 
 
Urine Drug ScreenM 
X 
 
 
X 
 
 
 
X 
 
Urinalysis (w/MicroscopyF) 
X 
 
 
X 
 
 
 
X 
 
Attach Cough MonitorG 
X 
 
X 
 
X 
X 
X 
X 
X 
Collect Cough Monitor 
XH 
 
 
X 
XH 
XH 
XH 
XH 
XH 
LCQN 
 
 
 
X 
 
 
 
X 
 
Global Rating of Change ScaleN 
 
 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Adverse Event 
 
 
X 
X 
X 
X 
X 
X 
X 
Taste Effects QuestionnaireL 
 
 
XO 
X 
X 
X 
X 
X 
X 
Procedure 
Visit 1 
ScreeningA, B 
Day -14 to -1 
Day -4 to Day 1 
Randomization 
Visit 2 & 8 
Day 0D & Day 30D 
(Baseline) 
Visit 3 & 9 
Day 1 & 
Day 31C 
Visit 4 & 10 
Day 4D &  
Day 34D 
Visit 5 &11 
Day 8D &  
Day 38D 
Visit 6 & 12 
Day 12D &  
Day 42D 
Visit 7 & 13 
Day 16 &  
Day 46 / Early 
Termination 
Visit 14 
Follow Up 
Day 60 
Dispense Study Medication &/or 
Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
Plasma PK Sample J 
 
 
 
X 
X 
X 
X 
X 
 
  
 
 
 
X 
 
 
 
 
 
 
 
 
A: Multiple Screening Visits may be required to complete all screening assessments 
B: The Screening Period may be extended beyond 14 days if required and approved by the Medical Monitor (e.g. additional follow-up on findings from any of the Screening assessments) 
C: Washout period may be 10-14 days to allow for flexible scheduling. Days in the table are based on a 14-day washout period.  The Washout Period may be extended beyond 14 days if required and 
approved by the Medical Monitor. 
D: Visits may be conducted at subjects’ home (by Mobile Research Nurse) 
E: If not done within the past 12 months patient is ineligible 
F: Microscopy to be performed only if clinically indicated 
G: Cough monitor should be attached before 10am, pre-dose and worn for 24 hours during each assessment. 
H: Cough monitor to be returned to site by courier by the subject after 24-hour recording 
I: Visit 3/Day 1 only 
J: PK samples taken pre-dose 
 
K: For Women of Childbearing Potential 
L: Completed only if taste AEs are reported 
M: Subjects who test positive may be re-tested if consumed poppy seeds on bread products 
N: To be completed before morning dose 
O: Visit 8/Day 30 only 
P: Visit 9/Day 31 only. 
. 
[Randomization] * triggers shipment of additional treatment kits to the site. 
[Randomization] **At visit 3/Day 1 if not already completed;  
[Initial shipment of IP to a site is triggered 
 once the first subject has started screening]. 








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1. 
INTRODUCTION 
Cough represents an essential defensive mechanism for the airways by preventing inhalation or aspiration 
of harmful gases or particles from the environment. It also helps mucous clearing from the lower 
respiratory tract. However, cough can also be a sign of many inflammatory diseases of the respiratory 
tract. Cough represents one of the most frequent complaints leading patients to seek medical attention 
(Schappert, 2006). In cough guidelines, such as those published by the American College of Chest 
Physicians and the British Thoracic Society (Irwin, 2006; Morice, 2006), cough is characterized by the 
length of time a patient is coughing:  
• 
Acute - up to 3 weeks,  
• 
Sub-Acute - from 3 to 8 weeks, 
• 
Chronic - greater than 8 weeks.  
Patients who present to a physician for a persistent cough are evaluated and treated for obvious and 
common causes of cough. If a patient continues to cough, he/she is evaluated for conditions that are 
commonly associated with chronic cough. These include asthma, gastroesophageal reflux disease 
(GERD), and upper airway cough syndrome (UACS) (Dicpinigaitis, 2011; Morice, 2006). A patient may 
be evaluated for less common diseases based on the patient’s history, other symptoms, or physical 
findings. Patients in whom no treatable cause of their cough can be found are characterized as having 
“refractory chronic cough” (Gibson, 2016). The prevalence of chronic cough has been estimated as 
affecting 11-13% of the population (Ford, 2006; Song,2014). It most commonly appears in the fifth and 
sixth decades of life, and can persist for years (Morice, 2000; Morice, 2014). Patients are most commonly 
women (approximately 66%-75% of patients are women). Chronic cough can seriously impair quality of 
life as it has physical (exhaustion, sleep deprivation, urinary incontinence, vomiting, headache, rib 
fracture) social (interference with lifestyle and leisure, embarrassment of coughing in public, social 
exclusion) and psychosocial (depression, frustration, anxiety) consequences with a marked effect on 
Quality of Life as measured by instruments such as the Leicester Cough Questionnaire (LCQ) (Birring, 
2003;  Kelsall, 2008). The disabling effects of chronic cough are understandable, given that patients with 
the condition cough hundreds or even thousands of times per day for months to years (Smith, 2016). 
The management of chronic cough is based on the diagnosis and treatment of the underlying disease. 
However, there are a significant proportion of patients with unexplained or refractory chronic cough who 
do not respond to treatment of the underlying disease or do not have an underlying condition identified 
and treatment options for these patients are very limited (Morice, 2006). Patients and clinicians will 
frequently try over-the-counter agents such as dextromethorphan, guaifenesin, and antihistamines with 
little benefit. Prescription options in the U.K. include low-dose oral morphine, and in the U.S. include 
benzonatate, codeine and related opiate products. Studies have evaluated amitriptyline (tricyclic 
antidepressant) and gabapentin (neuromodulator) (Dicpinigaitis, 2014) with some patients having some 
benefit but with some significant adverse events (Ryan, 2012). Over-the-counter (OTC) antitussive 
products that contain antihistamine and/or dextromethorphan are also widely used for cough, but these 
compounds have limited efficacy. 
Importantly, there have been no FDA approvals for a novel pharmaceutical agent to treat cough in over 50 
years. 
1.1. Cough Reflex Mechanism 
Primarily, the cough reflex is mediated by peripheral sensory nerves in the airways. Two main subtypes 
of sensory vagal afferent nerves are involved in cough reflex. The first subtype is myelinated sub-
epithelial Aδ fibers that are found in the upper airways and respond to mechanical stimuli 
(mechanoreceptors) and rapid change in pH. It is fast conducting and is thought to mediate the protection 


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against acid and foreign body aspiration. The second subtype is C-fibers; these are unmyelinated 
nociceptive nerves that are sensitive to chemical irritants (chemoreceptors) and endogenous inflammatory 
mediators (Morice, 2010). C-fibers are thought to be involved in the exaggerated cough experienced in 
chronic cough.   Histological and electrophysiological experiments in the rat and guinea pig revealed that 
C-fibers innervating the pulmonary system are derived from two distinct vagal sensory ganglia (Undem, 
2004): 1) the jugular ganglion neurons, which project C-fibers to the upper airways (larynx, trachea, 
bronchus) and the lung parenchymal tissue; and 2) the nodose ganglion neurons, which project C-fibers to 
the structures within the lungs, exclusively. 
Vagal C-fibers innervating the airways express P2X3 receptors and can be activated by adenosine 
triphosphate (ATP) released into the airways. The resulting depolarisation can initiate action potentials 
that are transmitted centrally and interpreted as urge to cough. P2X3 receptors are ATP-gated ion 
channels that belong to a family of purinergic receptors. Members of this family assemble as 
homotrimeric (three subunits of P2X3) and heterotrimeric (two subunits of P2X3 and one subunit of 
P2X2) ion channels. Furthermore, immunohistochemistry and single cell RT-PCR analysis have shown 
that C-fibers arising from nodose ganglia expressed both P2X2 and P2X3 subunits while those from the 
jugular ganglia expressed primarily P2X3 subunits (Kwong, 2008). These data indicate that C-fibers 
derived from the jugular ganglia are activated primarily by P2X3 homotrimeric receptors, whereas the C-
fibers from the nodose ganglia are stimulated by P2X2/3 heterotrimeric receptors.   
In chronic cough, the majority of stimuli triggering cough is affecting the upper airways (e.g. strong 
odour/smoke, cold air, post-nasal drips, aspiration of gastroesophageal reflux, speaking). Furthermore, the 
greatest concentration of cough receptors is in the larynx, carina and bifurcation of the medium to large-
sized bronchi. These observations indicate that the upper airways play a major role in cough. Therefore, 
given that upper airways are innervated by jugular C-fibers that express primarily P2X3 channels, it 
suggests that P2X3 homotrimeric receptors are responsible for the increase in cough reflex sensitivity 
(Undem, 2004; Kwong, 2008).  
The role of P2X2/3 receptors in taste function is supported by immunohistochemistry and behavioural 
taste studies performed in rodents.  Immunohistochemical staining of the C-ﬁbers innervating the taste 
buds of rodents showed the presence of both P2X2 and P2X3 channels colocalized at the C-fibers 
concentrated in the taste buds, indicating the formation of P2X2/3 receptors (Bo, 1999). Studies of double 
knock-out mice showed that complete loss in taste function required knock out of both P2X2 and P2X3 
channels, suggesting that both channels play an important role in taste signal transduction (Finger, 2005). 
Therefore, these results support the hypothesis that a drug that would inhibit only P2X3 homotrimeric 
receptors would have no or minimal impact on taste perception. 
1.2. BLU-5937 Pharmacology 
BLU-5937, a small molecule of the imidazopyridine chemical class, is a potent, selective and non-
competitive P2X3 homotrimeric receptor antagonist. P2X3 receptors are ATP ion-gated channels located 
on primary afferent neurons. ATP released from damaged or inflamed tissues in the airways acts on P2X3 
receptors on primary afferent neurons, triggering depolarisation and action potentials that are transmitted 
centrally and interpreted as urge to cough. There are preclinical and clinical evidence supporting the role 
of P2X3 receptors in hypersensitization of the cough reflex, leading to chronic cough. By inhibiting P2X3 
receptors on the primary sensory neurons, BLU-5937 would inhibit the hypersensitization of the cough 
reflex and, hence, the exaggerated cough experienced in chronic cough patients.  
1.3. Clinical Indication 
BLU-5937 is an investigational drug that is developed for the treatment of unexplained or refractory 
chronic cough. 














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• 
Baseline Period 1: 1 day 
• 
Treatment Period 1 (BLU-5937 or Placebo):  
16 days (escalating doses of 25, 50, 100, 200 mg BID or placebo; 4 days for each dose) 
• 
Washout: 10-14 days 
• 
Baseline Period 2: 1 day 
• 
Treatment Period 2 (Placebo or BLU-5937):  
16 days (escalating doses of 25, 50, 100, 200 mg BID or placebo; 4 days for each dose) 
• 
Follow-Up Period:  10-14 days 
Individual subject participation is expected to be approximately 74 days including Screening, Baseline, 
Treatment periods and Follow-Up period.  
3.1. Discussion of Study Design 
This randomized, double-blind, placebo-controlled, two-period crossover, dose escalation study design 
has been previously used to characterize the efficacy and safety of other drugs in patients with 
unexplained, refractory chronic cough and was deemed acceptable by the Health Authorities in a context 
of early Phase 2 investigation. This particular study design will allow the testing of several doses in a 
restricted number of patients in view of gathering initial safety and efficacy data in the target patient 
population and for the selection of optimal doses to be evaluated in other clinical studies.  
 
4. 
SUBJECT POPULATION 
Subjects who meet all the inclusion criteria and none of the exclusion criteria at the screening visit will be 
eligible for participation in this study. Continued eligibility will be assessed upon admission to the 
clinical site at Visit 3 (Day1), prior to the first study drug administration. 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. 
4.1. Inclusion Criteria 
Subjects who meet all of the following criteria will be included in the study: 
1. Have provided written consent and are willing and able to comply with all aspects of the protocol. 
2. Women and Men between 18 and 80 years of age inclusive. 
3. Chest radiograph or CT thorax within the last 5 years from screening not demonstrating any 
abnormality considered to be significantly contributing to the chronic cough in the opinion of the 
Principal Investigator and Medical Monitor. 
4. Have unexplained, refractory chronic cough for at least one year: a cough that is unresponsive to 
at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, 
asthma and post-nasal drip or unexplained cough; or a cough for which no objective evidence of 
an underlying trigger can be determined after investigation (see Appendix 1).  
5. Awake Cough Count of ≥ 10 per hour (Cough Count at Screening). 
6. A score of ≥ 40mm on the Cough Severity VAS at Screening.  
7. Women of child-bearing potential must have a negative serum pregnancy test at Screening. 




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a. QTcF interval >450 milliseconds  
b. Atrial fibrillation or atrial flutter  
c. Heart rate <40 beats per minute >110 bpm 
d. Second degree or third degree (complete) AV block 
e. Left bundle branch block (including hemiblock)  
f. Wolf-Parkinson-White Syndrome 
g. Personal or family history of congenital long QT syndrome or family history of sudden 
death 
 
15. Clinically significant abnormal laboratory tests at Screening, including: 
a. Alkaline phosphatase (ALP), alanine aminotransferase (ALT, SGPT), aspartate 
aminotransferase (AST, SGOT) >150% of the upper limit of normal (ULN), gamma-
glutamyl transferase (GGT) >200% of the upper limit of normal (ULN), or Total bilirubin 
above the upper limit of normal (ULN) 
b. Creatinine >200% of the upper limit of normal (ULN) 
c. Unexplained creatine kinase concentration >3 x ULN 
d. haemoglobin < 10 g/dL, WBC count <2500 mm3, neutrophil count <1500 mm3, platelet 
count <100 × 103/mm3 
e. Positive tests for drugs of abuse (certain drugs of abuse are acceptable for non-cough 
indications see section 4.4) 
16. Significant coagulopathy as defined by a known hereditary deficiency of coagulation factors or 
platelet function or an unexplained elevation of the prothrombin time (PT) or international 
normalized ratio (INR) of ≥1.5. 
17. Criteria No.17 removed from here in protocol v5.0. See 15c above for details.   
18. Breastfeeding.  
19. Criteria No.19 removed from here in protocol v5.0. See Table 2 section 4.4 for details.    
20. Blood donation within 56 days or plasma donation within 7 days prior to dosing. 
21. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with trial participation or investigational product administration 
or may interfere with the interpretation of trial results and, in the judgment of the Investigator or 
Sponsor, would make the subject inappropriate for entry into this trial. 
4.3. Withdrawal Criteria 
4.3.1. Before First Treatment Administration 
Before the first treatment administration, inclusion/exclusion criteria will govern the subjects to be dosed. 
Subjects who have been screened but who have not been randomized into the study may be re-screened 
once for participation if approved by the medical monitor and Sponsor e.g. subject has upper respiratory 
tract infection or has a positive poppy seed drug test at the screening visit. Subjects who do not meet the 
awake cough count criteria at screening (Awake Cough Count of ≥ 10 per hour) cannot be re-screened. 


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Awake cough count results must not be rounded. Subjects may not be randomized into the study more 
than once.   
Subjects who report a taste disturbance at Day 0 should not be randomized and should not be re-screened. 
4.3.2. 
After First Treatment Administration 
Subjects may, at any time, voluntarily withdraw from the study or be removed from the study at the 
discretion of the Investigator or Sponsor.  
If such withdrawal occurs, or if the subject fails to return for visits, the Investigator should determine the 
primary reason for a subject’s premature withdrawal from the study and record the reason in the subject’s 
study documents.  
Attempts should be made to have such subjects complete the EOS/ET assessments. EOS/ET assessments 
should be performed as soon as possible after the last study treatment administration. 
The blind may be broken only in emergency situations, where knowledge of the treatment that the subject 
received is necessary for safety management (Section 5.2.4). 
Details of reasons for removal of subjects will be recorded, reported to the Sponsor and documented in 
the clinical study report. 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), the investigator should show "due 
diligence" by documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. 
4.3.3. Individual Subject Stopping Rules 
Possible reasons for discontinuation from the study are: 
• 
The investigator may decide to terminate a subject’s participation in the study for safety or 
administrative reasons e.g. AE, a clinically significant laboratory value, or other medical 
condition or situation such that continued participation in the study would not be in the best 
interest of the subject. Appropriate medical measures are to be taken accordingly, and the Sponsor 
or Sponsor designee is to be notified immediately. 
• 
Subject may be discontinued due to poor study treatment compliance (Section 5.2.6). 
• 
A female subject has a confirmed pregnancy, or, in the case of a male subject, his female partner 
becomes pregnant. 
• 
At any time during the study a subject may decide to end his/her participation in the study.  
• 
The Investigator or the Sponsor, for any reason, terminates the study. 
4.3.4. Liver Function Stopping Criteria 
 Stopping criteria for an individual subject, after a re-test if needed: 
• 
Any subjects with ALT or AST > 8x ULN 
• 
Any subjects with ALT or AST > 3x ULN and total bilirubin > 2x ULN or INR > 1.5 
• 
Any subjects with ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right 
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Neuromodulators e.g.  Gabapentin / 
pregabalin, baclofen, amitriptyline and 
other tricyclics taken for another clinical 
indication (not for cough)  
Stable dose for at least 8 weeks prior to screening 
visit and throughout the study 
ACE-inhibitor therapy  
Not permitted within 12 weeks of screening or 
throughout the study 
Investigational drugs (including P2X3 
antagonist) 
Not permitted within 60 days of the first dose of 
study medication or plans to take another within 
30 days of study completion 
Beta blockers, NSAIDs, and aspirin-
containing products 
Prohibited if any previous history of 
bronchospasm with these products 
Biologics 
Not permitted within 60 days of the first dose of 
study medication or plans to take another within 
30 days of study completion 
Physio / Physical / Speech and language 
Therapy  
Only permitted if they have completed a course 
of the therapy and it will be stable from 
screening and  throughout the study 
# Please contact the Medical Monitor 
 to discuss any case 
* Alginate therapy is accepted but should not be taken concomitantly with study medication which should be taken 
an hour before or 2 hours after alginate. 
$ Stopping chronic corticosteroid use should be approved and supervised by a physician before stopping 
 
 
5. 
STUDY TREATMENTS 
5.1. Investigational Product and Placebo 
All doses of the investigational product and placebo will be provided by the sponsor. 
5.1.1. BLU-5937 tablets 
BLU-5937 (drug product) is manufactured by 
 for oral administration. BLU-5937 will 
be provided as 25 mg and 200 mg tablets. 
5.1.2. Placebo 
Placebo tablets (25 mg and 200 mg) matched to Sponsor’s BLU-5937 investigational product 
manufactured by 
 will be supplied. The excipients in the placebo formulation are 
identical to the excipients as BLU-5937. 
5.2. Investigational Product Management 
5.2.1. Packaging, Labelling and Dispensing 
The sponsor will be responsible for ensuring that the investigational product and placebo are 
manufactured in accordance with applicable current Good Manufacturing Practice (cGMP) regulations 
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The investigational product and placebo will be labelled according to the requirements of local law and 
legislation.  
BLU-5937 tablets or placebo will be provided for Period 1 and 2 by 
 in treatment 
kits containing 4 opaque HDPE bottles per kit for each period. Each bottle represents one of 4 dose levels 
(25, 50, 100, 200 mg BID). The investigational product will be administered as 25 mg tablets (for the 25, 
50, 100 mg BID dose levels) or 200 mg tablets (for the 200 mg BID dose level) or matching placebos. 
BID dosing means every 12 hours, +/- approximately 1 hour. Each bottle will contain sufficient 
medication to cover the 4 -day treatment duration plus 1 extra day (total 5 days). When a new dose is 
dispensed it is to be started the following morning after the cough recording device is removed. There is 
no flexibility in visit window for Treatment visits; each dose is to be taken for 4 days.    
Table 3. Treatment Kit Dispensing 
Study DayNo.# 
BLU-5937 Dose*/Placebo 
Period 1 (treatment kit dispensing)  
Days 1-4  
25 mg (1 tablet) BID or placebo 
Days 5-8  
50 mg (2 tablets) BID or placebo 
Days 9-12  
100 mg (4 tablets) BID or placebo 
Days 13-16  
200 mg (1 tablet) BID or placebo 
Washout 10-14 days  
Day 17-30 
No treatment  
Period 2 (treatment kit dispensing) 
 Days 31-34 
25 mg (1 tablet) BID or placebo 
 Days 35-38 
50 mg (2 tablets) BID or placebo 
 Days 39-42 
100 mg (4 tablets) BID or placebo 
 Days 43-46 
200 mg (1 tablet) BID or placebo 
*Product can be administered without regard to meals 
#Day No. in the table assumes a 14-day washout period 
Once it is confirmed the subject has provided written consent and meets all the inclusion and none of the 
exclusion criteria the investigational product and placebo will be dispensed to individual subjects as per 
the randomization schedule. 
Further details regarding packaging, labelling and accountability can be found in the pharmacy manual. 
5.2.2. Storage and Handling 
Investigational product will be shipped from 
storage directly to site as subject screening 
commences. Additional kits will be sent once patients are randomized. 
 
Each site will maintain an inventory record of the investigational product and placebo kits received, 
stored (in a secure restricted area), and dispensed per the randomization schedule and per treatment 
period.  
The investigational product and placebo will be provided to study subjects only. 
5.2.3. Method of Assigning Subjects to Treatment Groups 
Subjects who have met all the inclusion/exclusion criteria and have read, understood and signed the 
informed consent form will be randomized 1:1 to treatment sequence (placebo then study drug or study 


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drug then placebo). The randomization will be produced by 
 The treatment will be 
allocated via a web-based electronic data capture system.  
5.2.4. Blinding 
This study is double-blind. Treatment assignments will be blinded to the investigator, subjects and all 
clinical and research staff for the entire study. 
 supplied and managed by 
 is the 
randomization system in use for this study. Blinded kit allocation to eligible subjects is managed by site 
staff via 
 (randomization & Resupply). 
The study blind will be broken upon completion of the clinical study and after the study database has been 
locked. 
During the study, the randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by the qualified investigator for further treatment 
to the subject or to complete a serious adverse event (SAE) report. The qualified investigator (PI or 
delegated Sub-Investigator) will unblind the subject via the 
. In case of 
emergency & neither the PI & Sub-Investigator are available, the Medical Monitor can as last resort 
conduct the unblinding through the 
 . The date and reason for breaking the 
blind will be recorded, and Sponsor & Medical Monitor will be notified. This information is to be stored 
in the subject’s source files with as few of the site staff unblinded as is clinically reasonable. 
5.2.5. Study Drug Accountability 
Complete and accurate inventory records of all study drugs will be kept. This includes acknowledgment 
of receipt of each shipment of study product (kit quantity and condition), subject dispensing records, and 
returned or lost study product. Drug accountability will be performed at the end of each dose level. 
All unused investigational products and all medication containers will be returned to the Sponsor.  
5.2.6. Treatment compliance  
The prescribed dosage, timing and mode of administration for study medication should not be changed 
from the protocol schedule. Departures from the intended regimen will be reported as protocol non-
compliance. At each visit when a dose is ending, prior to dispensing study medication, previously 
dispensed study medication will be retrieved by the Investigator or designee and compliance assessed. 
Subjects exhibiting poor compliance, as assessed by tablets counts, should be counselled on the 
importance of good compliance with the study dosing regimen. 
However, in exceptional circumstances and in discussion with medical monitor a subject may defer a visit 
by 1 day while continuing study medication. 
Noncompliance is defined as taking more or less than 100% of prescribed study medication during any 
evaluation period (visit to visit). 
6. STUDY PROCEDURES 
Unless otherwise stated in this protocol, the standard operating procedures (SOPs) of the sites, will be 
followed during this study. 
Any deviation from protocol procedures should be noted in the Case Report Forms (CRFs)/source 
documents.  Protocol waivers and exemptions will not be authorised. 
An overview of the study activities is detailed in the Schedule of Activities (Table 1) located after the 
Synopsis. 


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6.1. Safety Assessments 
Safety assessments will include physical examination, vital signs, 12-lead ECG, clinical laboratory tests, 
and AE/concomitant medication monitoring. Additional safety measurements may be performed at the 
discretion of the investigator for reasons related to subject safety. 
6.1.1. Medical History 
The medical history at screening will include all queries by the medical and clinical staff related to the 
subject’s well-being and history of relevant past medical events/experiences. Medical history will include 
all demographic data (year of birth, gender, race, body weight, height, and BMI). Alcohol and any 
smoking history will also be recorded. 
6.1.2. Physical Examination 
A complete physical examination will be performed by a medically qualified and licensed individual as 
scheduled in Table 1 (Schedule of Activities) at screening and end of study or early termination. The 
physical examination will include a general review of the following body systems (at minimum): head 
and neck, cardiovascular, respiratory, abdomen, brief neurological and general appearance. A brief 
physical examination (general appearance, lungs, heart, abdomen) evaluation will be performed at other 
site visits. 
6.1.3. Vital Signs 
Vital signs (sitting systolic and diastolic blood pressure, pulse, respiration, temperature) will be measured 
as specified in Table 1 (Schedule of Activities). The subject’s height and weight will be measured at 
Screening. Body mass index (BMI) will be calculated. 
6.1.4. 12-Lead Electrocardiogram 
A twelve-lead ECG will be performed at screening. ECG measurements will be taken during the study 
periods as specified in Table 1 (Schedule of Activities). 
6.1.5. Laboratory Evaluations 
Samples for Biochemistry, Haematology, Urinalysis, Urine Drug screen, and pregnancy testing (when 
necessary) will be collected as outlined in Table 1 (Schedule of Activities) and analysed at a central 
laboratory unless otherwise specified. Detailed instruction regarding sample collection, processing, and 
shipments may be found in the Laboratory Manual.  
Laboratory assessments will include the following: 
Table 4 Clinical Laboratory Evaluations 
Clinical Laboratory Test 
Panel 
Description 
Visits 
General biochemistry: 
Sodium, potassium, chloride, 
glucose, blood urea nitrogen (BUN), 
creatinine, albumin, amylase, uric 
acid, creatinine kinase (CK), calcium, 
chloride, magnesium, glucose, 
potassium, sodium, bicarbonate.  
 
Lipids: TC, HDL-C, LDL-C, and 
TGs 
 
Screening, Day 1, 16, 31, 46.  
 
 
 
 
 
 
 
Day 1, 16, 31, 46. 
 






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• 
ECG (12 lead) 
• 
Record all concomitant medication use 
• 
Urine and blood for clinical laboratory tests, coagulation, LFTs, lipids, urine drug screen 
and urinalysis, including serum pregnancy test for women of childbearing potential 
• 
Instruct subject in the use of the cough monitor, and arrangements for its collection 
• 
Attach and activate the Screening (Day -14 to Day -1) cough monitor (preferably before 
10am). Cough Monitor is to be removed 24 hours later, prior to the start of the new dose.  
The Screening Period may be extended (beyond 14 days) by the Medical Monitor if additional 
information is required to ensure subject safety. 
6.6.2. Randomization (Day -4 to Day 1) 
Initial shipment of IP to a site is triggered (in 
by PM or delegate) once their first subject has 
started screening. During the screening period the subject will be assessed for eligibility for the trial. Once 
it is confirmed the subject is eligible (between days -4 and Day 1) the subject will be randomized 
(triggering additional shipment to the site of  investigational drug kits for further treatment 
period/randomizations).  
6.6.3. Baseline Visit Procedures Period 1 (Visit 2/Day 0) in clinic or at home 
The following procedures and evaluations may be performed at the clinic or at the subject’s home by the 
home health nurse: 
• 
Attach and activate the Baseline cough monitor (preferably before 10am). Cough Monitor is to be 
removed 24 hours later, prior to the start of the new dose. 
• 
Record any Adverse Events (AEs) since Consent was confirmed, or add to Medical History 
• 
Record any change in concomitant medication use 
• 
Perform cough severity VAS, for cough severity over the past 24 hours  
• 
Schedule Visit 3/Day 1 at clinic 
6.6.4. Treatment Visit Procedures (Visit 3/Day 1) 
 The following procedures and evaluations will be performed: 
• 
Confirm inclusion and exclusion criteria 
• 
Vital signs (sitting systolic and diastolic blood pressure, pulse, respiration, temperature) 
pre-dose  
• 
ECG (12 lead) pre-dose and 
 
• 
Urine and blood for clinical laboratory tests 
 
coagulation, LFTs, lipids, urine drug screen and urinalysis, including urine pregnancy test 
for women of childbearing potential (pre-dose) 
• 
Brief physical examination (pre-dose)  
• 
The following will be completed by the subject (pre-dose): 
• 
LCQ 


















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An adverse reaction (AR) is any AE for which there is a reasonable possibility the drug caused the AE. 
‘Reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the 
AE Table 5. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
An AE may be: 
• 
A new illness, 
• 
Worsening of a concomitant illness, 
• 
An effect of the study medication including comparator; it could be an abnormal clinical 
laboratory value as well as a significant shift from baseline within normal range which the 
investigator considers to be clinically important. 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability or incapacity (defined as a substantial disruption of a 
person’s ability to conduct normal life functions), 
• 
Is a congenital anomaly or birth defect, 
• 
Is an important medical event that may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above (according to medical judgment of the 
investigator) 
The following is not considered to be an SAE: 
• 
Any elective procedures that require admission to hospital as well as any planned elective 
procedures (e.g., angioplasty) planned prior to signing a consent sent form are not considered 
SAEs (unless the underlying condition has worsened or the procedure results in a worsening of 
the subject’s condition). This should be recorded in the medical history. 
• 
A visit to an Emergency Room or other hospital department <24 hours that does not result in an 
admission to hospital (unless it is considered an important medical event or life threatening event) 
these should be recorded as an AE. 
 
7.2. Severity Assessment 
All AEs will be graded as mild, moderate, or severe according to the following definitions: 
Mild: 
Causing no limitation of usual activities; the subject may experience transient slight 
discomfort 
Moderate: 
Causing some limitation of usual activities; the subject may experience annoying discomfort 
Severe: 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain 
Every effort will be made to obtain an adequate evaluation of the severity. 




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If necessary, every effort will be made to obtain an adequate follow-up of the subjects. Should any subject 
choose to withdraw from the study, they will be advised of the safety precautions to be taken. 
The Investigator must make every effort to follow-up any AE which remains unresolved as of the last visit 
regardless of attribution until judged resolved or a reasonable explanation for its persistence found or is 
deemed mild and safely resolving or the subject is lost to follow up.   
In the case of AEs deemed related to the Investigational Product, every effort will be made to determine 
the final outcome. 
Classification of AEs will be performed by System Organ Class (SOC) and Preferred Term (PT) using the 
most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medications will be coded using the most recent version of the World Health Organization 
drug dictionary. 
7.5. Reporting of Pregnancy 
Pregnancy in a female study subject shall be reported to the sponsor on the provided pregnancy reporting 
form within 24 hours of the knowledge of its occurrence by the qualified investigator or delegate (for 
pregnancies occurring during the course of the study or within 4 weeks after the last drug administration). 
Because of the possibility the foetus/embryo could have been exposed to the study drug through the 
parent and for the subject’s safety, the pregnancy will be followed up to determine its outcome, including 
spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, congenital 
anomalies, or maternal and/or newborn complications. 
Pregnancy that occurs within 4 weeks after the last drug administration in a female partner of a male 
study subject shall be reported to the sponsor within 24 hours of the knowledge of its occurrence by the 
clinical site that such pregnancy occurred during the course of the study or right after. Because of the 
possibility that the foetus/embryo could have been exposed to the study drug through the parent and for 
the safety of the subject’s female partner, the pregnancy will be followed up to determine its outcome, 
including spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, 
congenital anomalies, or maternal and/or newborn complications and will be reported as an SAE. 
The pregnancy will be recorded and reported by the clinical site to the sponsor. Pregnancy follow-up will 
also be properly recorded to ensure quality and completeness of the data belonging to the study drug and 
will include an assessment of the possible causal relation between the study drug and any pregnancy 
outcome. Any SAE experienced during pregnancy will be reported on an SAE Report Form. 
Please see the Pregnancy Reporting Form Completion Guidelines for safety reporting instructions as per 
Diamond PV Safety Plan. 
7.6. Serious Adverse Event Reporting 
The site will notify any SAE to the sponsor, pharmacovigilance, Medical Monitor, Regulatory team and 
Illingworth, within 24 hours after becoming aware of its occurrence (as per Diamond PV Safety Plan). 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, that AE 
should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of the current illness and SAE, 
and an assessment of the causal relationship between the event and the investigational product(s). 
Information not available at the time of the initial report (e.g. an end date for the AE, laboratory values 
received after the report, or hospital discharge summary) must be documented. All follow-up information 
must be reported as soon as the relevant info is available. 




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The Randomized Set will include all subjects assigned a randomization number, irrespective of whether 
they go on to receive treatment.  If this analysis set coincides with the intention-to-treat analysis set, it 
will be omitted. 
The Intention-to-treat (ITT) Set will include all randomized subjects who take at least one dose of study 
medication and provide at least one baseline and at least one post-baseline cough frequency measurement. 
Analyses will be conducted by planned treatment.  This analysis set will be the primary efficacy analysis 
set. 
The Per-Protocol (PP) Set will be a subset of the ITT set who do not violate inclusion or exclusion 
criteria and/or deviate from the protocol, in a way that could influence their efficacy assessment. 
Consequently this analysis set will be used for sensitivity analyses of efficacy endpoints. Given the 
crossover design the inclusion in this set will consider each study period separately (i.e. a subject could be 
included in this set for one period but excluded from the other). 
The Safety Analysis (SAF) Set will include all subjects who receive at least one dose of either BLU-
5937 or placebo. Analyses will be conducted by treatment received. 
The Pharmacokinetic Set will include all subjects in the SAF set who have at least one evaluable (i.e. not 
impacted by any important protocol deviations or other events) post-dose PK measurement (even if below 
the limit of quantification).  Subjects will be analyzed according to the treatment received and dose taken. 
 
8.2. General Approach 
Full details of all planned analyses shall be specified in the SAP which will be finalized prior to database 
lock. 
For continuous variables, the number of observations, mean, standard deviation, median, minimum and 
maximum shall be presented as appropriate. For categorical values, the number of observations and 
percentages shall be presented as appropriate. 
Subject-level listings shall be provided to support all tabulated output. 
8.3. Demographic Data and Other Baseline Characteristics 
Disposition, demographic data (e.g. age, gender and race) and other baseline characteristics  including 
medical and medication history shall be summarized.  
8.4. Efficacy Analysis 
8.4.1. 
Primary Endpoint – Awake Cough Count 
The primary efficacy endpoint is change from baseline in awake cough count by dose level derived as 
follows: 
Change in Awake Cough Count =  Post-treatment Cough Count - Baseline Cough Count 
Hence a negative result indicates a decrease in cough frequency while a positive result indicates an 
increase.  
Due to the skewed nature of cough frequency data, awake cough frequency will be log transformed prior 
to analysis. 
The baseline scores will be recorded on Day 0 (Visit 2) and Day 30 (Visit 8) for Periods 1 and 2 
respectively.  
If there are any zero cough frequencies within the data all values will have 0.1 added to their cough 
frequency (equates to 1 cough every 10 hours) prior to transforming the data.  


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A repeated measures mixed model analysis of variance will be used to evaluate the primary endpoint. The 
log transformed awake cough frequency measured at assessment visits within periods will be the repeated 
measure.  
A repeated measure mixed model (MMRM) suitable for a crossover design with repeated measures within 
periods will be used. The fixed effects, random effects and repeated measure structure for the model will 
be as follows: 
Fixed effects: Sequence (AB, BA), Period (1, 2), Treatment (BLU-5937, Placebo), Assessment Visit 
(1 to 4 within each period) and the Treatment by Assessment Visit interaction.  Average baseline 
(average of the 2 period baselines) and period specific baselines will be included as covariates. 
Random Effects: Subject 
Repeated measures structure: the model will take account of the assessment visits within subject 
periods  
Contrast statements will be used to compare each dose of active treatment against placebo at the 
corresponding assessment visits of the periods. The mean change from baseline (on the log scale), with 
associated standard errors will be presented for each treatment at each assessment visit. Treatment 
differences vs placebo with corresponding 95% CIs will also be presented for each dose. Means will be 
back-transformed to estimate the ratio of the visit to baseline for each treatment at each visit and the 
treatment differences will be back-transformed to estimate the ratio of the visit to baseline for the active 
group, adjusted for the placebo effect.  All ratios will be accompanied by their 95% CIs and the p-values 
comparing active doses to placebo will be presented.   
Geometric mean profile plots against day will be produced with asymmetric error bars (back-transformed 
from the log scale), with separate lines for each treatment. 
The percent difference change between BLU-5937 doses and placebo will be estimated by 100 * e(diff - 
1); where diff is the difference provided by the analysis of the log-transformed variable. 
Using an MMRM analysis is suitable when assuming missing data is missing at random (MAR).  
Alternative sensitivity analyses will be performed:   
• 
the reasons for data being missing will be reviewed prior to unblinding the randomization. If the 
reason for missingness is deemed as being potentially related to lack of treatment response, the 
missing value will be imputed with the worst cough score (for that patient) recorded. If the 
subject withdraws prior to Period 2 their missing Period 2 data will not be imputed in this way.  
After imputation scores will be analysed using the methods described for the primary analysis. 
• 
the primary analysis will be repeated using the PP analysis set. 
• 
the primary analysis assumes that the data are log-normally distributed.  An analysis will also be 
performed of the untransformed data.  On this scale changes from baseline and differences with 
placebo for the changes from baseline will be estimated along with 95% confidence intervals. 
 
8.4.2. 
Secondary Endpoints 
The following secondary endpoints will be analysed using the ITT analysis set. 
• 
Change from baseline in 24-hour cough frequency at end of each dose level and follow-up  
• 
Change from baseline in awake cough frequency at follow up 


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• 
Change from baseline in cough severity as measured by the Visual Analogue Scale (VAS) at end 
of each dose level and follow-up 
• 
Change from baseline in Leicester cough questionnaire (LCQ) total scores at end of each treatment 
period 
• 
Global rating of change scale at end of each dose level and follow-up 
Statistical approaches for analysis of the secondary endpoints will be detailed in the SAP and will be 
generally similar in approach to that of the primary endpoint.  Only cough count data will be log 
transformed prior to analysis. 
Global rating of change scale will be remapped and given scores to create a continuous endpoint. A lower 
score will be considered a more positive outcome.   
8.4.3. 
Exploratory Efficacy Endpoints 
The analyses of exploratory endpoints will be described in the statistical analysis plan. 
Cough data will be log transformed prior to analysis and appropriately back transformed for presentation 
of results.  
8.5. Multiplicity 
No adjustment for multiplicity is required. 
8.6. Extent of Exposure 
Exposure data will be summarized by treatment group. 
8.7. Safety Analysis  
Adverse events will be classified into standardized medical terminology from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will 
be presented by preferred term nested within System Organ Class. Verbatim description and all MedDRA 
level terms, including the lower level terms, for all AEs will be contained in the data listings of the CSR. 
Adverse events will be summarized by presenting, for each treatment group, the incidence of AEs. Although 
a MedDRA term may be reported more than once for a subject, that subject will be counted only one time 
in the incidence count for that MedDRA term. In addition to presenting summaries by treatment group, 
AEs emergent from Days 1-4, Days 4-8, Days 8-12 and Days 12-16 will also be presented, with the break 
points being the start of dosing for each dose phase. 
Only treatment-emergent adverse events (TEAEs) will be summarized. Adverse events that are not 
treatment-emergent will be listed. Treatment-emergent adverse events are defined as AEs that 
• 
emerge during treatment, having been absent at pre-treatment (Baseline) or: 
• 
re-emerge during treatment, having been present at Baseline but stopped prior to treatment, or 
• 
worsen in severity during treatment relative to the pre-treatment state, when the AE is continuous 
Taste disturbance AE’s will also be presented and summarized. 
8.8. Laboratory Values 
Clinical laboratory results post-Baseline will be evaluated for markedly abnormal values.  




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9.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles that have their 
origins in the Declaration of Helsinki, the International Council on Harmonisation (ICH) Guideline E6 for 
Good Clinical Practice (GCP), the FDA GCP Code of Federal Regulations (CFR) Title 21 (part 56), the 
European regulation EU 536/2014, and the Tri-Council Policy Statement (Canada). 
9.3. Subject Information and Consent 
Before screening activities commence, each patient will be given a copy of the approved (IEC/IRB 
approval) PIL/ICF to read, this will provide a full explanation of the purpose of the study, the procedures 
to be carried out, and the potential risks of the study participation, in non-technical terms. Once this 
essential information is provided to the patient and the Investigator or delegate has the conviction the 
patient understands the implications of participating in the study, if the patient chooses to continue the 
screening process, they will be asked to sign and date a properly executed ICF prior to screening. Subjects 
will be assured they may withdraw from the study at any time without jeopardizing their medical care or 
future study participation (for which they qualify) related to or required as a result of study participation. 
The original signed ICF will be maintained in the investigator site file, Subjects will be given a signed 
copy of the ICF.  
If an amended or revised ICF is approved during the study, each subject will be re-consented at the next 
site visit. 
9.4. Subject Confidentiality 
The investigators and the sponsor will preserve the confidentiality of all subjects taking part in the study, 
in accordance with GCP and local regulations. Subjects are provided with a unique subject identifier via 
the Syne-Clin randomization system, this will be used on all documents to identify the subjects. No 
subject identifiable data will be provided to the sponsor.  
In compliance with local regulations/ICH GCP Guidelines, it is required the investigator and institution 
permit authorised representatives of the company, of the regulatory agency(ies), and IRB access to review 
the subject’s original medical records for verification of study-related procedures and data.  
The handling, processing and storage of laboratory samples will be described in the laboratory manual. 
The anonymised samples will be retained while research on the study treatment continues but no longer 
than 3 months after the end of the study. 
Explicit consent to obtain the data and to share the data will be obtained from each subject as part of the 
informed consent process, prior to performing any study procedures. 
10. DATA COLLECTION, RETENTION, AND MONITORING 
10.1. Case Report Forms 
Data required by the protocol is captured on Source Documents, then transcribed into an electronic data 
capture software (Syne-clin) by sites. This will be completed by appropriately delegated and trained site 
personnel for each subject included in the study (i.e. screening failure subjects and those who received an 
IP treatment).  
The study monitor will review all source data (via access to medical records, laboratory data and other 
source documents) to allow the required CRF entries to be verified as accurate. 
The cleaned and locked data will be approved and electronically signed by the Principal Investigator (PI) 
or delegate. The PI will subsequently be provided with a copy of their site’s anonymised eCRF data for 
archiving with their ISF at study close-out. The data will be output in a CRF format to be included with 


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the final report provided to the sponsor.  The sponsor only has access to anonymised data, no personal 
identifiable data will be shared with the sponsor. 
10.2. Data Management and Processing 
Data management activities will be performed using the
 
 
Data entered will be checked for accuracy through QC checks. When the database is declared to be 
complete and accurate, it will be locked. 
10.3. Record Retention 
All essential documents and records will be maintained by the clinical site in accordance with, and for the 
period specified in the applicable regulatory requirement(s) seen to be 25 years. 
10.4. Monitoring of the Study 
The sponsor or its delegated study monitors will be responsible for monitoring the conduct of the study.  
A separate Monitoring Plan will include details regarding responsibilities of the study monitors, 
investigator responsibilities in providing access to records and addressing issues identified, frequency and 
structure if monitoring visits and adherence to subject confidentiality as outlined in the ICF.  
The clinical site will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s).  
11. 
ADMINISTRATIVE PROCEDURES 
11.1. Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, safety and 
well-being of the study subjects, the study will be conducted as described in the approved protocol and 
performed according to ICH GCP, local Regulations and guidelines. Any deviation from the protocol will 
be recorded and explained. Subject-related Protocol Deviation (PDs) will be logged in the 
 
by each site. Lists per site will be printed & signed by their Principal Investigator. 
If amendments to the protocol and/or amendments or revisions to the ICF are required, the modifications 
will be documented and submitted to an IEC/IRB for approval.   
11.2. Statement of Investigator 
The form “Principal Investigator Undertaking” will be signed by the investigator responsible for the 
medical decisions per site and care provided to their subjects (being also referred to as the “qualified 
investigator”) prior to the commencement of his responsibilities with respect to the clinical trial, as 
required by the Food and Drug Regulations. The undertaking form will be maintained with the trial 
records and will be made available upon request. 
11.3. Delegation of Investigator Duties 
The Principal Investigators will ensure all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-related 
duties and functions. 
The Principal Investigators will maintain a list of Sub-Investigator(s) and other appropriately-qualified 
persons to whom he/she delegates significant trial-related duties. 
11.4. Clinical Trial Application 
A Clinical Trial Application must be submitted to the MHRA and an IND to the FDA prior to the study, 
and a “No Objection Letter” must be obtained before any drug administration whenever relevant. 


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11.5. Exemption Application for Controlled Substances 
This trial does not involve a controlled substance. 
11.6. Disclosure & Confidentiality 
The contents of this protocol and any amendments and results obtained during the course of this study 
will be kept confidential by the investigator(s), the investigator’s staff will not be disclosed in whole or in 
part to others or used for any purpose other than reviewing or performing the study without the written 
consent of the Sponsor.  No data collected as part of this study will be used in any written work, including 
publications (e.g. manuscripts, abstracts, oral/slide presentations, book chapters), without the written 
consent of Sponsor.  These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in the Confidentiality Agreement between the Sponsor and the investigator(s), and 
investigators sites. 
 


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12. REFERENCES 
Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy B, Ford A, Smith J. P2X3 Receptor 
Antagonist (AF-219) in Refractory Chronic Cough: A Randomised, Double-Blind, Placebo-
Controlled Phase 2 Study. Lancet. 2015;28;385(9974):1198-205. 
 
Birring S, Prudon B, Carr A, et al. Development of a Symptom Specific Health Status 
Measure for Patients with Chronic Cough: Leicester Cough Questionnaire (LCQ). 
Thorax. 2003;58:339-343. 
 
Bo X, Alavi A, X iang Z, Oglesby I, Ford A, Burnstock G. Localization of ATP-gated P2X2 and 
P2X3 receptor immunoreactive nerves in rat taste buds. Neuroreport.1999; 10: 1107–1111. 
Dicpinigaitis P. Cough: An Unmet Clinical Need. Br J Pharmacol. 2011;163:116-124. 
Dicpinigaitis P, Morice A, Birring S, et al. Antitussive drugs—past, present and future. 
Pharmacol Rev. 2014;66(2):468-512. 
 
Finger TE, Danilova V, Barrows J, et al. ATP signaling is crucial for communication from taste 
buds to gustatory nerves. Science. 2005; 310: 1495–1499. 
Ford AC, Forman D, Moayyedi P, Morice AH. Cough in the community: a cross sectional 
survey and the relationship to gastrointestinal symptoms. Thorax. 2006; 61: 975-979. 
Gibson P, Wang G, McGarvey L, et al. Treatment of Unexplained Chronic Cough: CHEST 
Guideline and Expert Panel Report. Chest. 2016;149(1):27-44. 
 
Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med. 2000; 343:1715-
1721. 
Irwin R, Baumann M, Bolser D, et al. Diagnosis and Management of Cough Executive 
Summary: ACCP Evidence-Based Clinical Practice Guidelines. Chest. 2006;129(1Suppl):1S-
23S. 
Kelsall A, Decalmer S, Webster D, Brown N, McGuinness K, Woodcock A, Smith J. How to 
Quantify Coughing: Correlations with Quality of Life in Chronic Cough. Eur Respir 
J. 2008;32: 1–5. 
 
Morice AH, McGarvey L, Pavord I on behalf of the British Thoracic Society Cough  
Guideline Group. Recommendations for the Management of Cough in Adults. Thorax.  
2006;61(Suppl I):1-i24.  
 
Morice A, Kastelik   JA, Thompson RH. Gender differences in airway behaviour. Thorax. 2000; 
55: 629. 
Morice AH, Jakes AD, Faruqi S, et al. A worldwide survey of chronic cough: a manifestation of 
enhanced somatosensory response. Eur. Respir. J. 2014; 44: 1149-1155. 
 


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Morice AH. The cough hypersensitivity syndrome: a novel paradigm for understanding cough. 
Lung. 2010; 188 Suppl 1: S87-90. 
Ryan N, Birring S, Gibson P. Gabapentin for Refractory Chronic Cough: A Randomised, 
Double-Blind, Placebo-Controlled Trial. Lancet. 2012;380:1583-89. 
 
Schappert SM, Burt CW. Ambulatory care visits to physician offices, hospital outpatient 
departments, and emergency departments: United States 2001-02. Vital Health Stat. 2006; 13: 
159-166. 
Sheridan, C. Merck stakes out “irritable” neuron territory with $1.25 billion, Nat. Biotechnol. 34 
(2016) 900. doi:10.1038/nbt0916-900. 
Shionogi & Co., Ltd.  Research and Development report at Shionogi .  S-600918  proof of 
concept study in refractory chronic cough March 14, 2019 p 89-93.Smith JA, M. Kitt, M. Sher, 
P. Butera, A.P. Ford. Profound antitussive response to P2x3 blockade with Af-219 permits 
correlation of objective measure of cough with improvement in patient reported outcomes.  Am 
J.  Respir. Crit Care Med. 2016:A2886. 
Smith JA, Woodcock A, “Chronic Cough,” N Engl J Med. 2016; 375, no. 16:1544-1551. 
Smith JA, M.M. Kitt, A.H. Morice, S.S Birring, L.P. McGarvey, M.R. Sher, A.P. Ford. Mk-
7264, A P2X3 receptor antagonist, reduces cough frequency in patients with refractory chronic 
cough: results form a randomized, controlled, phase 2b clinical trial. Eur. Respir. J. Crit Care 
Med. 2017;195:A7608. 
Song WJ, Chang YS, Faruqi S, et al. The global epidemiology of chronic cough in adults: a 
systematic review and meta-analysis. Eur. Respir. J. 2015; 45: 1479–1481. 
Undem BJ, Chuaychoo B, Lee MG, Weinreich D, Myers AC, Kollarik M. Subtypes of vagal 
afferent C-ﬁbres in guinea-pig lungs. J Physiol. 2004; 556: 905–917. 
 


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13. APPENDIX 1: ACCP/BTS Guidelines 
 




Pr ot oc ol N o B U S -P 2 - 0 1 
S p o ns or Pr oject N o C L - 5 9 3 7- 0 2 
 
Versi o n 5 . 0 (2 6 / SE P / 2 0 19 )  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
       Pa ge 6 7  of 6 8  
1 5.  A P P E N DI X 3 : G L O B A L  R A TI N G of C H A N G E S C A L E  
 O ver all, h as t here bee n a n y c h a n ge i n y o ur c o u g h fre q ue nc y si nce y o u st arte d t he ne w me dici ne ? 
Ple ase i n dic ate if t here h as bee n a n y c h a n ge i n y o ur s y m pt o ms b y c h o osi n g o ne of t he f oll o wi n g 
o pti o ns. Are y o ur s y m pt o ms:   
  W O R S E  
  A B O U T T H E S A M E  
  B E T T E R  
[ P atie nts w h o st ate t hey are better are t he n aske d:]  
H o w m uc h better are y o ur s y m pt o ms ? Are t he y:   
1.  A L M O S T T H E S A M E, H A R D L Y A N Y B E T T E R A T A L L  
2.  A LI T T L E B E T T E R  
3.  S O M E W H A T B E T T E R  
4.  M O D E R A T E L Y B E T T E R  
5.  A G O O D D E A L B E T T E R  
6.  A G R E A T D E A L B E T T E R  
7.  A V E R Y G R E A T D E A L B E T T E R  
[ P atie nts w h o st ate t hey are w orse are t he n aske d:] 
H o w m uc h w orse are y o ur s y m pt o ms ? Are t he y:  
8.  A L M O S T T H E S A M E, H A R D L Y A N Y W O R S E A T A L L  
9.  A LI T T L E W O R S E  
1 0.  S O M E W H A T W O R S E  
1 1.  M O D E R A T E L Y W O R S E  
1 2.  A G O O D D E A L W O R S E  
1 3.  A G R E A T D E A L W O R S E  
1 4.  A V E R Y G R E A T D E A L W O R S E  
O ver all, h as t here bee n a n y c h a n ge i n y o ur c o u g h se verit y  si nce y o u st arte d t he ne w me dici ne ? 
Ple ase i n dic ate if t here h as bee n a n y c h a n ge i n y o ur s y m pt o ms b y c h o osi n g o ne of t he f oll o wi n g 
o pti o ns. Are y o ur s y m pt o ms:   
  W O R S E  
  A B O U T T H E S A M E   
  B E T T E R  
[ Patie nts w h o state t he y are better/ w orse are as ke d t o clarif y as bel o w:] 
 


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[Patients who state they are better are then asked:]  
 How much better are your symptoms? Are they:  
1. ALMOST THE SAME, HARDLY ANY BETTER AT ALL  
2. A LITTLE BETTER  
3. SOMEWHAT BETTER  
4. MODERATELY BETTER  
5. A GOOD DEAL BETTER  
6. A GREAT DEAL BETTER  
7. A VERY GREAT DEAL BETTER  
[Patients who state they are worse are then asked:] 
How much worse are your symptoms? Are they: 
8. ALMOST THE SAME, HARDLY ANY WORSE AT ALL  
9. A LITTLE WORSE  
10. SOMEWHAT WORSE  
11. MODERATELY WORSE  
12. A GOOD DEAL WORSE  
13. A GREAT DEAL WORSE  
14. A VERY GREAT DEAL WORSE