A Double-Blind, Randomised, Placebo Controlled, Two Period Cross-Over Study to Evaluate the Efficacy and Safety of Orvepitant in Chronic Cough in Patients With Idiopathic Pulmonary Fibrosis
Phase: PHASE2
Conditions: Cough, Idiopathic Pulmonary Fibrosis
Sponsor: Nerre Therapeutics Ltd.

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Protocol No.: ORV-PF-01 
ORVEPITANT 
 
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CLINICAL STUDY PROTOCOL 
 
A DOUBLE-BLIND, RANDOMISED, PLACEBO CONTROLLED, TWO PERIOD CROSS-
OVER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ORVEPITANT IN 
CHRONIC COUGH IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
 
Short Study Title: 
Phase 2 Efficacy and Safety Study of Orvepitant for Chronic Cough in 
Patients with IPF 
 
IND No:  
132343 
EudraCT No: 
2021-006278-22  
Protocol No. / Name: 
ORV-PF-01 / IPF COMFORT 
Version No:  
Final V4.0 (US) 
Date of Protocol:  
16 May 2024 
 
Sponsor:            
 
NeRRe Therapeutics Ltd,  
 
 
 
 
SBC, Incubator Building,  
 
 
 
 
Gunnels Wood Rd.,  
 
 
 
 
Stevenage, 
 
 
 
 
SG1 2FX, 
 
 
 
 
United Kingdom  
 
SAE Reporting: 
  
 
 
 
 
 
 
 
Confidentiality Statement: 
This protocol contains information which is the property of NeRRe Therapeutics Ltd and therefore is 
provided to you in confidence for review by you, your staff, an applicable ethics 
committee/institutional review board and regulatory authorities. It is understood that this information 
will not be disclosed to others without the written approval from NeRRe Therapeutics Ltd. 
 
This study will be conducted in compliance with Good Clinical Practice (GCP), the General Principles 
of the Declaration of Helsinki (with amendments), and in accordance with local legal and regulatory 
requirements. 
 
 

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than the extent of fibrosis according to the reported 
results of the most recent scan  
5. Mean early morning cough scale 
and rest of 
the day cough scale score <5 (after rounding) during 
the second week of the baseline assessment period 
(assessed at Visit 2) 
6. Cough that is predominantly productive in nature and 
attributable to lung pathology such as chronic 
bronchitis or bronchiectasis 
7. Known clinically significant pulmonary hypertension
(World Health Organisation functional class III or IV)  
that is causing greater functional limitation than is 
attributable to IPF. 
8. A history of clinically relevant drug or alcohol abuse 
[according to Diagnostic and Statistical Manual of 
Mental Disorders 5 criteria (or later edition if 
applicable)] within 6 months before Screening 
9. Any other clinically significant or unstable medical or 
psychiatric condition that would, in the opinion of the 
 to 
participate safely in the study 
10. Any malignancy in the past 3 years unless non-
invasive and in remission. Written approval must be 
obtained from the Sponsor for a subject with any 
history of malignancy 
11. Any clinically significant abnormal laboratory test
result(s), measured at Screening4 
12. Inability to comply with the use of prohibited and 
allowed medications as described below: 
a. Strong or moderate inhibitors of CYP3A4 are not 
allowed from the day of Visit 2 until 1 week after 
the last dose of study medication  
b. Strong or moderate inducers of CYP3A4 are not 
allowed from Screening until 1 week after the last 
dose of study medication 
c. Strong or moderate P-glycoprotein inhibitors are 
not allowed from Screening until 1 week after the 
last dose of study medication  
d. Angiotensin converting enzyme (ACE) inhibitors 
are not allowed within 3 months of Screening and 
throughout the study 
                                                 
4 The investigator should judge the clinical relevance of any abnormal laboratory parameters in the context of the 
subj
 

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e. Other treatments for cough management (opioids, 
dextromethorphan, 
gabapentin, 
pregabalin, 
baclofen, 
antihistamines, 
thalidomide, 
benzonatate or tricyclic antidepressants (e.g. 
amitriptyline)) are not allowed from 4 weeks 
before 
the 
Baseline 
visit 
until 
Visit 
8. 
Medications in these classes may be continued 
provided they have been prescribed solely for the 
management of another comorbidity and the dose 
has been stable for at least 4 weeks before the 
screening visit.  
f. The use of other NK1 antagonists (eg aprepitant, 
fosaprepitant, rolapitant) is not permitted for any 
reason from 4 weeks before the Baseline visit 
until completion of Visit 8  
g. Immune-suppressant 
drugs 
and 
systemic 
corticosteroids taken for co-morbidities are 
permitted provided the dose has been stable for at 
least 2 weeks before the screening visit and they 
are expected to be used at this dose throughout the 
study. Any other use is prohibited 
h. Supplemental oxygen is permitted provided it has 
been used for at least 2 weeks before the screening 
visit and is expected to be used throughout the 
study 
13. Participation in any clinical research study evaluating 
another investigational drug or therapy within 30 days 
or within 5 half-lives (whichever is longer) of the 
investigational drug prior to Screening. If the subject 
was in an observational clinical study, no washout is 
required 
14. Subjects who have previously received orvepitant at 
any time 
15. Known allergy to any of the excipients used in the 
investigational medicinal product (IMP) (orvepitant 
or placebo tablets) 
16. Subjects who, in the opinion of the Investigator, 
should not participate in the study for any other 
reason 
17. Subjects who are dependent on the Sponsor, CRO or 
investigator for employment of education 
 
PATIENT REPORTED OUTCOMES DEVELOPMENT AND VALIDATION 
After completing Visit 7, a subgroup of patients from sites in all participating countries will be 
invited to take part in detailed cognitive debriefing interviews. These interviews form part of the 

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ongoing development and validation of the patient reported outcomes being used to assess 
burden of cough.  
STATISTICAL CONSIDERATIONS  
PLANNED SAMPLE SIZE  
Assuming a common standard deviation of 2.7 for the 
difference between treatment periods, a sample size of 37
subjects per cohort (18-19 per sequence) has 90% power 
if the difference between treatments on the IPF Coughing
Severity Scale is 1.5 points and assuming a two-sided 
type I error of 0.05, not adjusted for multiple 
comparisons. To allow for non-evaluable subjects/
missing data, the withdrawal rate and extent of missing 
data will be monitored as the trial progresses and the 
actual sample size will be increased accordingly such that 
data is available for 37 evaluable subjects.. 
Additional subjects (up to a maximum of 10 per cohort) 
may be recruited if the emerging IPF Coughing Severity 
Scale data is found to have greater variance than allowed 
for in the original sample size estimate.  
Subjects will be randomised to cohort and then further 
randomised to treatment order. 
KEY ELEMENTS OF THE 
ESTIMAND 
Estimand: Improvement in cough severity after 4 weeks 
of treatment, as assessed by change from baseline in IPF 
Coughing Severity Scale score. 
Estimator: Change from baseline in weekly mean IPF 
Coughing Severity Scale score 
Intercurrent Event Strategies:  Sensitivity analyses 
will be undertaken to assess the impact of possible 
intercurrent events on the primary estimand. Intercurrent 
events that are expected to occur during the study are 
initiation of concomitant medication, withdrawal from 
study treatment, withdrawals from the study due to death.
 
STATISTICAL METHODS 
Relevant Screening and Baseline data (i.e., data collected 
prior to the treatment administration), and demographic 
characteristics will be summarised descriptively for each 
treatment group. Efficacy and safety endpoints will be 
summarised by descriptive statistics for each treatment 
group and for each time point. 
All statistical hypothesis tests and confidence intervals 
will be two sided, using a type I error rate of 0.05. No 
adjustments for multiple comparisons are planned for this 
study. 
The primary analysis of change from baseline in weekly 
average of the mean daily IPF Coughing Severity Scale 

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score will be conducted via an ANCOVA model. 
Secondary efficacy endpoints will also be analysed using 
an ANCOVA model. 
The safety and tolerability profile will be assessed versus 
Baseline conditions and differences between treatment 
groups and descriptive statistics will be produced, where 
applicable. 
Plasma concentrations of orvepitant will be summarised 
descriptively; possible exposure-response relationships 
will be explored. 
Selected efficacy parameters will be summarised and 
analysed for the following sub-groups: 
- 
By use of concomitant disease modifying 
therapies at Baseline (yes, no [nintedanib and/or 
pirfenidone]) 
- 
By IPF Coughing Severity Scale score at Baseline 
- 
By cough frequency at Baseline  
Other sub-groups (e.g., age, sex, ethnicity) will be 
evaluated if there are sufficient subjects to warrant 
analysis. 
Selected safety parameters will be summarised for the 
following sub-groups: 
- 
By use of concomitant disease modifying 
therapies at Baseline (yes, no [nintedanib or 
pirfenidone]) 
 
STUDY MEDICATION 
ORVEPITANT 
FORMULATION/DOSE 
Orvepitant 10 mg tablets  
Orvepitant 30 mg tablets  
REFERENCE 
FORMULATION/DOSE 
Matching placebo  
ROUTE OF ADMINISTRATION 
Oral 
DURATION/FREQUENCY OF 
TREATMENT 
Once daily dosing in the evening for 28 days in each of 
the two Treatment Periods  
 
 
 

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ORVEPITANT 
 
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Protocol No.: ORV-PF-01 
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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ................................................................................................... 2 
2. 
TABLE OF CONTENTS ................................................................................................. 12 
3. 
LIST OF ABBREVIATIONS .......................................................................................... 16 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE ..................................... 18 
5. 
BACKGROUND INFORMATION ................................................................................ 20 
5.1 
Orvepitant ......................................................................................................................... 20 
5.2 
Idiopathic Pulmonary Fibrosis ......................................................................................... 20 
5.3 
Cough in Patients with IPF .............................................................................................. 20 
5.4 
Cough Hypersensitivity in IPF ......................................................................................... 21 
5.5 
Role of Substance P and the NK1 Receptor System in Cough Hypersensitivity ............. 21 
5.6 
Orvepitant in the Treatment of Cough Hypersensitivity .................................................. 22 
6. 
STUDY OBJECTIVES AND PURPOSE ........................................................................ 25 
6.1 
Primary objectives ............................................................................................................ 25 
6.2 
Secondary objectives ........................................................................................................ 25 
6.3 
Exploratory objectives ..................................................................................................... 25 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 26 
7.1 
Subject numbers ............................................................................................................... 26 
7.2 
Inclusion criteria............................................................................................................... 26 
7.3 
Exclusion criteria ............................................................................................................. 26 
7.4 
Withdrawal criteria........................................................................................................... 28 
7.5 
Criteria for Stopping the Study ........................................................................................ 29 
8. 
STUDY DESIGN ............................................................................................................. 30 
8.1 
Primary endpoint .............................................................................................................. 30 
8.2 
Secondary efficacy endpoints .......................................................................................... 30 
8.3 
Safety endpoints ............................................................................................................... 31 
8.4 
Exploratory endpoints ...................................................................................................... 33 
8.5 
Patient Reported Outcomes Development and Validation .............................................. 33 
8.6 
Study design ..................................................................................................................... 33 
8.6.1 
Justification for Study Design ......................................................................................... 34 
8.7 
Study Visits ...................................................................................................................... 34 
8.7.1 
Screening ......................................................................................................................... 34 
8.7.2 
Baseline Visit (Visit 2) .................................................................................................... 35 
8.7.3 
Visits 3 and 6 ................................................................................................................... 36 
8.7.4  
Visit 4 .............................................................................................................................. 36 

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8.7.5  
Wash-out Period .............................................................................................................. 37 
8.7.6  
Visit 5 (End of Wash-out / Start of Treatment Period B)................................................ 37 
8.7.7  
Visit 7 .............................................................................................................................. 38 
8.7.8  
Visit 8 .............................................................................................................................. 38 
9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION .................................... 39 
9.1 
Selection of doses in the study ......................................................................................... 39 
9.2 
Investigational medicinal product .................................................................................... 39 
9.3 
Allocation to Treatment ................................................................................................... 40 
9.4 
Study Treatment and Administration ............................................................................... 40 
9.4.1 
Missed dose ..................................................................................................................... 40 
9.4.2 
Dose interruption ............................................................................................................. 40 
9.5 
Duration of Subject Participation ..................................................................................... 40 
9.6 
Treatment Accountability and Compliance Checks ......................................................... 40 
9.7 
Treatment Blinding Code ................................................................................................. 41 
9.8 
Permitted Concomitant Medications ................................................................................ 41 
9.9 
Prohibited Concomitant Medications ............................................................................... 41 
9.10 
Other Study Restrictions .................................................................................................. 42 
9.10.1 
Driving and Operation of Machinery .............................................................................. 42 
9.10.2 
Contraception .................................................................................................................. 42 
10. 
STUDY SCHEDULE ...................................................................................................... 43 
10.1 
Efficacy Assessments ....................................................................................................... 45 
10.1.1 
IPF Coughing Severity Scale .......................................................................................... 45 
10.1.2 
Additional Cough Scales ................................................................................................. 45 
10.1.3 
Other Symptom Scales .................................................................................................... 45 
10.1.4 
Global Rating of Status Questionnaire for Cough Severity ............................................ 46 
10.1.5 
Global Rating of Change Questionnaire for Cough Severity .......................................... 46 
10.1.6 
Ambulatory Cough Monitor ............................................................................................ 46 
10.1.7 
Leicester Cough Questionnaire ....................................................................................... 47 
10.1.8 
Kings Brief Interstitial Lung Disease (K-BILD) Health Status Questionnaire ............... 47 
10.1.9 
PROMIS SD SF 8b ......................................................................................................... 47 
10.1.10 
Hospital Anxiety and Depression Scale .......................................................................... 47 
10.1.11 
Hull Airway Reflux Questionnaire ................................................................................. 47 
10.2 
Safety Assessments .......................................................................................................... 48 
10.2.1 
Medical history and concomitant diseases ...................................................................... 48 
10.2.2 
Physical examinations ..................................................................................................... 48 

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10.2.3 
Pulmonary function ......................................................................................................... 49 
10.2.4 
12-Lead ECGs ................................................................................................................. 49 
10.2.5 
Clinical chemistry ........................................................................................................... 49 
10.2.6 
Haematology ................................................................................................................... 49 
10.2.7 
Urinalysis ........................................................................................................................ 50 
10.2.8 
Vital signs ........................................................................................................................ 50 
10.3 
Biomarkers ....................................................................................................................... 50 
10.4 
Pharmacokinetic Assessments ......................................................................................... 51 
10.5 
Adverse events ................................................................................................................. 51 
10.5.1 
Definitions ....................................................................................................................... 51 
10.5.2 
Assessment of Severity ................................................................................................... 52 
10.5.3 
Assessment of Causality.................................................................................................. 52 
10.5.4 
Adverse Event Reporting ................................................................................................ 52 
10.6 
Pregnancy ......................................................................................................................... 53 
10.7 
Data Safety Monitoring Board ......................................................................................... 53 
11. 
STATISTICAL CONSIDERATIONS ............................................................................. 55 
11.1 
General Statistical Considerations ................................................................................... 55 
11.1.1 
Definition of Baseline ..................................................................................................... 55 
11.2 
Carry Over Effects ........................................................................................................... 55 
11.3 
Estimated Sample Size ..................................................................................................... 56 
11.3.1 
Sample size re-estimation................................................................................................ 56 
11.4 
Estimand ........................................................................................................................... 56 
11.5 
Analysis Sets .................................................................................................................... 57 
11.6 
Data Analysis ................................................................................................................... 57 
11.7 
Demographics and Baseline Characteristics .................................................................... 57 
11.8 
Statistical Methods for Efficacy Parameters .................................................................... 58 
11.9 
Statistical Methods for Safety Parameters ....................................................................... 58 
11.10 
Pharmacokinetics Analysis .............................................................................................. 59 
11.11 
Missing Data .................................................................................................................... 59 
12. 
END OF THE STUDY .................................................................................................... 60 
13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT ......................................... 61 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and Relevant 
Authorities ........................................................................................................................ 61 
13.2 
Ethical Conduct of the Study ........................................................................................... 61 
13.3 
Informed Consent ............................................................................................................. 61 

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14. 
STUDY AND DATA MANAGEMENT ......................................................................... 62 
14.1 
Protocol Amendments ...................................................................................................... 62 
14.2 
Monitoring ....................................................................................................................... 62 
14.3 
Quality Assurance ............................................................................................................ 62 
14.4 
Data Recording................................................................................................................. 62 
14.4.1 
Data to be Considered as Source Data ............................................................................ 62 
14.5 
Confidentiality ................................................................................................................. 63 
14.6 
Retention of Study Data ................................................................................................... 63 
14.7 
Communication and Publication of Results ..................................................................... 64 
14.8 
Indemnification ................................................................................................................ 64 
15. 
REFERENCES ................................................................................................................. 65 
16. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ................................... 68 
17. 
APPENDICES ................................................................................................................. 70 
17.1 
APPENDIX 1: Prohibited Concomitant Medications ...................................................... 71 
17.2 
APPENDIX 2: Numerical / Verbal Rating Scales ........................................................... 73 
17.3 
APPENDIX 3: Patient Global Ratings ............................................................................. 75 
17.4 
APPENDIX 4: Leicester Cough Questionnaire ............................................................... 77 
17.5 
APPENDIX 5: Kings Brief Interstitial Lung Disease Questionnaire .............................. 79 
17.6 
APPENDIX 6: PROMIS SD SF 8b Sleep Questionnaire ................................................ 82 
17.7 
APPENDIX 7: Hospital Anxiety and Depression Scale .................................................. 83 
17.8 
APPENDIX 8: Hull Airway Reflux Questionnaire ......................................................... 85 
 

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3. 
LIST OF ABBREVIATIONS 
ACM 
Ambulatory Cough Monitor 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of covariance 
BP 
Blood Pressure 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
DLCO 
Diffusion Capacity for Carbon Monoxide 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EGFRi 
Epidermal Growth Factor Receptor inhibitor 
ERS 
European Respiratory Society 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GRC  
Global Rating of Change 
GRS 
Global Rating of Status 
H0 
Null Hypothesis 
H1 
Alternative Hypothesis 
HADS 
Hospital Anxiety and Depression Scale 
HARQ 
Hull Airway Reflux Questionnaire 
IB 
Investigators Brochure 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IPF 
Idiopathic Pulmonary Fibrosis 
IWRS 
Interactive Web Response System 
K-BILD 
Kings Brief Interstitial Lung Disease (questionnaire) 
LCQ 
Leicester Cough Questionnaire 
MeDRA 
Medical Dictionary for Regulatory Activities 
NK 
Neurokinin 
NRS 
Numerical Rating Scale 
PAH 
Pulmonary Arterial Hypertension 

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PK 
Pharmacokinetic 
Pop PK 
Population PK 
PRO 
Patient Reported Outcome 
PROMIS SD SF 8b 
Patient-Reported Outcomes Measurement Information System Sleep 
Disturbance short form 8b questionnaire 
RUCC 
Refractory or Unexplained Chronic Cough 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SP 
Substance P 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Events 
TMF 
Trial Master File 
VAS 
Visual Analogue Scale 
 
 

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4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
 
Chief Investigator 
 
 
 
 
 
 
 
 
 
 
Medical Expert  
 
NeRRe Therapeutics Ltd
SBC, Incubator Building,  
Gunnels Wood Rd.,  
Stevenage, SG1 2FX, UK 
 
  
 
Contract Research Organization / 
Monitors 
 
  
 
 
Statistical Consultants 
 
 
 
 

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GENERAL INFORMATION (continued) 
 
Central Clinical Laboratories 
 
 
 
Pharmacokinetic Laboratory 
  
 
 
 
Biomarker Laboratory 
 
   
   
    
Ambulatory Cough Monitor Provision 
and Reading Centre 
 
Denmark Hill,  
London SE5 9RS, UK 
Pharmacovigilance Provider 
 
  
  
  
  
 
  
 

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5. 
BACKGROUND INFORMATION 
5.1 
Orvepitant 
Orvepitant is a potent and selective inhibitor of the human neurokinin (NK) 1 receptor where it 
blocks the effects of Substance P (SP), the preferred endogenous ligand of the NK1 receptor. The 
safety and efficacy of orvepitant has previously been evaluated in more than 900 patients and 
healthy volunteers, including two studies in patients with chronic cough. A full summary of the 
pharmacology, pre-clinical safety, pharmacokinetics and clinical safety and efficacy can be found 
 
5.2 
Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a rare and specific form of chronic, progressive, fibrosing 
interstitial pneumonia in which fibrosis is limited to the lungs. The prevalence is difficult to 
determine accurately because of the diagnostic criteria used and the populations examined, but the 
best estimates put the prevalence in the United States (US) at between approximately 14 per 
100,000 using narrow criteria and 43 per 100,000 using broad criteria [1]. The National Institute 
for Health and Care Excellence estimates that the prevalence in the United Kingdom is around 15 
to 25 per 100,000 population [2]. The histologic appearance on biopsy is of usual interstitial 
pneumonia (UIP). IPF is a diagnosis of exclusion and other causes of lung fibrosis, particularly 
connective tissue disorders, need to be considered and excluded. Diagnosis is made on the basis of 
high-resolution computerised tomography scan findings and histopathology, where available. The 
etiology is unknown [3]. 
The incidence of IPF increases with older age, with presentation typically consisting of insidious 
onset of symptoms in the sixth and seventh decades of life [1]. It is more common in men than 
women and most patients are current or past smokers [4]. A history of gastro-oesophageal reflux 
is also common [5,6]. IPF usually assumes a course of relentless physiologic deterioration although 
in some patients it remains stable for extended periods. Nonetheless, the prognosis is worse than 
that of many cancers and other forms of lung fibrosis, and median life expectancy after diagnosis 
is just 2 to 5 years [7].  
The symptoms of IPF have typically been present for months to years before diagnosis. 
Breathlessness with exertion and cough are the most common symptoms that lead to diagnosis. 
Fatigue and anxiety are also common symptoms. Bi-basilar fine inspiratory crackles (so-called 
Velcro crackles) are the most frequent physical examination finding and digital clubbing is seen in 
25 to 50% of patients. Features of right heart failure and peripheral oedema develop late in the 
clinical course [4,8]. 
A minority of patients is eligible for lung transplantation and so, in the absence 
treatment, the goal of therapy is to slow disease progression and two antifibrotic drugs which 
achieve this are available (pirfenidone and nintedanib). It is doubtful whether antifibrotic drugs are 
able to improve dyspnea and cough.  Given the limited improvements that can be made to the 
underlying disease, alleviating symptoms and improving quality of life is both a goal and a major 
challenge of treatment [9]. 
5.3 
Cough in Patients with IPF 
Cough is a common symptom in patients with IPF and is one of the most burdensome aspects of 
the disease [10]. However, the overall prevalence of cough is unclear, probably due to differences 
in the definitions used to determine cough (any versus disabling cough). In some studies, up to 80% 
of patients report cough [4,11] although lower prevalence has also been reported [12].   

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When cough is present it is often severe and difficult to treat [13]. The cough of IPF is chronic and 
is most often described as dry and non-productive, although a productive cough can occur, 
particularly on waking from sleep. It is often accompanied by a sense of continually having the 
urge to cough that is not relieved by coughing [14]. 
The burden of cough in IPF is high. The limited data available on frequency shows average awake 
cough counts of up to 55 coughs/hour [13,15] with a range that can occur into the hundreds.  This 
frequency is higher than most respiratory disorders associated with chronic cough but not as high 
as RUCC [13]. In treatment studies (in which patients are selected because they have significant 
cough symptoms) the average cough severity scores at baseline are typically greater than 65 mm 
on a 100 mm VAS [13,15]. This burden is similar to that of patients with refractory chronic cough 
presenting to specialist cough clinics and is greater than that of cough in asthma or chronic 
obstructive pulmonary disease [13]. 
Chronic cough, regardless of its cause, can impact markedly on health-related quality of life 
[16,17]. Co-morbid sequelae of repeated coughing can include musculoskeletal chest pain, fatigue, 
sleep disturbance, urinary incontinence and, in extreme cases, syncope or rib fractures. Chronic 
cough can cause relationship difficulties, avoidance of public areas (particularly during the current 
COVID-19 situation), decreased social interaction and work-related problems affecting physical, 
mental and social health [18].  
5.4 
Cough Hypersensitivity in IPF 
Most respiratory diseases associated with cough, such as chronic bronchitis, asthma and acute viral 
infections, predominantly affect the airways or upper respiratory tract where sensory innervation 
is dense. By contrast, pathological changes in IPF principally affect the lung parenchyma and 
alveoli where innervation is sparse. It is therefore surprising that cough is so common in this 
disorder [19]. The pathophysiology of cough in IPF is not yet fully understood, but whilst it is most 
likely multi-factorial in origin, at least in part it is due to development of hypersensitivity in the 
cough reflex pathway [9].  Possible explanations for the hypersensitivity are that mechanical 
distortion of the lung, caused by the fibrosis, directly influences afferent nerve fibres, and/or that 
efferent nerves that inhibit cough are destroyed by the fibrosis [9]. An imbalance between afferent 
stimuli and the (efferent) responses then results in increased coughing such that minor, and usually 
innocuous, stimuli such as talking, eating, temperature change and aromas triggers a cough.  
Capsaicin, when inhaled, induces coughing and the dose of capsaicin required to trigger coughing 
is an indicator of the sensitivity of the cough reflex pathway. Evidence that IPF patients have an 
increased cough reflex sensitivity is provided by studies showing an amplified response to inhaled 
capsaicin compared to healthy controls [20,21]. Hypersensitivity of the cough reflex pathway has 
also been shown by the increased cough reflex sensitivity response induced by mechanical 
percussion of the chest wall in IPF patients [19]. The sensitivity is greatest over the lung base where 
fibrosis is most extensive. These data not only demonstrate hypersensitivity of the cough reflex but 
support the hypothesis that lung distortion contributes to the pathogenesis of cough in IPF. 
5.5 
Role of Substance P and the NK1 Receptor System in Cough Hypersensitivity 
The airways are innervated by vagal sensory nerve fibres, some of which evoke coughing when 
activated [22]. Patients with chronic cough hypersensitivity likely have elevated levels of 
proinflammatory mediators. Vagal sensory nerve terminals within the airway mucosa express a 
range of receptors for these proinflammatory mediators and continued activation results in altered 
sensory neuron activity. Blocking sensory nerve activation by inflammatory mediators (notably 
with P2X3 receptor antagonists) has proved promising but does not completely suppress excessive 
coughing, suggesting multiple mechanisms may need to be targeted [23].  

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Vagal sensory neurons synapse in the brainstem cough centre and connect into circuits that ascend 
to the higher brain. Reflex cough, the urge to cough and behavioural modulation of coughing can 
occur through these lower and higher order brain circuits. Evidence supports an imbalance of 
ascending excitatory activity and reduced descending inhibitory activity in brain networks 
controlling cough in patients with cough hypersensitivity [22].  
Among the neuromodulators that are up-regulated in cough hypersensitivity is SP. It does not 
appear to be functionally important under normal physiological conditions [24] but is implicated 
in induction and maintenance of peripheral and central cough reflex hypersensitivity [24-26]. SP 
has been identified as one of the neurotransmitters released by vagal afferent c-fibres in the 
brainstem cough centre which activate post synaptic brainstem neurons and hence propagate the 
signal to cough [27]. 
In addition to the central role, a direct role in stimulating cough in IPF has been shown for SP [21].  
Hope-Gill and colleagues found that inhaled SP induced a cough response within a few seconds in 
seven of ten IPF patients compared with none of the ten healthy volunteers. 
Raised levels of SP in biological fluids (plasma, induced sputum, nasal secretions and 
bronchoalveolar lavage fluid) have been reported in patients suffering with multiple different cough 
conditions [27-31], including cough associated with asthma and acid reflux, post-infectious cough 
and RUCC.  
As previously noted, patients with IPF [21], as well as those with acute cough [32], also appear to 
have increased sensitivity to SP cough challenge. In animal models, cough can be induced by direct 
injection of SP into the brainstem [33] and evoked cough (induced by, for example, capsaicin 
inhalation) can be blocked with NK1 receptor antagonists[25]. 
5.6 
Orvepitant in the Treatment of Cough Hypersensitivity 
A cough hypersensitivity syndrome can occur both in patients with and without underlying 
pulmonary disease [34,35]. In many patients with a chronic cough (defined as a cough of at least 8 
uration) there is either no obvious underlying cause for the cough or it is refractory to 
treatment of the underlying disease (refractory or unexplained chronic cough, RUCC). It is now 
well established that patients with RUCC have increased sensitivity of the cough reflex pathway 
such that they cough in response to what should be an innocuous stimulus, for example singing, 
talking, perfumes and cold air at all (allotussia) and have increased sensitivity to noxious stimuli 
(hypertussia) [36]. This has been demonstrated experimentally in many challenge studies with, for 
example, inhaled capsaicin [37-40]. 
The frequency of coughing in this group of patients tends to be higher than in other disorders 
associated with chronic cough [13,40]. RUCC patients commonly report a sensation of an urge to 
cough which is not relieved by coughing [41] and have a reduced ability to voluntarily inhibit 
coughing [37]. Collectively, these characteristics indicate a form of sensory neuropathy.  
Orvepitant has been evaluated in two Phase 2 studies in patients with RUCC and has shown clear 
evidence of benefit in these trials. The first study, VOLCANO-1, was an open label pilot study in 
13 subjects. After 4 weeks of treatment with orvepitant 30 mg once daily there was a significant 
reduction from baseline in awake cough frequency (-18.9 coughs/hour, p<0.001) that appeared to 
be sustained for a further 4 weeks after the end of treatment. After 4 weeks there were also 
improvements in the cough severity VAS (approximately 28% reduction from baseline, p=0.002) 
and a small (~8%) but significant improvement in the Cough Quality of Life Questionnaire score.  
The second study, VOLCANO-2, was a randomised, double-blind, placebo-controlled dose range 
finding study. Three hundred and fifteen RUCC patients were randomised to receive placebo or 
orvepitant 10, 20 or 30 mg once daily for 12 weeks.  Orvepitant improved all the patient reported 

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frequency is low. Most notably, in the pooled analysis of the two phase 3 studies with the P2X3 
antagonist gefapixant in more than 2000 patients with RUCC there is no effect of treatment on 
cough frequency in the lower frequency sub-group whereas there is a significant improvement in 
the higher frequency sub-group [42,43]. 
 

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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1 
Primary objectives 
 To evaluate the effect of orvepitant once daily on cough severity, as perceived by patients, 
with IPF 
 To evaluate the safety of orvepitant once daily in patients with IPF 
 
6.2 
Secondary objectives 
 To evaluate the effect of orvepitant once daily on other measures of cough burden and on 
health-related quality of life in patients with IPF 
 To evaluate the effect of orvepitant on other comorbidities in patients with IPF 
 
6.3 
Exploratory objectives  
 To evaluate the effect of orvepitant once daily on markers of disease activity in patients 
with IPF 
 To evaluate the relationship between plasma concentrations of orvepitant and efficacy in 
patients with IPF 
 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject numbers 
In the first instance, approximately 88 subjects will be recruited into the study in two equal sized 
cohorts.  
The number of subjects enrolled may be increased to a maximum of 108 if the interim sample size 
re-estimation indicates that 88 is insufficient (see Section 11.3). 
Subjects will be enrolled at approximately 30 sites across North America and Europe. Additional 
sites and regions may be added. 
7.2 
Inclusion criteria  
1. 
 
2. Able to understand and comply with the requirements of the study and give informed consent 
3. Diagnosis of IPF established according to the 2018 or 2022 joint ATS/ERS/JRS/ALAT Clinical 
Practice Guideline 
4. FEV1/FVC 
at the screening visit 
5. Haemoglobin-corrected diffusion capacity of carbon monoxide 
 of the 
screening visit5 
6. Arterial oxygen saturation on room air or oxygen 90% at Screening 
7. Life expectancy of at least 12 months 
8. Cough that is attributed to IPF, which has not responded to anti-tussive treatment, and which 
has been present for at least 8 weeks prior to Screening 
9. Mean daily IPF Coughing Severity Scale score 5 (after rounding) during the second week of 
the baseline assessment period (assessed at Visit 2) 
10. If taking pirfenidone or nintedanib6, it must have been started at least 3 months prior to 
screening and the prescribed dose must have been stable for at least 1 month prior to screening  
11. Female subjects must not be of child-bearing potential (i.e., they must be surgically sterilised 
or post-menopausal7)  
12. Male subjects who have partners of child-bearing potential must agree to use a condom from 
the Baseline visit until 30 days after the last dose of study medication  
7.3 
Exclusion criteria  
A subject meeting any of the following exclusion criteria will not be permitted to participate: 
1. Recent respiratory tract infection (<8 weeks prior to Screening)  
2. Recent acute exacerbation of IPF (<8 weeks prior to Screening) 
3. Current smokers or ex-smokers with <6 
 
                                                 
5 Subjects who are unable to complete the DLCO assessment for reasons such as coughing may have this criterion 
waived   
6 Use of both nintedanib and pirfenidone is not permitted 
7 Post-menopausal is defined as >1 year since the last menstrual period for women >55 years of age or >1 year since 
their last menstrual period and have an FSH level in the menopausal range for women <55years of age. 

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4. E
-resolution computed tomography, or the extent of emphysema is 
greater than the extent of fibrosis according to the reported results of the most recent scan  
5. Mean early morning cough scale 
and rest of the day cough scale score <5 (after 
rounding) during the second week of the baseline assessment period (assessed at Visit 2) 
6. Cough that is predominantly productive in nature and attributable to lung pathology such as 
chronic bronchitis or bronchiectasis 
7. Known clinically significant pulmonary hypertension (World Health Organisation functional 
class III or IV) that is causing greater functional limitation than is attributable to IPF. 
8. A history of clinically relevant drug or alcohol abuse [according to Diagnostic and Statistical 
Manual of Mental Disorders 5 criteria (or later edition if applicable)] within 6 months before 
Screening 
9. Any other clinically significant or unstable medical or psychiatric condition that would, in the 
 
10. Any malignancy in the past 3 years unless non-invasive and in remission. Written approval 
must be obtained from the Sponsor for a subject with any history of malignancy 
11. Any clinically significant abnormal laboratory test result(s), measured at Screening8 
12. Inability to comply with the use of prohibited and allowed medications as described below: 
a. Strong or moderate inhibitors of CYP3A4 are not allowed from the day of Visit 2 until 1 
week after the last dose of study medication  
b. Strong or moderate inducers of CYP3A4 are not allowed from Screening until 1 week after 
the last dose of study medication 
c. Strong or moderate P-glycoprotein inhibitors are not allowed from Screening until 1 week 
after the last dose of study medication  
d. Angiotensin converting enzyme (ACE) inhibitors are not allowed within 3 months of 
Screening and throughout the study. 
e. Other treatments for cough management (opioids, dextromethorphan, gabapentin, 
pregabalin, baclofen, antihistamines, thalidomide, benzonatate or tricyclic antidepressants 
(e.g. amitriptyline)) are not allowed from 4 weeks before the Baseline visit until Visit 8.  
Medications in these classes may be continued provided they have been prescribed solely 
for the management of another comorbidity and the dose has been stable for at least 4 weeks 
before the screening visit.  
f. The use of other NK1 antagonists (e.g., aprepitant, fosaprepitant, rolapitant) is not permitted 
for any reason from 4 weeks before the Baseline visit until completion of Visit 8  
g. Immune-suppressant drugs and systemic corticosteroids taken for co-morbidities are 
permitted provided the dose has been stable for at least 2 weeks before the screening visit 
and they are expected to be used at this dose throughout the study. Any other use is 
prohibited. 
h. Supplemental oxygen is permitted provided it has been used for at least 2 weeks before the 
screening visit and is expected to be used throughout the study. 
                                                 
8 The investigator should judge the clinical relevance of any abnormal laboratory parameters in the context of the 
history, and any know contributing factors  

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13. Participation in any clinical research study evaluating another investigational drug or therapy 
within 30 days or within 5 half-lives (whichever is longer) of the investigational drug prior to 
Screening. If the subject was in an observational clinical study, no washout is required 
14. Subjects who have previously received orvepitant at any time 
15. Known allergy to any of the excipients used in the investigational medicinal product (IMP) 
(orvepitant or placebo tablets) 
16. Subjects who, in the opinion of the Investigator, should not participate in the study for any other 
reason. 
17. Subjects who are dependent on the Sponsor, CRO or investigator for employment of education.   
7.4 
Withdrawal criteria 
The subjects will be informed that they have the right to withdraw from the study at any time 
without stating a reason and without prejudice to further treatment.  
The Investigator may withdraw subjects from the study or may discontinue study treatment at any 
time. 
Withdrawal from the study or early discontinuation from the IMP is to be registered in the 
electronic Case Report Form (eCRF). 
Early withdrawal or early discontinuation from the IMP of any subject who has given informed 
consent to participate will be recorded including the reason for withdrawal. The primary reason will 
be selected from the following standard categories of early discontinuations or withdrawals: 
 Failed to meet randomisation criteria (screen failure) 
 Adverse Event: One or more adverse events (AE) occurred that in the medical judgment of the 
investigator are grounds for discontinuation from participation in the best interests of the 
subject 
 Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study. The subject is not obliged to provide any reason for withdrawal of consent, but where a 
reason is given, this will be recorded on the electronic Case Report Form (eCRF) 
 Protocol Violation: The subject failed to adhere to the protocol requirements, and in the 
opinion of the investigator, this failure to comply increased the risk to the subject to an 
unacceptable level. 
 Lost to Follow-Up: The subject stopped coming for visits and study personnel were unable to 
contact the subject. 
 Other: The subject was terminated for a reason other than those listed above 
Subjects who withdraw or are withdrawn from participation in the study after randomisation should 
attend an Early Termination visit at which the procedures scheduled for the Visit 8 Follow Up will 
be undertaken. If the subject withdraws due to an AE, the event should be followed until resolution 
usual physician. 
Subjects who are withdrawn after randomisation will not be replaced.  
In some circumstances, the Investigator may discontinue study treatment without the need to 
withdraw the subject from participation in the study. When subjects permanently discontinue IMP, 
effort should be made to continue following the subject through to the end of scheduled visits for 
safety and to obtain efficacy assessments that can be assigned to the originally randomised 
treatment. 

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7.5 
Criteria for Stopping the Study 
The Sponsor may terminate the study for safety or administrative reasons at any time.  
The safety of orvepitant will be monitored by the Data Safety Monitoring Board (DSMB). Full 
study for safety reasons are 
described in the ORV-PF-01 DSMB Charter.  

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informed consent must be taken first. The formal screening visit may then be delayed to allow 
completion of the concomitant medication wash-out period such that the screening assessments are 
completed within 28 days before the Baseline visit.   
The screening period will last a minimum of 14 days so that the baseline electronic diary (eDiary) 
assessment can be completed.  
eligibility for 
inclusion into the study: 
 Full physical examination, 12 lead ECG, vital signs, pulse oximetry and spirometry (FEV1 
and FVC) 
 If the subject has not had diffusion capacity of carbon monoxide (DLCO) measured within 
12 months before screening, then this should be undertaken at the screening visit9.  
 
particular other concomitant respiratory medications, both prescribed and/or over the 
counter medications 
 Blood sampling for clinical chemistry and haematology, and urine sample collection 
urinalysis 
Subjects should be carefully pre-screened so that the outcome of most eligibility criteria can be 
anticipated at the formal screening visit. If necessary, non-routine assessments (e.g., DLCO) should 
be pre-arranged for the screening visit.  
Subjects who satisfy all criteria (other than safety laboratory tests the results of which are unlikely 
to be immediately available) and in whom no clinically relevant laboratory abnormalities are 
anticipated can be provided with the eDiary and be trained on its use (including review of a patient 
information video). The eDiary should be completed for 14 days before the subject returns for the 
baseline visit. 
8.7.2 Baseline Visit (Visit 2) 
A limited set of data will be collected for subjects who withdraw from the study after providing 
informed consent but prior to randomisation onto the study (Screen Failures). 
Eligibility for randomisation will be reviewed based on the results of the eDiary cough score 
recordings. To be eligible to continue the subject must: 
 Have completed the eDiary on at least 4 of the 7 days prior to the Visit 
 Meet the cough scale score eligibility criteria (Sections 7.1 and 7.2). 
been no changes 
which might make them ineligible.   
The Baseline visit will be Day 0. Prior to randomisation on Day 0, the following assessments will 
be completed:  
 Symptom directed physical examination 
 Vital signs (
) 
 Spirometry 
                                                 
9 Subjects who are unable to complete the DLCO assessment for reasons such as coughing may have this criterion 
waived 

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 12-lead ECG  
 Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  
 Blood sample for biomarkers  
 Subjects will be asked to complete the study questionnaires: GRS, LCQ, K-BILD, PROMIS 
SD SF8b, HADS and HARQ  
 Subjects will be fitted with an ambulatory cough monitor (ACM), which will be initiated 
prior to the subject leaving the clinic to monitor cough frequency over the next 24 hours. 
Immediately after the end of this period the subjects will either return the ACM to the clinic 
or collection of the ACM from the subjects will be organised.  
 A review of changes in concomitant medications and any changes in health status (AEs) 
The subjects will be reminded of the eDiary completion requirements and will undergo re-training 
on the use of the diary if required.  
Eligible subjects will be randomised on Day 0 in a 1:1 ratio to either Cohort 1 or Cohort 2, and 
then within each cohort will be further randomised in a 1:1 ratio to receive either placebo or 
orvepitant in Treatment Period A. Randomisation will be performed centrally via an IWRS. 
Subjects will be dispensed sufficient study medication for 28 days (plus overage) which they should 
begin taking the evening of the following day before retiring to bed. Starting study medication, the 
following day enables ACM monitoring to be completed before study medication starts.  
8.7.3 Visits 3 and 6 
Visits 3 and 6 should be scheduled 14 (±3) days after the start of each Treatment Period. The 
assessments are to be undertaken remotely by telephone or videoconference.  
A review for adverse events or changes in concomitant medications will be undertaken.  
Subjects will complete the GRS and GRC assessments (verbally) and will be reminded of the 
eDiary completion requirements, as necessary. 
8.7.4  Visit 4  
Visits 4 should be scheduled 28 (±3) days after the Baseline visit. The following assessments and 
procedures will be undertaken at the clinic site or during a home visit: 
 Vital signs  
 Spirometry 
 12-lead ECG  
 Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  
 Blood sample for biomarkers  
 Blood sample for orvepitant concentration 
 Subjects will be asked to complete the study questionnaires: GRS and GRC, LCQ, K-BILD, 
PROMIS SD SF8b, HADS and HARQ  
 Subjects will be fitted with an ambulatory cough monitor (ACM), which will be initiated 
prior to the subject leaving the clinic to monitor cough frequency over the next 24 hours. 

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Immediately after the end of this period the subjects will either return the ACM to the clinic 
or arrangements will be made to collect it from the subject.  
 A review of changes in concomitant medications and any changes in health status (AEs) 
The subjects will undergo re-training on the use of the diary, if required, and will be reminded of 
the need to continue to record their IPF Coughing Severity Scale, additional cough scales and other 
symptom scales in the eDiary during the wash-out period.   
Study medication compliance for Treatment Period A will be checked during the visit. The 
medication bottle will be returned to the patient so that they can take the last dose the same evening, 
with the medication being finally returned to the site at the same time and using the same method 
(delivery by patient or collection by courier/ site staff) as the ACM. Compliance will be checked 
again when the bottle is returned. 
8.7.5  Wash-out Period 
At the end of Treatment Period A subjects will enter a washout period during which they will not 
take study medication. Subjects will, however, continue to complete the IPF Coughing Severity, 
additional cough severity, and other symptom scales in the eDiary each day.  
The nominal washout period duration will be 21 days although it may be varied by up to ±3 days 
to accommodate subject and clinic schedules.    
8.7.6  Visit 5 (End of Wash-out / Start of Treatment Period B) 
This visit occurs at the end of the wash-out period and the start of Treatment Period B. The 
following assessments and procedures will be undertaken at the clinic site or during a home visit: 
 Vital signs  
 Spirometry 
 12-lead ECG  
 Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  
 Blood sample for biomarkers  
 Blood sample for orvepitant concentration 
 Subjects will be asked to complete the study questionnaires: GRS and GRC, LCQ, K-BILD, 
PROMIS SD SF8b and HADS  
 A review of changes in concomitant medications and any changes in health status (AEs) 
The subjects will undergo re-training on the use of the diary, if required, and will be reminded of 
the need to continue to record the IPF Coughing Severity, additional cough severity, and other 
symptom scales in the eDiary daily for the next 4 weeks.    
Study medication for Treatment Period B will be dispensed and the subject instructed to begin 
taking it the evening of the following day (to align with the start of treatment in Treatment 
Period A). 

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8.7.7  Visit 7   
Visits 7 should be scheduled 28 (±3) days after Visit 5. The following assessments and procedures 
will be undertaken at the clinic site or during a home visit: 
 Vital signs  
 Spirometry 
 12-lead ECG  
 Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  
 Blood sample for biomarkers  
 Blood sample for orvepitant concentration 
 Subjects will be asked to complete the study questionnaires: GRS and GRC, LCQ, K-BILD, 
PROMIS SD SF8b, HADS and HARQ  
 The subject will be fitted with an ACM, which will be initiated prior to the subject leaving 
the clinic to monitor cough frequency over the next 24 hours. Immediately after the end of 
this period the subjects will either return the ACM to the clinic or arrangements will be 
made to collect it from the subject.  
 A review of changes in concomitant medications and any changes in health status (AEs) 
The subject will be instructed that they should record the IPF Coughing Severity, additional cough 
severity, and other symptom scales in the eDiary for the final time that evening and then return the 
device to the site at the Follow up visit. 
Study medication compliance for Treatment Period B will be checked during the visit. The 
medication bottle will be returned to the patient so that they can take the last dose the same evening, 
with the medication being finally returned to the site at the same time and using the same method 
as for the ACM. Compliance will be checked again when the bottle is returned. 
8.7.8  Visit 8  
Visit 8 is the follow up / early termination visit for the study. It should be scheduled for 14 (±3) 
days after Visit 7 or at the earliest opportunity if the subject withdraws early. 
The following assessments and procedures will be undertaken at the clinic site or during a home 
visit: 
 Vital signs  
 Symptom directed physical examination 
 Spirometry 
 12-lead ECG  
 Safety labs: blood samples for clinical chemistry and hematology and urine sample for 
urinalysis  
 Global ratings of cough status and change 
 A review of changes in concomitant medications and any changes in health status (AEs) 
 

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Only authorised investigational site study staff members are to dispense the IMP. 
9.3 
Allocation to Treatment 
The IMP each subject receives will be allocated by an IWRS tool provided by 
 
on behalf of the Sponsor. 
The study will be conducted in a double-blind manner, with the subjects, Investigators and Sponsor 
all blinded to the treatment allocated. Both orvepitant (10 mg and 30 mg) and placebo will be 
presented as white tablets, identical in size and shape. 
Following the Screening period and confirmation of eligibility, subjects will be randomised in a 
1:1 ratio to either Cohort 1 or Cohort 2, and then further randomised in a 1:1 ratio to receive either 
placebo in Treatment Period A or orvepitant in Treatment Period A. 
9.4 
Study Treatment and Administration 
IMP will be taken once daily. IMP doses are fixed and will not be adjusted for individual subjects 
during the study.  
At each visit (where appropriate, see Section 8.7) subjects will be dispensed IMP for self-
administration for daily dosing until the subsequent visit, with overage included to allow for visit 
windows. An interim check of compliance will be made at all in person study visits (as appropriate).  
Subjects will be required to take one tablet of IMP once-daily in the evening before retiring to bed. 
The study medication may be taken with or without food. 
9.4.1 Missed dose 
All doses are to be taken at approximately the same time each evening. If a subject forgets to take 
a dose in the evening it may be taken any time up until 9 am the following morning. After this time 
the dose should not be taken, and it will be considered a missed dose.  
9.4.2 Dose interruption 
If a subject experiences an AE which the investigator believes is treatment related and which the 
subject finds intolerable, a break in dosing of up to 1 week is permitted. If on reintroduction of the 
IMP, the AE recurs and remains intolerable the IMP will then be withdrawn altogether. A break in 
dosing will not result in extension of the overall dosing period.   
9.5 
Duration of Subject Participation 
The total planned duration of participation in the study for an individual subject is up to 17 weeks, 
which comprises the following: 
 Initial Screening phase of up to four weeks (excluding any additional periods for washout 
of prohibited concomitant medications) 
 4 weeks each for Treatment Periods A and B 
 3 weeks for the wash-out period 
 2 weeks for follow up 
9.6 
Treatment Accountability and Compliance Checks 
In accordance with regulatory requirements, the Investigator or designated site staff must document 
the amount of IMP dispensed and/or administered to study subjects, the amount returned by study 
subjects, and the amount received from and returned to the Sponsor (or representative) when 
applicable. IMP accountability records must be maintained throughout the course of the study. The 

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accountability unit for this study is a tablet. Discrepancies are to be reconciled or resolved. 
Procedures for final disposition of unused IMP will be provided. 
The Investigator has overall responsibility in ensuring that the study treatment is received and 
managed at the study site in accordance with Good Clinical Practice (GCP). 
Limited responsibility may be delegated to a nominated study site representative and this delegation 
must be documented. Study treatment will be dispensed by a nominated person at each study site. 
The Sponsor will be permitted upon request to audit supplies, storage and dispensing records and 
procedures. 
Every effort should be made to encourage subject compliance with the dosage regimen as per the 
protocol. All subjects will be instructed to return their medication bottle with any unused tablets at 
each visit. A record of the tablets dispensed, taken, and returned will be recorded at each visit and 
compliance calculated.   
9.7 
Treatment Blinding Code 
Study investigators will be given access to the IWRS system for the purposes of emergency 
unblinding. The IWRS will be incorporated within the eCRF. Investigators are permitted to unblind 
treatment for a subject if it is deemed that knowledge of the subjec s treatment will impact 
medical monitor or Sponsor medical expert should 
be notified prior to the blind being broken. If this is not possible, the medical monitor or Sponsor 
medical expert must be notified as soon as possible if a code break was performed.  
If a suspected unexpected serious adverse reaction (SUSAR) occurs that requires expedited 
reporting to the relevant regulatory agencies and Institutional Review Board (IRB) /Independent 
Ethics Committee (IEC), then the blind will be broken for the relevant subject by the Bionical Emas 
safety group before reporting. A blinded copy of the report will be provided to the investigators. 
If unblinding occurs accidentally this will be considered a protocol deviation. It must be 
documented in the subject
be informed. 
9.8 
Permitted Concomitant Medications 
All concomitant medications taken during the study will be recorded in the eCRF with indication, 
dose information, and dates of administration. Any medication that is not specifically prohibited is 
allowed.  
Throat or cough lozenges (also known as a candies, drops, sweets or pastilles) and mucolytic agents 
are permitted. 
9.9 
Prohibited Concomitant Medications 
A list of prohibited concomitant medications is provided in Appendix 1. 
Due to their potential effect on cough reflex sensitivity, the use of opioids, dextromethorphan, 
gabapentin, pregabalin, baclofen, antihistamines, thalidomide, benzonatate or tricyclic 
antidepressants (e.g. amitriptyline) for treatment of cough is not allowed throughout the study 
(through to Visit 8). Subjects must have discontinued these drugs at least 4 weeks prior to the 
Baseline visit and should not have them started during the study. Subjects may, however, be 
permitted to continue to use these drugs if they have been prescribed solely for the management of 
another disorder (eg neuropathic pain, depression) and the dose has been stable for at least 1 month 
prior to screening. 

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Angiotensin converting enzyme (ACE) inhibitors are not allowed within 3 months of Screening 
and throughout the study. 
The use of other NK1 antagonists (e.g., aprepitant, fosaprepitant, rolapitant) is not permitted for 
any reason from 4 weeks before the Baseline visit until completion of Visit 8 
Strong or moderate inhibitors of CYP3A4 are excluded from the day of Visit 2 until one week after 
the last dose of IMP in the study. 
The following classes of medication are excluded from Screening until one week after the last dose 
of IMP in the study: 
 Strong or moderate inducers of CYP3A4 (including but not limited to rifampicin, 
carbamazepine, efavirenz, bosentan, modafinil, St. John's Wort) 
 Strong or moderate inhibitors of P-glycoprotein inhibitors  
9.10 
Other Study Restrictions 
9.10.1 Driving and Operation of Machinery 
Somnolence and dizziness have been identified as non-serious adverse reactions to orvepitant. 
Subjects will be instructed neither to drive nor operate machinery if they experience somnolence 
or dizziness. 
9.10.2 Contraception  
Female subjects of childbearing potential are excluded from the study and hence there are no 
contraceptive requirements for them. 
Male subjects who are sexually active with a female partner of child-bearing potential (i.e., the 
partner is not surgically sterilised or postmenopausal) must agree to use a condom for the duration 
of participation in the study and for 30 days after the last dose of study medication.

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10.1 
Efficacy Assessments 
10.1.1 
IPF Coughing Severity Scale 
The IPF Coughing Severity Scale is a numerical rating scale (NRS) which will be completed in the 
eDiary during the study, starting at Visit 1 and continuing through to the day of Visit 7.  It will be 
completed once a day by the subject, in the evening, just before retiring to bed.  
Subjects are asked to rate the severity of their coughing in the past 24 hours using an 11-point scale 
ranging from 0 (no coughing) to 10 (coughing as bad as you can imagine) (Appendix 2).  
The eDiary will have a reminder function and will include a time window during which completion 
is permitted. On expiry of the window the assessment will be lo
will be considered missing for that day.  
Daily scores will be transferred 
 
database to 
for 
statistical analysis. Scores will be averaged over 7-day periods to provide weekly average IPF 
Coughing Severity Scale scores for each assessment timepoint. A minimum of 4 daily assessments 
will be required for a valid weekly average.  
10.1.2 
Additional Cough Scales 
10.1.2.1 
Early morning cough scale 
The early morning cough scale will be completed in the eDiary during the study in the same manner 
as the IPF Coughing Severity Scale. 
Subjects are asked to rate the severity of their coughing first thing that morning on waking or rising 
using an 11-point NRS ranging from 0 (no coughing) to 10 (coughing as bad as you can imagine) 
(Appendix 2).  
10.1.2.2  
Rest of the day cough scale 
The rest of the day cough scale will be completed in the eDiary in the same manner as the IPF 
Coughing Severity Scale. 
Subjects are asked to rate the severity of their coughing during the rest of the last 24 hours 
(excluding the coughing first thing on waking) using an 11-point NRS ranging from 0 (no 
coughing) to 10 (coughing as bad as you can imagine) (Appendix 2).  
10.1.3 
Other Symptom Scales 
10.1.3.1 Urge to Cough Scale 
The urge to cough scale will be completed in the eDiary during the study in the same manner as 
the IPF Coughing Severity Scale. 
Subjects are asked to rate the severity of their urge to cough in the past 24 hours using an 11-point 
NRS ranging from 0 (no urge to cough) to 10 (urge to cough as bad as you can imagine) (Appendix 
2).  
10.1.3.2 
Cough Frequency Scale 
The cough frequency scale will be completed in the eDiary during the study in a similar manner to 
the IPF Coughing Severity Scale. 
Subjects are asked to rate the frequency of their coughing in the past 24 hours using a 5-point verbal 
rating scale ranging from Never to All the time (Appendix 2). 
 

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10.1.3.3 
Dyspnoea Scale 
The dyspnoea scale will be completed in the eDiary during the study in the same manner as the IPF 
Coughing Severity Scale.  
Subjects are asked to rate the severity of their shortness of breath in the past 24 hours using an 11-
point scale ranging from 0 (no shortness of breath) to 10 (shortness of breath as bad as you can 
imagine) (Appendix 2).  
10.1.4 
Global Rating of Status Questionnaire for Cough Severity 
The global rating of status questionnaire comprises three questions that subjects will complete at 
Visits 2, 3, 4, 5, 6, 7 and 8 
Subjects will be asked to rate the overall severity of: 
- 
All coughing 
- 
Coughing first thing in the morning 
- 
Any other coughing 
over the past week as either none, mild, moderate, severe or very severe (Appendix 3).  
It will be completed during the study visit by the subject directly onto a tablet device except at 
a member of the site staff. 
10.1.5 
Global Rating of Change Questionnaire for Cough Severity 
The global rating of change questionnaire comprises three questions that subjects will complete at 
Visits 3, 4, 5, 6, 7 and 8 
Subjects will be asked to rate the overall change in severity since starting the study of: 
- 
All coughing 
- 
Coughing first thing in the morning 
- 
Any other coughing 
They will select one of 7 responses that range from very much worse through no change to very 
much better (Appendix 3). 
It will be completed during the study visit by the subject directly onto a tablet device except at 
a member of the site staff. 
10.1.6 
Ambulatory Cough Monitor 
Subjects will be fitted with an ACM (the Leicester Cough Monitor10 [LCM]) to record cough 
frequency over 24 hours at Visits 2, 4 and 7. 
The LCM will be started prior to the subject leaving the clinic to monitor cough frequency over 24 
hours. After this period, the subjects will either return the monitor to the clinic or collection from 
the subjects will be organised. Cough frequency will be determined by a central evaluation service 
                                                 
10 
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10.2 
Safety Assessments 
10.2.1 
Medical history and concomitant diseases 
A review of medical and medication history will be performed at Screening to confirm subject 
eligibility. This must be reviewed and by the investigator or a medically qualified sub-investigator. 
All medically relevant information should be recorded, regardless of the time since the date of 
diagnosis. 
History should include (but not be limited to): 
 All medications currently being taken, and any other medications taken within six months 
before the Screening Visit  
 The date of diagnosis of IPF, which should be consistent with the requirements of the 2018 
or 2022 joint ATS/ERS/JRS/ALAT Clinical Practice Guideline, and the date of onset of the 
 
 Any other respiratory disorders 
 Relevant medical history relating to cardiac, vascular, neurological, gastrointestinal, renal, 
hepatic, psychiatric disorders, and any other diseases. 
10.2.2 
Physical examinations 
A full physical examination will be conducted at the Screening visit and a symptom directed 
physical examination at other visits, as shown in the Schedules of Events (Table 2). This will be 
completed by a physician or an appropriately qualified delegate. 
A full physical examination is composed of a review of the following body systems: 
 General appearance 
 Skin 
 Head, eyes, ears, nose and throat 
 Respiratory 
 Cardiovascular 
 Abdomen (including liver and kidneys) 
 Musculoskeletal 
 Neurological 
Any abnormalities that are identified at the Screening Visit will be documented on the medical 
history eCRF page. Any changes (including new and worsening findings) between the Screening 
Visit and final study visit should be 
ed as AEs 
on the AE eCRF page. 
medical history occurs during the study, it should be recorded in the 
source notes. If there 
is resolution of a physical examination finding previously noted as an AE, then the event resolution 
and stop date should be recorded on the AE eCRF page 
. 

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10.2.3 
Pulmonary function 
Lung function will be assessed by spirometry in accordance with the joint 2019 American Thoracic 
Society and European Respiratory Society Technical Update on Standardization of Spirometry.11 
Measurements will be made and assessed locally at the study sites.  The same model of spirometer 
should be used throughout the study for any given subject. 
Spirometry will be performed at Visits 1, 2, 4, 5, 7 and 8. 
Where possible (recognising that patients with IPF often find spirometry challenging), the highest 
values from three technically satisfactory attempts will be recorded and used for the purpose of 
eligibility. If three technically satisfactory attempts cannot be completed by the subject, the best 
attempt should be used.  
Short acting bronchodilator agents should be withheld for at least 12 hours before a spirometry 
assessment and long acting bronchodilator agents should be withheld for at least 24 hours. 
10.2.4 
12-Lead ECGs 
Resting 12-lead ECG data will be recorded after the patient has rested for at least five minutes in a 
semi-recumbent position. The same model of ECG recorder should be used throughout the study 
for any given subject. 
ECGs will be recorded Visits 1, 2, 4, 5, 7 and 8 
ECG reports must be reviewed, signed, and dated by the Investigator or delegated physician. 
abnormal findings and determine whether they are clinically significant. These assessments will be 
recorded in the eCRF, and clinically significant findings must also be reported as AEs in the eCRF. 
10.2.5 
Clinical chemistry 
Blood for clinical chemistry assessments will be collected and sent to the central laboratory for 
analysis at Visits 1, 2, 4, 5, 7 and 8 
The following clinical chemistry parameters will be assessed: sodium, potassium, glucose, 
urea/urea nitrogen, creatinine, creatine kinase, albumin, calcium, phosphate, bilirubin (total), 
alkaline phosphatase, aspartate transaminase, alanine transaminase, gamma glutamyl transferase, 
bicarbonate, magnesium, chloride, total protein. Subjects do not need to fast before clinical 
chemistry samples are taken. 
Clinical chemistry test reports must be reviewed, signed, and dated by the Investigator or delegated 
physi
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as adverse events in the eCRF. 
10.2.6 
Haematology 
Blood for haematology assessments will be collected and sent to the central laboratory for analysis 
at Visits 1, 2, 4, 5, 7 and 8. 
                                                 
11 Graham B, Steenbruggen I, Miller M, Barjaktarevic I, Cooper B, Hall G, et al. Standardization of Spirometry 2019 
Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir 
Crit Care Med 2019;200,e70 e88. 

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The following haematology parameters will be assessed: red blood cell count, white blood cell 
count, haematocrit, haemoglobin, mean cell volume, platelet count and white cell differentials. 
All haematology test reports must be reviewed, signed, and dated by the Investigator or delegated 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as adverse events in the eCRF. 
10.2.7 
Urinalysis 
Urine for urinalysis assessments will be collected and sent to the central laboratory for analysis at 
Visits 1, 2, 4, 5, 7 and 8. 
Parameters to be measured will comprise glucose, bilirubin, ketones, specific gravity, blood, pH, 
protein, urobilinogen, nitrites, leucocyte esterase, sedimentation.  
Urinalysis test reports must be reviewed, signed, and dated by the Investigator or delegated 
 medical record. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. Clinically 
significant findings must also be reported as adverse events in the eCRF.  
10.2.8 
Vital signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, arterial oxygen saturation 
[SpO2]) will be measured at Visits 1, 2, 4, 5, 7 and 8. 
Blood pressure will be measured using a standardised process: 
 
measurement arm supported 
so that the midpoint of the manometer cuff is at heart level 
 Use an automatic blood pressure device with an appropriately sized cuff with the bladder 
centered over the brachial artery 
 Measure and record the blood pressure using the same arm throughout the study 
SpO2 will be measured using a pulse oximeter.  
Additionally, weight will be measured at Visits 2 and 8. 
All measurements are to be recorded on the Vital Signs eCRF. 
All vital signs must be reviewed by the Investigator or delegated physician. The Investigator will 
comment on all abnormal results and determine whether they are clinically significant. These 
assessments will be recorded in the eCRF, and clinically significant findings must also be reported 
as adverse events in the eCRF. 
10.3 
Biomarkers 
Serum/plasma will be collected for assessment of biomarkers at Visits 2, 4, 5 and 7. 
Biomarkers to be assessed are: 
Potential mechanistic / 
pharmacodynamic markers 
 Monocyte chemo-attractant protein 1 (MCP-1) 
 Interleukin (IL)-
 
 IL-6 
 IL-17A 

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Potential markers of 
disease progression 
 C3M 
 
10.4 
Pharmacokinetic Assessments 
A single spot  blood sample for analysis of plasma orvepitant concentrations will be collected at 
Visits 4, 5 and 7. 
Details of PK blood sample collection (including volume to be collected), processing, storage and 
shipping procedures will be provided in the Laboratory Manual. 
10.5 
Adverse events 
10.5.1 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a subject or clinical trial subject administered an IMP and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of an IMP, whether or not considered 
related to the IMP. 
Adverse Drug Reaction 
All AEs considered to be untoward and unintended responses to an IMP related to any dose should 
be considered adverse drug reactions. The definition also covers medication errors and uses outside 
what is foreseen in the protocol, including misuse and abuse of the product. 
to an IMP
the IMP and an AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Serious Adverse Event (SAE) 
An adverse event that: 
 Results in death 
 Is life-threatening (i.e., the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
 Requires in-patient hospitalisation or prolongation of existing hospitalisation (see 
explanation below) 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is considered to be an important medical event 
Based upon medical and scientific judgment, important medical events that may not be 
immediately life-threatening, or result in death or hospitalisation, but may jeopardize the subject 
and/or12 may require intervention to prevent one of the other outcomes listed in the definition above 
may be considered a SAE. 
                                                 
12 The definition varies between regulatory jurisdictions 

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Hospitalisations are defined as initial or prolonged admissions that include an overnight stay. 
Hospitalisation or prolonged hospitalisation for technical, practical, or social reasons, in the 
absence of an adverse event is not an SAE and neither is attendance at an Emergency Room / 
Accident and Emergency Department that takes place in the evening or night and does not result 
in formal admission to the hospital. 
Adverse Events of Special Interest 
For the purposes of this study, any 
event that do
an SAE is to be considered an adverse event of special interest (AESI) and should be reported by 
the investigator to the Sponsor in an expedited manner by completing the AESI form and sending 
it by email to the medical monitor. This will enable the Sponsor to monitor for potentially relevant 
safety findings that do not meet the definition of serious. Non-serious respiratory decline events 
include (but are not limited to) the following:  
 Unscheduled visits to a healthcare professional for respiratory status deterioration. 
 Urgent care visit for respiratory status deterioration. 
In addition, any adverse event relating to suicidal ideation or suicidal behaviour that 
the definition of an SAE is to be considered an AESI and should be reported by the investigator to 
the Sponsor in an expedited manner by completing the AESI form and sending it by email to the 
medical monitor. 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with the reference safety 
. 
Reports which add significant information on the specificity, increase of occurrence, or severity of 
a known, already documented serious adverse reaction may also constitute unexpected events. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse event that is suspected to be related to the administered medicinal product and 
the nature or severity of which is unexpected. 
10.5.2 
Assessment of Severity 
The severity (intensity) of each adverse event will be classified as: 
Mild 
Awareness of sign or symptom, but easily tolerated by the subject 
Moderate 
Sign or symptom causes 
normal activities 
Severe 
activities 
10.5.3 
Assessment of Causality 
A determination will be made of the relationship (if any) between an AE and the study drug. A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the drug. AEs will be classified as either related or unrelated.  
10.5.4 
Adverse Event Reporting 
Adverse events may be volunteered spontaneously by the subject, or discovered as a result of 
general, non-leading questioning. Adverse events occurring from the Screening Visit up to the final 

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study visit will be recorded. All AEs should be recorded in the eCRF 
notes. 
Any SAE occurring from the time the Screening Visit until 30 days after the last dose of IMP must 
be reported immediately (within 24 hours of the investigator becoming aware of it) and recorded 
on the SAE Form. Detailed instructions for the reporting of SAEs will be provided. All subjects 
with an SAE must be followed up and the outcomes reported. The investigator must supply the 
Sponsor and the relevant regulatory and ethics authorities with any additional requested 
information (e.g., autopsy reports and terminal medical reports). Any follow-up information on a 
previously reported SAE will also be reported within 24 hours of awareness. 
If the Investigator does not have all information regarding an SAE, he/ she will not wait to receive 
additional information before reporting the event and completing the appropriate data collection 
form. The Investigator will always provide a preliminary assessment of causality at the time of the 
initial report as described in Section 10.5.3. 
The primary mechanism for reporting SAEs will be a paper collection form. 
S
preferred method to transmit this information to the project 
contact for SAE receipt although fax transmission is also acceptable. In rare circumstances and in 
the absence of email capability or fax equipment, notification by telephone is acceptable, with a 
copy of the SAE data collection form sent by overnight mail. Initial notification via the telephone 
does not replace the need for the Investigator to complete and sign the SAE data collection form 
within the designated reporting periods. 
NeRRe is required to expedite to regulatory authorities reports of SUSARs in line with the relevant 
legislation. Fatal or life-threatening SUSARs must be reported within 7 calendar days and other 
SUSARs within 15 calendar days. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. If required 
by local reporting regulations, each Investigator must then notify his or her relevant Institutional 
Review Board (IRB) or Research Ethics Committee (REC). NeRRe will submit to the regulatory 
authorities all safety updates and periodic reports, as required by applicable regulatory 
requirements. 
10.6 
Pregnancy 
Male subjects who are sexually active with a female partner of child-bearing potential must agree 
to use a condom for the duration of participation in the study and for 30 days after the last dose of 
study medication.  
However, if the partner 
in the study and for up to 30 days after the last dose of IMP, this should be reported to the 
investigator. Consent will be sought from the partner and, if granted, any pregnancy will be 
followed and the status of mother and/or child will be reported to the sponsor after delivery. 
10.7 
Data Safety Monitoring Board 
A DSMB will be convened with the primary remit of providing independent safety oversight of the 
study. The composition of the DSMB, its terms of reference and its operating procedures will be 
described in the DSMB Charter which will be finalised before the first subject is randomised into 
the study.  
The DSMB may, at any time, make recommendations to the NeRRe Chief Medical Officer of 
changes to the conduct of the study, including temporary or permanent discontinuation of the trial, 
to ensure the benefit-risk balance to participants remains appropriate. The default assumption is 

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that DSMB recommendations will be implemented by the Sponsor, although exceptionally there 
may be further consultation with third parties (for example regulatory agencies) before changes to 
study conduct are implemented.  

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11. 
STATISTICAL CONSIDERATIONS 
11.1 
General Statistical Considerations 
Subjects will be randomised to cohort and then further randomised to treatment order.  
The primary objective of the study is to evaluate the effect of orvepitant once daily on cough 
severity, as perceived by patients, with IPF. The corresponding primary endpoint is the mean 
change from Baseline to Week 4 (the last 7 days of treatment) in weekly average of the daily IPF 
Coughing Severity Scale score. 
The primary objective will be assessed by testing the following hypotheses for each orvepitant dose 
group separately: 
Null hypothesis (H0): There is no difference in the mean change in mean IPF Coughing Severity 
Scale scores for the orvepitant treatment group compared to placebo. 
H0: µ (active) = µ (placebo) 
Alternative hypothesis (H1): There is a difference in the mean change in mean IPF Coughing 
Severity Scale scores for the orvepitant treatment group compared to placebo. 
H1: µ 
µ (placebo) 
Each comparison will be carried out at the two-sided 5% level of statistical significance. No 
adjustment will be made for the multiple orvepitant versus placebo group comparisons in this phase 
2 study (two in total: 10 mg versus placebo, 30 mg versus placebo) as each dose cohort is tested 
independent (versus the corresponding placebo) and each is adequately powered. 
11.1.1 
Definition of Baseline 
Baseline values will be defined separately for each treatment period, unless stated otherwise.   
For the primary efficacy endpoint, period-specific baseline will be used in the analysis, which 
is the average of the 7 calendar days up to and including the date of Visit 2 for Treatment Period 
A and the average of 7 calendar days up to and including the date Visit 5 for Treatment Period 
B. 
For secondary efficacy endpoints related to change from baseline, the period-specific baseline 
will be used when available; for those endpoints for which a period-specific baseline is not 
available (cough frequency and Hull Airway Reflux Questionnaire), the baseline in Treatment 
Period A will be used. 
For safety assessments, baseline will be Visit 2 for Treatment Period A and for Treatment Period 
B it will be Visit 5.  
For both safety and efficacy assessments, if the period-specific baseline is missing for Treatment 
Period A the value from Visit 1 will be used. If this is missing change from baseline will not be 
calculated. If the period-specific baseline is missing for Treatment Period B the value from Visit 
2 (first preference) or Visit 1 (second preference) will be used. If both are missing change from 
baseline will not be calculated. 
11.2 
Carry Over Effects 
A potential limitation of any cross-over study is the occurrence of confounding carry over effects 
between treatment periods. The wash-out period for this study is 3-weeks which, given that the 
half-life of orvepitant is approximately 33 hours, is expected to be sufficient for the drug to be fully 
cleared and for cough symptoms to return to baseline levels.   

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Period-specific baseline values will be used in the analysis of primary and secondary efficacy 
endpoints, and safety endpoints, when available, to protect against possible carryover effect.   
11.3 
Estimated Sample Size 
Assuming a common standard deviation of 2.7 for the difference between treatment periods, a 
sample size of 40 subjects per cohort (18 -19 per sequence) has 90% power if the difference 
between treatments on the IPF Coughing Severity Scale is 1.5 points and assuming a two-sided 
type I error of 0.05, not adjusted for multiple comparisons. To allow for non-evaluable subjects/ 
missing data the withdrawal rate and extent of missing data will be monitored as the trial progresses 
and the actual sample size will be increased accordingly such that data is available for 37 evaluable 
subjects.  
As there have been no previous studies using NRS for cough severity the standard deviation of 2.7 
was obtained based on historical data of the change in cough severity measured using VAS. A 2-
week observational study has since been completed in which the standard deviation of the change 
from baseline in NRS was 1.45 (95% CI: 1.14 - 2.01). Using the upper bound of the 95% CI and 
applying an inflation factor of 1.3 (derived from the observed increase in standard deviation from 
week 2 to week 12 in the historical VAS study data) resulted in an estimated standard deviation of 
2.6. As this is very similar to, and lower than, the standard deviation originally used in the sample 
size estimation the estimated sample size required was not updated. 
11.3.1 Sample size re-estimation 
After at least 12 subjects in each cohort have completed Treatment Period B, the variance of the 
IPF Coughing Severity Scale data will be reviewed on a fully blinded basis. Additional subjects 
(up to a maximum of 10 per cohort) may be recruited if the emerging IPF Coughing Severity Scale 
data is found to have greater variance than allowed for in the original sample size estimate. Any 
possible impact on the type I error due to this blinded sample size re-assessment procedure is 
believed to be negligible [45]. 
11.4 
Estimand 
The primary objective of the study is to evaluate the efficacy of orvepitant as a treatment for 
chronic cough in patients with IPF.  
The treatment of interest is orvepitant (at a dose of 10 or 30 mg once daily). The effects of 
orvepitant will be compared to placebo.  
The population is patients with IPF and troublesome chronic cough in whom the cough is 
attributed to the IPF.  
The main variable being used to assess the estimand is the IPF Coughing Severity Scale. 
The estimand will be summarised by comparing the mean changes from baseline in weekly cough 
severity score for the orvepitant treatment period versus the placebo treatment period. 
Intercurrent events that are expected to occur during the study are initiation of concomitant 
medication, withdrawal from study treatment, withdrawals from the study due to death.  
A treatment policy strategy will be used for the initiation of concomitant medication as well as for 
early withdrawal from study treatment, essentially following the intention to treat principal. Any 
patients who discontinue treatment early will be followed up until the end of the study, with the 
aim of collecting all scheduled data.  

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A while on-treatment strategy will be used for withdrawal from the study due to death. All data for 
any subjects who die will be included up to the point of their withdrawal or death and no imputation 
will be made for any visits that may have occurred after the intercurrent event. 
The estimand can then be defined as the difference between orvepitant and placebo in the change 
from baseline in weekly IPF Coughing Severity Scale score, measured using an NRS, in patients 
with IPF and troublesome chronic cough in whom the cough is attributed to the IPF, regardless of 
their need for concomitant medications or whether they discontinue study treatment, up until they 
complete the study, withdraw from the study or die (whichever comes first).  
11.5 
Analysis Sets 
The following data sets will be used for the statistical analysis. 
1. Safety Set: All subjects who receive at least one dose of double-blind study drug 
irrespective of treatment received. Subjects will be analysed according to treatment 
received 
2. Full Analysis Set (FAS): All randomised subjects who received at least one dose of double-
blind study drug, irrespective of treatment received, and have sufficient IPF Coughing 
Severity Scale data for at least one post-treatment assessment. Subjects will be analysed 
according to randomised treatment. This is the primary efficacy analysis set for the study. 
3. Per Protocol (PP) Set: All subjects in the FAS excluding those identified as having a 
relevant protocol violation, where a relevant violation is one that potentially confounds the 
analysis of the primary efficacy endpoint. 
4. Exposure-Response (ER) Set: all subjects who received at least one dose of double-blind 
study drug and for whom the PK data are considered sufficient. 
Analysis Sets will be agreed at a blinded data review meeting prior to the unblinding of the study. 
11.6 
Data Analysis 
Full details of the proposed statistical analyses will be documented in the SAP. In the event that 
text pertaining to statistical analysis differs between the SAP and protocol, the text in the SAP will 
take precedence.  
Cohorts 1 and 2 will be analysed separately for efficacy.  
For continuous data and for ordered categorical data, if appropriate, the number of non-missing 
observations, mean, standard deviation, geometric mean (where appropriate), median, first and 
third quartiles, minimum and maximum will be calculated. For ordered categorical data and 
nominal data, absolute counts, and relative frequencies (in %) will be calculated. 
All statistical hypothesis tests and confidence intervals will be two sided, using a type I error rate 
of 0.05. No adjustment for multiple comparisons will be used for this study. 
All raw data will be listed. 
11.7 
Demographics and Baseline Characteristics 
Relevant Screening and Baseline data (i.e., data collected prior to the treatment administration) and 
demographic characteristics will be summarised descriptively for each treatment sequence and 
overall. 

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11.8 
Statistical Methods for Efficacy Parameters 
An analysis of covariance (ANCOVA) model will be used to assess the primary and secondary 
endpoints in the study.  It is expected that the response variable will be the change from baseline 
in the mean score at the later time point of interest, and the predictor variables will be treatment, 
baseline mean score for each endpoint, treatment*period.  Other covariates, such as age and sex, 
and their impact on the results may be done post-hoc. More details will be provided in the SAP. 
Selected efficacy parameters will be summarised and analysed for the following sub-groups: 
- 
By use of concomitant disease modifying therapies at Baseline (yes, no [nintedanib or 
pirfenidone]) 
- 
By IPF Coughing Severity Scale score at Baseline  
- 
By cough frequency at Baseline  
Other sub-groups (e.g., age, sex, ethnicity) will be evaluated if there are sufficient subjects to 
warrant analysis. 
11.9 
Statistical Methods for Safety Parameters 
Safety data will be summarised descriptively for each treatment. No formal inferential tests will be 
performed on safety data. 
The number of treatment emergent AEs (TEAEs), and subjects with TEAEs, will be compared 
between treatments. TEAEs are defined as AEs that first occurred or worsened in severity after the 
first dose of IMP.  
TEAEs will be summarised for all causality AEs and for treatment-related AEs (those with related 
relationship to IMP and missing). TEAEs will be summarised by MeDRA body system and 
preferred term. TEAEs will also be reported by severity. 
Any deaths, SAEs and AEs leading to discontinuation of IMP administration will also be 
summarised by treatment group. 
SAEs will be presented in a similar way to AEs. 
Vital signs will be summarised for each treatment group by visit. Summary statistics will be 
presented for absolute values and the change from Baseline. 
ECGs will be assessed by the Investigator for abnormal findings. These will be categorised and 
summarised as normal, abnormal-not clinically significant, or abnormal-clinically significant. ECG 
intervals will be recorded and summarised as absolute values and changes from Baseline.  
Clinical laboratory data for individual subjects will be listed and any out of range values will be 
highlighted. Laboratory data will be summarised for each treatment group by visit. Summary 
statistics will be presented for absolute values and change from Baseline, as well as an analysis of 
shifts from Baseline. 
Extent of exposure and compliance will be summarised. 
Selected safety parameters will be summarised for the following sub-groups: 
- 
By use of concomitant disease modifying therapies at Baseline (yes, no [nintedanib or 
pirfenidone]) 

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11.10 Pharmacokinetics Analysis 
The plasma orvepitant concentrations will used to confirm individual subject exposure to orvepitant 
and to explore exposure differences in the two doses being evaluated. The data may also be 
analysed using a population pharmacokinetic (Pop PK) approach by nonlinear mixed effects 
modeling (NONMEM®). The Pop PK model will be used to evaluate the relationship between 
orvepitant exposure and clinical endpoints. The details of the analysis will be described in a Pop 
PK Data Analysis Plan and the data will be reported separately from the safety and efficacy 
findings.  
11.11 Missing Data 
Summary statistics will be based primarily on non-missing values, with no imputation of any 
missing data (as per the strategies for treatment for the intercurrent events outlined in Section 11.4). 
For hypothesis tests, estimates and confidence intervals, missing values for continuous efficacy 
endpoints analysed via likelihood methods (e.g., repeated measures mixed models) will not be 
directly imputed as they are handled within the analysis itself, under the assumption that the model 
specification is correct, and that the data is missing at random. Sensitivity analyses may be 
conducted to check the robustness of the analysis results under alternative assumptions with regards 
to missing data. Further details on the handling of missing values, including rules applied to 
incomplete questionnaires and any planned sensitivity analyses will be defined in the SAP. 

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12. 
END OF THE STUDY 
The end of the study will be defined as the last subject
 

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13. 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
13.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and 
Relevant Authorities 
The final study protocol, the subject information and consent form and any other subject facing 
materials (e.g., questionnaires, advertisements) will be approved by an appropriately constituted 
IRB/IEC. Approval will be received in writing before initiation of the study. 
Clinical study authorisation will be obtained prior to initiation of the study from the relevant 
Regulatory Authority. 
13.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the local regulations, the principals of Good 
Clinical Practice (GCP) as described by the International Council for Harmonization (ICH), and 
the ethical principles that have their origins in the Declaration of Helsinki. 
13.3 
Informed Consent 
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the principal investigator or one of his/her associates will 
explain orally and in writing the nature, duration, purpose of the study, and the action of the study 
drug in such a manner that the subject is aware of the potential risks, inconveniences, or adverse 
effects that may occur. They will be informed that their medical records may be reviewed by 
appropriately qualified monitors of the Sponsor or Sponsor Representative, and by auditors or 
regulatory authorities to ensure the accuracy of the details recorded as part of the study. They will 
be informed that they may withdraw from the study at any time without prejudice to further 
treatment. They will receive all information that is required by local regulations and ICH 
guidelines.  

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14. 
STUDY AND DATA MANAGEMENT 
14.1 
Protocol Amendments 
Once approved by the applicable Regulatory Authorities and IRBs/IECs, the protocol must not be 
amended without approval by NeRRe. Unless an amendment is required to be implemented 
urgently in the interests of safety, or is deemed administrative by NeRRe, any amendments to the 
protocol must be authorised by the applicable Regulatory Authorities and IRB/IEC prior to 
implementation. 
14.2 
Monitoring 
In accordance with applicable regulations including GCP and NeRRe 
Operating Procedures (SOP), approved clinical research monitors will contact the site prior to the 
start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and NeRRe requirements. When reviewing data 
collection procedures, the discussion will also include identification, agreement and documentation 
of data items for which the eCRF will serve as the source document. A list of what is to be classed 
Plan. 
NeRRe will monitor the study and sites to verify: 
 Data are authentic, accurate and complete 
 Safety and right of the subjects are being protected 
 IMP accountability 
 SAE reporting 
 Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP and all applicable regulatory requirements 
The investigator[s]/institution[s] will permit study-related monitoring, providing direct access to 
source data/documents. 
14.3 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the 
investigator[s]/institution[s] will permit study-related audits, IRB/IEC review, and regulatory 
inspection[s], providing direct access to source data/documents. 
14.4 
Data Recording 
14.4.1 
Data to be Considered as Source Data 
An eCRF will be used to capture subject data into a secure, validated database. Access to enter data 
in the eCRF will be limited to delegated and trained investigator site staff only. eDiary, tablet (for 
questionnaires), ACM and safety laboratory data will be transferred electronically into the database 
periodically during the study. PK and biomarker data will be transferred electronically into the 
database at study end. 
Source data may be defined as information from an original record or certified copy of the original 
record containing patient information for use in the trial.  The information may include, but is not 
limited, to clinical findings, observations, or other activities necessary for the reconstruction and 
evaluation of the trial.  Source data are contained in source documents (original records or certified 

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copies) (ICH E2A Guideline). Examples of source data include subject identification and 
randomisation identification.  
14.5 
Confidentiality 
The Investigator must assure that the subjects
anonymity will be maintained. On all study 
documentation, with the exception of the consent form and subject ID logs, subjects will only be 
identified by their unique identification code and will not be referred to by name. 
Study data will be handled with utmost discretion within the c
On the eCRFs and other study specific documents, subjects are not identified by their names, but 
by a unique subject number. Names of participating subjects and data generated as a result of this 
study will not be passed on to unauthorised persons. 
The Investigator must assure that the subjects are properly anonymised throughout the study. On 
all study documentation which is intended to leave the site (i.e., to be transmitted to NeRRe, CRO 
or third parties), subjects will only be identified by their unique identification code and will not be 
referred to by name. 
NeRRe may transfer some data collected during the study to a different company or regulatory 
authority outside of the US or EU for the purpose of processing, review, analysis or storage. 
used only for the purpose for which it was collected. 
Safety and biomarker analysis samples collected during the study will be analysed at a central 
laboratory. 
 All safety 
samples will be destroyed after the assays have been completed. 
Blood samples for analysis of orvepitant concentrations will be shipped to Aptuit Srl, Italy for 
analysis. 
Following 
completion of the analysis, all samples will be destroyed. 
14.6 
Retention of Study Data 
Following closure of the study, the Investigator must maintain all site study records, except for 
those required by local regulations to be maintained by someone else, in a safe and secure location. 
The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and staff. Where permitted by local laws/ regulations 
or institutional policy, some or all of these records can be maintained in a format other than hard 
copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such 
action is taken. The Investigator must assure that all reproductions are legible and are a true and 
accurate copy of the originals, and meet accessibility and retrieval standards, including re-
generating a hard copy, if required. Furthermore, the Investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for making 
these reproductions. 
NeRRe will inform the Investigator of the time period for retaining these records to comply with 
all applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that site for the study, as dictated by any institutional requirements or local laws or 
regulations, or NeRRe, 
25 years. 
The Investigator must notify NeRRe of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event the 

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Investigator leaves the site. The Investigator may not dispose of any records without prior approval 
from NeRRe. 
14.7 
Communication and Publication of Results 
Where required by applicable regulatory requirements, an Investigator signatory will be identified 
for the approval of the clinical study report (CSR). The Investigator will be provided appropriate 
access to statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results at NeRRe or another mutually agreeable location. 
The original eCRFs and all data generated during the study under this protocol will become the 
property of the Sponsor. 
Information about the study will be posted to a publicly available website such as 
(clinicaltrials.gov). Upon completion of the CSR, NeRRe will ensure public disclosure of the 
clinical trial research results according to NeRRe  SOP.  A summary of the results will be posted 
to the public website.  
It is the intent of all parties that the results of the study be published at an appropriate scientific 
conference and/or in a peer-reviewed journal in a timely manner consistent with academic 
standards and with due consideration given to the protection of intellectual property rights. The 
Chief Investigator and NeRRe will be responsible for assembling the proposed publication; this 
must happen with due diligence and with minimal delay.  
Any proposed publication or presentation (including a manuscript, abstract or poster) initiated by 
an Investigator for submission to a journal or scientific meeting should be sent to the Sponsor for 
review at least sixty (60) days prior to submission. The Sponsor's comments on the proposed 
publication shall be considered in good faith by the authors. Sponsor may delay such submission 
by a maximum of six months if it reasonably believes that publication of results may compromise 
its intellectual property rights or else insist that such information or data is removed from the 
proposed publication. Publication of the results will not include confidential information without 
the permission of the Sponsor. 
14.8 
Indemnification 
In the event of study-related damage or injuries, the clinical trial insurance of the Sponsor provides 
compensation for claims that arise in accordance with the regulatory requirements of the countries 
involved, except for claims that arise from willful misconduct or gross negligence. A copy of the 
country-specific insurance certificates will be held in the TMF and in the Investigator Site File. 
 
 

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15. 
REFERENCES 
1. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810 816. 
2. https://www.nice.org.uk/guidance/qs79/chapter/Introduction (Last accessed September 2021) 
3. American Thoracic Society, European Respiratory Society, American Thoracic Society. Idiopathic 
pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic 
Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 
2000;161:646 664. 
4. Behr J, Kreuter M, Hoeper MM, Wirtz H, Klotsche J, Koschel D, et al. Management of patients with 
idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. Eur Respir J 
2015;46:186 196. 14. 
5. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al. High prevalence of 
abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136
142. 15.  
6. Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of 
gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 
1998;158: 1804 1808. 
7. Meltzer EB & Noble PW. Idiopathic Pulmonary Fibrosis. Orphanet Journal of Rare Diseases 2008;3:8 
8. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial 
pneumonias. Proc Am Thorac Soc. 2006;3(4):285-292. 
9. van Manen M, Birring S, Vancheri C, Cottin V, Renzoni E, Russell A & Wijsenbeek M. Cough in 
idiopathic pulmonary fibrosis. European Respiratory Review 2016; 25: 278-286 
10. Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA). The 
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Focused 
Drug 
Development 
Initiative. 
Idiopathic 
Pulmonary 
Fibrosis. 
March 
2015.  
https://www.fda.gov/media/91396/download Date last updated: March 2015. Date last accessed: April 
2021. 
11. 
m diary for 
clinical studies of idiopathic pulmonary fibrosis. Respir Med 2018;134:130-138. 
12. Guenther A, Krauss E, Tello S, et al. . The European IPF registry (eurIPFreg): baseline characteristics 
and survival of patients with idiopathic pulmonary fibrosis. Respir Res 2018; 19: 141. 
13. Key AL, Holt K, Hamilton A, Smith JA, Earis JE. Objective cough frequency in idiopathic pulmonary 
fibrosis. Cough 2010;6:4e10. 
14. Swigris JJ, Stewart AL, Gould MK, et al. 
affects the quality of their lives. Health Qual Life Outcomes 2005; 3: 61. 
15. Birring S, Wijsenbeek M, Agrawal S, et al. A novel formulation of inhaled sodium cromoglicate 
(PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-
concept, phase 2 trial. Lancet Respir Med 2017; 5:806-815 
16. Morice AH, Fontana GA & Belvisi MG. ERS guidelines on the assessment of cough Eur Respir J, 29: 
1256-1276, 2007 
17. Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure for 
patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58: 339 343. 
18. Van Manen M & Wijsenbeek M. Cough, an unresolved problem in interstitial lung diseases. Curr Opin 
Support Palliat Care 2019, 13:143 151 
19. Jones R, Hilldrup S, Hope-Gill B, Eccles R & Harrison N. Mechanical induction of cough in 
Idiopathic Pulmonary Fibrosis. Cough 2011;7:2-11. 
20. Doherty MJ, Mister R, Pearson MG & Calverley PM. Capsaicin induced cough in cryptogenic 
fibrosing alveolitis. Thorax 2000;55:1028 1032 

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21. Hope-Gill B, Hilldrup S, Davies C, Newton R & Harrison N. A Study of the Cough Reflex in 
Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2003;168:995 1002. 
22. Singh N, Driessen A, McGovern A, Moe A, Farrell M & Mazzone. Peripheral and central mechanisms 
of cough hypersensitivity. J Thorac Dis 2020;12:5179-5193. 
23. Smith J, Kitt M, Morice A, Birring S, McGarvey L, Sher M et al. Gefapixant, a P2X3 receptor 
antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, 
controlled, parallel-group, phase 2b trial. 2020;8:775-785. 
24. Chen CY, Joad JP, Bric J, Bonham AC. Central mechanisms I: plasticity of central pathways. Handb 
Exp Pharmacol 2009;(187):187-201.  
25. Canning BJ. Central regulation of the cough reflex: therapeutic implications. Pulm Pharmacol Ther 
2009;22(2):75-81. 
26. Lavinka PC, Dong X. Molecular signaling and targets from itch: lessons for cough. Cough 2013;9(1):8. 
27. Mazzone S & McGarvey L. Mechanisms and Rationale for Targeted Therapies in Refractory and 
Unexplained Chronic Cough. Clin Pharmacol Ther. 2021 Mar;109(3):619-636 
28. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP. Increased tachykinin levels in 
induced sputum from asthmatic and cough patients with acid reflux. Thorax 2007;62(6):491-5. 
29. Lim KG, Rank MA, Kita H, Patel A, Moore E. Neuropeptide levels in nasal secretions from patients 
with and without chronic cough. Ann Allergy Asthma Immunol 2011;107(4): 360-3. 
30. Otsuka K, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H, et al. Plasma substance P levels 
in patients with persistent cough. Respiration 2011;82(5):431-8. 
31. Qiu Z, Yu L, Xu S, Liu B, Zhao T, Lü H, et al. Cough reflex sensitivity and airway inflammation in 
patients with chronic cough due to non-acid gastro-oesophageal reflux. Respirology 2011;16(4):645-
52. 
32. Katsumata U, Sekizawa K, Inoue H, Sasaki H, Takishima T. Inhibitory actions of procaterol, a beta-2 
stimulant, on substance P-induced cough in normal subjects during upper respiratory tract infection. 
Tohoku J Exp Med 1989;158(1):105-6. 
33. Mazzone SB, Mori N, Canning BJ. Synergistic interactions between airway afferent nerve subtypes 
regulating the cough reflex in guinea-pigs. J Physiol. 2005;569(Pt 2):559-73. 
34. Pacheco A. Chronic cough: from a complex dysfunction of the neurological circuit to the production 
of persistent cough. Thorax 2014; 69: 881 883. 
35. Morice AH, Millqvist E, Belvisi MG, et al. Expert opinion on the cough hypersensitivity syndrome in 
respiratory medicine. Eur Respir J 2014; 44: 1132 1148. 
36. Song W-J & Morice A. Cough Hypersensitivity Syndrome: A Few More Steps Forward. Allergy 
Asthma Immunol Res. 2017;9:394-402. 
37. Cho PSP, Fletcher HV, Turner RD, et al. Impaired cough suppression in chronic refractory cough. Eur 
Respir J 2019; 53: 
38. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-
blind, placebo-controlled trial. Lancet. 2012. Epub ahead of print. [PubMed] 
39. Yousaf N, Monteiro W, Parker D, Matos S, Birring S, Pavord ID. Long-term low-dose erythromycin in 
patients with unexplained chronic cough: a double-blind placebo controlled trial. Thorax. 
2010;65:1107 1110.  
40. Yousaf N, Monteiro W, Matos S, Birring S and Pavord I. Cough frequency in health and disease. Eur 
Respir J 2013;41:241-3 
41. Vertigan, A.E. & Gibson, P.G. Chronic refractory cough as a sensory neuropathy: evidence from a 
reinterpretation of cough triggers. J. Voice. 25, 596 601 (2011). 

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42. Mcgarvey L, Birring S, Dicpinigaitis P, Morice A, Pavord I, Smith J, et al. Efficacy in Predefined 
Subgroups of Patients with Chronic Cough Treated with Gefapixant in Two Phase 3 Randomised 
Controlled Clinical Trials. Presented at American Thoric Society Conference, May 2021 (online 
meeting) 
43. Smith J, Morice A, Mcgarvey L, Pavord I, Birring S, Dicpinigaitis P, et al. Objective Cough Frequency 
with Gefapixant in Chronic Cough: A Pooled Analysis of Two Phase 3 Randomised, Controlled Clinical 
Trials (COUGH-1 and COUGH-2). Presented at American Thoric Society Conference, May 2021 
(online meeting) 
44. Birring S, Morice A, Smith J, McGarvey L, Pavord I, Nguyen A, et al. Responder Analyses for Patient-
Reported Outcomes in a Pooled Analysis of Two Phase III Randomised Placebo Controlled Trials of 
Gefapixant, a P2X3 Receptor Antagonist for the Treatment of Chronic Cough. Presented at American 
Thoric Society Conference, May 2021 (online meeting) 
45. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the type 1 
error rate. Statist. Med 2003; 22:3571-3581. 
 
 
 

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Principal Investigator Agreement 
 
I agree to conduct the study according to the terms and conditions of this protocol, current Good 
Clinical Practice and with applicable regulatory requirements. All information pertaining to the 
study shall be treated in a confidential manner. 
 
 
 
 
Signature: 
_______________________________________          
 
 
                     
 
 
 
Name of Principal Investigator: 
 
 
 
Title: 
 
 
 
Date: 
 
 

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17. 
APPENDICES 
 
Appendix 1:  
Prohibited Concomitant Medications 
 
Appendix 2: 
Numerical /verbal rating scales for cough severity, urge to cough, cough 
frequency and dyspnoea 
 
Appendix 3:  
Global ratings of status and change in cough severity  
 
Appendix 4:  
Leicester Cough Questionnaire  
 
Appendix 5:  
Kings Brief Interstitial Lung Disease Questionnaire 
 
Appendix 6:  
PROMIS SD SF 8b sleep questionnaire 
 
Appendix 7:  
Hospital Anxiety and Depression Scale 
 
Appendix 8:  
Hull Airway Reflux Questionnaire 
 
 

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17.1 
APPENDIX 1: Prohibited Concomitant Medications 
Prohibited for the periods shown  
Medications potentially 
confounding efficacy  
Prescription Treatments 
Due to their potential effect on cough reflex sensitivity, the use of 
opioids, dextromethorphan, gabapentin, pregabalin, baclofen, 
antihistamines, 
thalidomide, 
benzonatate 
or 
tricyclic 
antidepressants (e.g. amitriptyline) is not permitted from 4 weeks 
before Visit 2 until completion of Visit 8. Subjects may, however, 
be permitted to continue to use these drugs if the dose has been 
stable for at least 4 weeks before Screening and they have been 
prescribed solely for the management of another disorder (e.g. 
neuropathic pain, depression). 
Immune-suppressant drugs and systemic corticosteroids taken for 
co-morbidities are permitted provided the dose has been stable for 
at least 2 weeks before the screening visit and they are expected 
to be used at this dose throughout the study. Any other use is 
prohibited.  
The use of other NK1 antagonists (eg aprepitant, fosaprepitant, 
rolapitant) is not permitted for any reason from 4 weeks before the 
Baseline visit until completion of Visit 8.  
Angiotensin converting enzyme (ACE) inhibitors are not allowed 
within 3 months of Screening and throughout the study. 
Note: Throat or cough lozenges (also known as a candies, drops, 
sweets or pastilles) and mucolytic agents are permitted. 
Prohibited from the day of Visit 2 until one week after the last dose of study medication 
Strong inhibitors of 
CYP3A4 (± P-
glycoprotein) 
atazanavir, boceprevir, cobicistat, clarithromycin, danoprevir and 
ritonavir, elvitegravir and ritonavir, idelalisib, indinavir and 
ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, 
nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir), posaconazole, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, 
voriconazole 
 
Moderate inhibitors of 
CYP3A4 
ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, 
dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, 
tofisopam, verapamil 
Prohibited from the Screening visit until one week after the last dose of study medication 
Strong or moderate P-
glycoprotein inhibitors 
amiodarone, carvedilol, lapatinib, propafenone, quinidine, 
ranolazine 
 

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17.2 
APPENDIX 2: Numerical / Verbal Rating Scales  
 
IPF Cough Severity Scale 
How severe was your coughing in the last 24 hours at its worst? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
coughing 
 
 
 
 
 
 
 
 
 
Coughing 
as bad as 
you can 
imagine 
  
Additional Cough Severity Scales 
Early Morning Cough Scale 
How severe was your coughing first thing this morning on waking or rising? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
coughing 
 
 
 
 
 
 
 
 
 
Coughing 
as bad as 
you can 
imagine 
 
Rest of the Day Cough Scale 
How severe was any other coughing during the last 24 hours at its worst, excluding any 
coughing first thing this morning? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
coughing 
 
 
 
 
 
 
 
 
 
Coughing 
as bad as 
you can 
imagine 
 
Other Symptom Scales 
Urge to Cough Scale 
How severe was your urge to cough in the last 24 hours at its worst? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No urge 
to cough 
 
 
 
 
 
 
 
 
 
Urge to 
cough as 
bad as 
you can 
imagine 
 
 

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Dyspnoea Scale 
How severe was your shortness of breath in the last 24 hours at its worst? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
shortness 
of breath 
 
 
 
 
 
 
 
 
 
Shortness 
of breath 
as bad as 
you can 
imagine 
 
Cough Frequency Scale 
How often did you cough in the last 24 hours? Select one answer  
Never  
Rarely  
Sometimes 
 
Often  
All the time 
 
 

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17.3 
APPENDIX 3: Patient Global Ratings 
 
Patient Global Ratings of Status 
 
GRS Question 1 
Please select the response that best describes how severe your coughing was in the last week: 
 
 
 
None, mild, moderate, severe, very severe 
 
GRS Question 2 
Please select the response that best describes how severe your coughing was first thing in the 
morning on waking or rising in the last week: 
 
 
 
None, mild, moderate, severe, very severe 
 
GRS Question 3 
Please select the response that best describes how severe any other coughing was, excluding any 
coughing first thing in the morning, during the last week: 
 
 
 
None, mild, moderate, severe, very severe 
 
Patient Global Ratings of Change 
 
GRC Question 1 
Please select the response that best describes the change in your coughing since the start of the 
study: 
 
-3 
-2 
-1 
0 
1 
2 
3 
Very 
much 
worse 
Somewhat 
worse 
Slightly 
worse 
No 
change 
Slightly 
better 
Somewhat 
better 
Very 
much 
better 
 
GRC Question 2 
Please select the response that best describes the change in your coughing first thing in the 
morning on waking or rising since the start of the study: 
 

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-3 
-2 
-1 
0 
1 
2 
3 
Very 
much 
worse 
Somewhat 
worse 
Slightly 
worse 
No 
change 
Slightly 
better 
Somewhat 
better 
Very 
much 
better 
 
 
GRC Question 3 
Please select the response that best describes the change in any other coughing, excluding any 
coughing first thing in the morning, since the start of the study: 
 
-3 
-2 
-1 
0 
1 
2 
3 
Very 
much 
worse 
Somewhat 
worse 
Slightly 
worse 
No 
change 
Slightly 
better 
Somewhat 
better 
Very 
much 
better 
 

Product:  
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ORVEPITANT 
 
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Protocol No.: ORV-PF-01 
Final V4.0 (US) 
Page 80 of 85 
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Protocol No.: ORV-PF-01 
Final V4.0 (US) 
Page 82 of 85 
16-MAY-2024 
17.6 
APPENDIX 6: PROMIS SD SF 8b Sleep Questionnaire 
Note: The version of the PROMIS SD SF 8b provided in this appendix is for reference only and 
may differ slightly from the actual versions used on the study. A license to use the PROMIS SD 
SF 8b for the purpose of the study will be obtained prior to study start. 
 
 

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17.7 
APPENDIX 7: Hospital Anxiety and Depression Scale  
Note: The version of the HADs provided in this appendix is for reference only and may differ 
slightly from the actual versions used on the study. A license to use the HADS for the purpose of 
the study will be obtained prior to study start. 
 
 
 

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HADS copyright © R.P. Snaith and A.S. Zigmond, 1983, 1992, 1994. 
Record form items originally published in Acta Psychiatrica Scandinavica 67, 361 70, copyright 
© Munksgaard International 
Publishers Ltd, Copenhagen, 1983. 
This edition first published in 1994 by nferNelson Publishing Company Ltd (now GL Assessment 
Ltd),1st Floor Vantage London, Great West Road, Brentford TW8 9AG 
GL Assessment Ltd is part of the GL Education Group.  
www.gl-assesssment.co.uk  
 
 
 

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