Conditions: Refractory and/or Unexplained Chronic Cough
Keywords: RUCC Chronic cough P2X3 receptor antagonist
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 310
Healthy volunteers: no

Brief summary:
Researchers in this study want to find the optimal therapeutic dose of drug BAY1817080 for patients with long-standing cough with or without clear causes (refractory and/or unexplained chronic cough, RUCC). Study drug BAY1817080 is a new drug under development for the treatment of long-standing cough. It blocks proteins that are expressed by the airway sensory nerves which are oversensitive in patients with long-standing cough. This prevents the urge to cough. Researchers also want to learn the safety of the study drug and how well it works in reducing the cough frequency, severity and urge-to-cough.

Participants in this study will receive either the study drug or placebo (a placebo looks like the test drug but does not have any medicine in it) tablets twice daily for 12 weeks. Observation for each participant will last about 18 weeks in total. Participants will be asked to wear a digital device to record the cough and to complete questionnaires every day to document the symptoms. Blood samples will be collected from the participants to monitor the safety and measure the blood level of the study drug.

Detailed description:

Arms:
arm 1: Each participant will be randomized to receive one of three oral doses of BAY 1817080 or placebo, administered twice daily over the course of 12 weeks. arm 2: Each participant will be randomized to receive one of three oral doses of BAY 1817080 or placebo, administered twice daily over the course of 12 weeks. arm 3: Each participant will be randomized to receive one of three oral doses of BAY 1817080 or placebo, administered twice daily over the course of 12 weeks. arm 4: Each participant will be randomized to receive one of three oral doses of BAY 1817080 or placebo, administered twice daily over the course of 12 weeks.

Interventions: intervention 1: BAY1817080 intervention 2: Placebo
Intervention descriptions: intervention 1: Study drug BAY1817080 will be administered orally as tablet. intervention 2: Matching Placebo for BAY1817080 will be administered orally as tablet.

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
Randomized, double-blind, parallel group, phase 2b dose-finding, 
efficacy and safety study of 12-week twice daily oral administration 
of BAY 1817080 compared to placebo in the treatment of refractory 
and/or unexplained chronic cough (RUCC) 
NCT Number: 
NCT04562155  
Document Date: 
28-Apr-2021 
 


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Title Page
Protocol Title: 
Randomized, double-blind, parallel group, Phase 2b dose-finding, efficacy and safety study of 
12-week twice daily oral administration of BAY 1817080 compared to placebo in the 
treatment of refractory and/or unexplained chronic cough (RUCC)
Protocol Number:
20393
Protocol Version:
3.0
Amendment Number:
2
Compound Number:
BAY 1817080
Study Phase:
Phase 2b
Short Title:
Dose-finding, efficacy and safety study of BAY 1817080 in the 
treatment of refractory and/or unexplained chronic cough
Acronym:
PAGANINI
Sponsor Name and Legal Registered Address:  
Non-US:
Bayer AG
D-51368 Leverkusen, Germany
US Territory:
Bayer Healthcare Pharmaceuticals Inc.
100 Bayer Boulevard, P.O. Box 915
Whippany NJ 07981-0915, USA
Regulatory Agency Identifier Numbers:
IND:
139697
EudraCT:
2019-004169-42
Protocol Amendment Date: 
28 APR 2021
Name:
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Medical Monitor name and contact information will be provided separately.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation.  Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD


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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
28 APR 2021
Amendment 1
17 JUL 2020
Amendment CZE-1
30 APR 2020
Original Protocol
19 DEC 2019
Amendment 2 (28 APR 2021)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
The main purpose of this amendment is to remove the description of the interim analysis. Due 
to unexpectedly rapid recruitment, the amount of 12-week efficacy and safety data at the 
planned interim analysis would not have been sufficient for a preliminary dose decision. 
Therefore, no interim analysis will be performed.
Section #
and Name
Description of Change
Brief Rationale
9.5 Interim Analyses
Description of interim analyses 
was deleted and the statement 
“not applicable to this study“ was 
included.
Due to unexpectedly rapid 
progression of the study, no
interim analysis will be performed. 
Primary analysis will be 
conducted once all participants 
have completed 12 weeks of 
intervention, as described in 
Section 9.4.2. 
9.4.1 General 
considerations
The term “database lock“ was 
changed to “unblinding of the 
database”.
To reflect the current convention 
in terminology of the company
4.3 Justification for Dose
The values of awake cough 
counts obtained from the proof of 
concept study for RUCC (study 
18184) were corrected (26.1% 
instead of 21.1% for the maximum 
technically feasible dose of 750 
mg BID or the next lower dose of
200 mg BID of BAY 1817080 and 
24.4% instead of 22.5% for the 
placebo).
Correction of error
Title page
Sponsor signatory was removed 
and a statement added that this is 
an electronically generated 
document that does not bear any 
sponsor signatures.
To reflect the current convention
of the company
Title page
The name of the sponsor’s 
medically responsible person was 
updated.
The previous medically 
responsible person is no longer 
involved in this study


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Section #
and Name
Description of Change
Brief Rationale
Title page
Header throughout the 
document
Protocol version number was 
included in the Title page and 
removed from the header. Date 
was added in the header.
To reflect the current convention
of the company


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Table of Contents
Title Page................................................................................................................................... 1
Protocol Amendment Summary of Changes Table............................................................... 2
Table of Contents ..................................................................................................................... 4
Table of Tables ......................................................................................................................... 6
Table of Figures........................................................................................................................ 7
1.
Protocol Summary ............................................................................................................ 8
1.1
Synopsis........................................................................................................................... 8
1.2
Schema........................................................................................................................... 10
1.3
Schedule of Activities (SoA) ......................................................................................... 11
2.
Introduction..................................................................................................................... 14
2.1
Study Rationale.............................................................................................................. 15
2.2
Background.................................................................................................................... 15
2.3
Benefit/Risk Assessment ............................................................................................... 15
2.3.1
Summary..................................................................................................................... 15
2.3.2
Potential Benefits........................................................................................................ 16
2.3.3
Risks and Undesirable Effects.................................................................................... 16
2.3.3.1
Taste-Related AEs................................................................................................... 16
2.3.3.2
Antithrombin III Activity Increase.......................................................................... 17
2.3.3.3
Potential Decrease in Heart Rate and Diastolic Blood Pressure............................. 17
2.3.3.4
Potential Changes in Liver Function Laboratory Parameters ................................. 18
2.3.3.5
Reproductive Toxicity............................................................................................. 18
2.3.3.6
Potential Phototoxicity............................................................................................ 18
2.3.3.7
Risk of contracting SARS-CoV-2 infection during study participation ................. 19
3.
Objectives and Endpoints............................................................................................... 20
4.
Study Design .................................................................................................................... 23
4.1
Overall Design ............................................................................................................... 23
4.1.1
Pre-Intervention Period............................................................................................... 23
4.1.2
Intervention Period ..................................................................................................... 23
4.1.3
Post-Intervention Period............................................................................................. 23
4.2
Scientific Rationale for Study Design ........................................................................... 24
4.3
Justification for Dose..................................................................................................... 25
4.4
End of Study Definition................................................................................................. 28
5.
Study Population............................................................................................................. 28
5.1
Inclusion Criteria ........................................................................................................... 28
5.2
Exclusion Criteria .......................................................................................................... 28
5.3
Lifestyle Considerations ................................................................................................ 30
5.4
Screen Failures............................................................................................................... 30
6.
Study Intervention .......................................................................................................... 31
6.1
Study Interventions Administered ................................................................................. 31
6.1.1
Medical Device........................................................................................................... 32
6.2
Preparation/Handling/Storage/Accountability............................................................... 32
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 32
6.4
Study Intervention Compliance ..................................................................................... 34


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6.5
Prior and Concomitant Therapy..................................................................................... 34
6.5.1
Other Treatment Considerations................................................................................. 36
6.6
Dose Modification ......................................................................................................... 37
6.7
Intervention after the End of the Study.......................................................................... 37
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 37
7.1
Discontinuation of Study Intervention........................................................................... 37
7.1.1
Rechallenge ................................................................................................................ 38
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 39
7.3
Lost to Follow Up.......................................................................................................... 39
8.
Study Assessments and Procedures............................................................................... 40
8.1
Efficacy Assessments .................................................................................................... 40
8.1.1
Cough Count Measurement........................................................................................ 40
8.1.2
Electronic Patient Reported Outcomes (ePROs)........................................................ 40
8.1.2.1
Severity of Chronic Cough Diary (SCCD) ............................................................. 42
8.1.2.2
Cough Severity Visual Analog Scale...................................................................... 42
8.1.2.3
Patient Global Impression of Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C)....................................................................................................... 43
8.1.2.4
Leicester Cough Questionnaire ............................................................................... 43
8.1.2.5
EQ-5D-5L................................................................................................................ 44
8.2
Safety Assessments........................................................................................................ 45
8.2.1
Physical Examinations................................................................................................ 45
8.2.2
Vital Signs .................................................................................................................. 45
8.2.3
Electrocardiograms..................................................................................................... 45
8.2.4
Spirometry (Lung Function Test)............................................................................... 45
8.2.5
Clinical Safety Laboratory Assessments .................................................................... 46
8.3
Adverse Events and Serious Adverse Events ................................................................ 47
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 47
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 48
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 48
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 48
8.3.5
Pregnancy ................................................................................................................... 49
8.3.6
Liver-Related AEs...................................................................................................... 49
8.4
Treatment of Overdose .................................................................................................. 51
8.5
Pharmacokinetics........................................................................................................... 51
8.6
Pharmacodynamics ........................................................................................................ 53
8.7
Genetics ......................................................................................................................... 54
8.8
Biomarkers..................................................................................................................... 54
8.8.1
Biomarkers Monitoring Disease Activity................................................................... 54
8.8.2
Pharmacogenetic Biomarkers..................................................................................... 54
8.8.3
Other Biomarkers ....................................................................................................... 55
8.9
Health Economics / Medical Resource Utilization and Health Economics................... 55
9.
Statistical Considerations ............................................................................................... 55
9.1
Statistical Hypotheses.................................................................................................... 55
9.2
Sample Size Determination ........................................................................................... 55
9.3
Populations for Analyses ............................................................................................... 56
9.4
Statistical Analyses........................................................................................................ 56
9.4.1
General considerations ............................................................................................... 56


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9.4.2
Primary Endpoints...................................................................................................... 57
9.4.3
Secondary Endpoints.................................................................................................. 59
9.4.4
Exploratory Endpoints................................................................................................ 60
9.4.5
Other Safety Endpoints............................................................................................... 60
9.4.6
Other Analyses ........................................................................................................... 60
9.5
Interim Analyses............................................................................................................ 60
10. Supporting Documentation and Operational Considerations .................................... 60
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 60
10.1.1
Regulatory and Ethical Considerations ...................................................................... 60
10.1.2
Financial Disclosure ................................................................................................... 61
10.1.3
Informed Consent Process.......................................................................................... 61
10.1.4
Data Protection ........................................................................................................... 61
10.1.5
Committees Structure ................................................................................................. 61
10.1.6
Dissemination of Clinical Study Data ........................................................................ 62
10.1.7
Data Quality Assurance.............................................................................................. 62
10.1.8
Source Documents...................................................................................................... 63
10.1.9
Study and Site Start and Closure................................................................................ 63
10.1.10 Publication Policy....................................................................................................... 63
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 64
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 66
10.3.1
Definition of AE......................................................................................................... 66
10.3.2
Definition of SAE....................................................................................................... 67
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 68
10.3.4
Reporting of SAEs...................................................................................................... 69
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 71
10.5
Appendix 5: Device Malfunction or Failure and Medical Device Related Events 
Reporting ....................................................................................................................... 74
10.6
Appendix 6: Country-specific Requirements ................................................................ 75
10.7
Appendix 7: Abbreviations............................................................................................ 76
10.8
Appendix 8: Protocol Amendment History ................................................................... 80
10.8.1
Amendment 1 (17 JUL 2020)..................................................................................... 80
10.9
References...................................................................................................................... 83
Table of Tables
Table 6–1: Study Interventions Administered ......................................................................... 32
Table 6–2: Prohibited Prior and Concomitant Therapy ........................................................... 35
Table 6–3: Medication Permitted on Stable Dose.................................................................... 36
Table 7–1: Liver Safety-Related Monitoring and Discontinuation Criteria ............................ 38
Table 8–1: Close Observation Liver Safety Required Laboratory Assessments ..................... 50
Table 8–2: PK Sampling (Visit 2)............................................................................................ 52
Table 8–3: PK Sampling (Visits 4 and 5) ................................................................................ 52
Table 8–4: PK Sampling (Visit 6)............................................................................................ 53
Table 9–1: Dose-Response Candidate Models......................................................................... 58
Table 10–1: Protocol-Required Safety Laboratory Assessments............................................. 65


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Table of Figures
Figure 1–1: Study design.......................................................................................................... 10
Figure 4–1: Model-Based Predicted Average Concentrations After Administration of 25, 75 
and 150 mg BID of BAY 1817080 Formulation B............................................... 27
Figure 9–1: Candidate Set of Dose Response Curves.............................................................. 58


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1.
Protocol Summary
1.1
Synopsis
Protocol Title: Randomized, double-blind, parallel group, Phase 2b dose-finding, efficacy 
and safety study of 12-week twice daily oral administration of BAY 1817080 compared to 
placebo in the treatment of refractory and/or unexplained chronic cough (RUCC)
Short Title: Dose-finding, efficacy and safety study of BAY 1817080 in the treatment of 
RUCC
Rationale: The objective of this study is to identify the optimal dose of P2X3 receptor 
antagonist BAY 1817080 in patients with RUCC and further assess efficacy and characterize 
safety and tolerability profile of BAY 1817080.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Primary Efficacy Endpoints

Assess the efficacy of P2X3 
receptor antagonist BAY 1817080 
as compared with placebo in 
terms of change in 24-hour cough 
count from baseline to week 12 

Change from baseline in 24-hour cough count 
(measured by cough recording digital wearable 
monitoring device) after 12 weeks of intervention
Secondary
Secondary Endpoints

Further assess efficacy of 
BAY 1817080
Secondary Efficacy Endpoints

Percentage of participants with a ≥30% reduction 
from baseline in 24-hour cough count after 12 
weeks of intervention (measured by cough 
recording digital wearable monitoring device)

Change from baseline in 24-hour cough count after 
2, 4, and 8 weeks of intervention (measured by 
cough recording digital wearable monitoring 
device)

Change from baseline in awake cough frequency 
per hour after 2, 4, 8 and 12 weeks of intervention 
(measured by cough recording digital wearable 
monitoring device)

Change from baseline in cough related quality of 
life (measured by Leicester Cough Questionnaire 
[LCQ]) after 12 weeks of intervention

Change from baseline in cough severity after 12 
weeks of intervention (measured by Cough 
Severity Visual Analogue Scale [VAS])

Percentage of participants with a ≥30 scale units 
reduction from baseline after 12 weeks of 
intervention (measured by cough Severity VAS)

Percentage of participants with a ≥1.3-point 
increase from baseline after 12 weeks of 
intervention (measured with LCQ Total Score)

Further characterize safety and 
tolerability profile of BAY 1817080
Safety and Tolerability Evaluation

Frequency and associated severity of treatment-
emergent adverse events (TEAEs)


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Overall Design:
Disclosure Statement:
This is a double-blind, parallel group intervention study.
Intervention Model:
Parallel group
Primary Purpose:
Treatment
Number of Arms:
4 arms including
o
Active intervention: 150 mg BID
o
Active intervention: 75 mg BID
o
Active intervention: 25 mg BID
o
Placebo
Blinding:
Participant, investigator and sponsor
Number of Participants:
Approximately 337 participants will be screened to achieve 236
randomly assigned to study intervention and 200 evaluable participants for an estimated total 
of 50 evaluable participants per intervention group.
Intervention Groups and Duration:
Study periods
Duration
Screening
Intervention
Safety Follow-up
14 days (2 weeks)
84 days (12 weeks)
30 days (approximately 4 weeks)
Total study duration
128 days (approximately 18 weeks)
Data Monitoring Committee:
No.


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1.2
Schema
Figure 1–1: Study design
Abbreviations: BID = bis in die (twice daily); n= number of completers
Screening
Randomization
Active Intervention - 150 mg BID (n=50)
Active Intervention - 75 mg BID (n=50)
Active Intervention - 25 mg BID (n=50)
Placebo (n=50)
Safety 
Follow-up
Pre-intervention Period
2 weeks (14 days)
Intervention Period
12 weeks (84 days)
Post-intervention 
Period (30 days)


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1.3
Schedule of Activities (SoA)
Procedure
Screening 
Intervention
Safety 
Follow-
up
Visit
V1
V21
V3
V4
V5
V62/TV3
SFU4
Day (Relative to start of intervention)
-16 up to -14
days
-1
0
14±2
28±2
56±2
83±2
84±2
30±5
Week (Relative to start of intervention)
-2
2
4
8
12
Informed consent
X
Baseline characteristics and medical history
Demography
X
Medical history and concurrent medical conditions
X
X
Eligibility assessment and randomization
Inclusion and exclusion criteria
X
X
Screening registration in IWRS
X
Randomization registration in IWRS
X5
Confirmation of randomization in IWRS6
X
Study intervention, pharmacokinetics and biomarkers
Visit/EoI registration in IWRS
X
X
X
X
Dispensation of study intervention 
X7
X
X
X
Study intervention return and accountability
X
X
X
X
Blood sample for PK8
X
X
X
X9
Blood sample for biomarkers
X10
X
  
X11
Blood sample for genetics12
X
Safety-related assessments
Physical examination, including weight and height13
X
X
X
Vital signs
X14
X
X
X
X
X
X
12-lead ECG
X
X
X
Blood sample for central safety laboratory testing15
X
X
X
X
X
Collection of samples for COVID-19 testing16
X
X
X
X
X
X
Pregnancy testing, if applicable17
X
X
X
X
X
X
Spirometry18
X


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Procedure
Screening 
Intervention
Safety 
Follow-
up
Visit
V1
V21
V3
V4
V5
V62/TV3
SFU4
Day (Relative to start of intervention)
-16 up to -14
days
-1
0
14±2
28±2
56±2
83±2
84±2
30±5
Week (Relative to start of intervention)
-2
2
4
8
12
Adverse events19
X
X
X
X
X
X
X
Prior and concomitant medication 
X
X
X
X
X
X
X
Survival status20
X
Efficacy / patient report outcomes assessments
Dispensation of cough recording device 
X
X
X
X
X
X
24-hour cough recording21
X
X
X
X
X
X
Dispensation of handheld device for diary 
completion
X
SCCD data collection22
===============================================
Cough Severity VAS23
=======================================================
LCQ24
X
X
X
X
X
X
X
EQ-5D-5L24
X
X
X
X
X
X
X
PGI-S24
X
X
X
X
X
X
X
PGI-C24
X
X
X
X
X
Abbreviations: ECG = electrocardiogram; EoI = end of intervention; EQ-5D-5L = European Quality of Life 5 Dimensions 5 Level Scale; IWRS = Interactive Web Response 
System; LCQ = Leicester Cough Questionnaire; PK = pharmacokinetics; PGI-C = patient global impression of change; PGI-S = patient global impression of severity; SCCD = 
Severity of Chronic Cough Diary; SFU = safety follow-up; TV = termination visit; V = visit


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1.
Visit 2 will be a 2-day visit. On the first day the cough recording device will be dispensed and cough recording started by the participant. On the 
second day, only after cough recording has been completed other procedures for Visit 2 can be performed.
2.
Visit 6 will be a consecutive 2-day visit. On the first day the cough recording device will be dispensed and cough recording started by the participant. 
On the second day, only after cough recording has been completed other procedures for Visit 6 can be performed.
3.
In case of premature discontinuation of the study intervention before week 12, a termination visit (TV) should be conducted. All procedures planned for 
Visit 6, with the exception of the sparse PK sampling and biomarker sampling, should be performed at the TV, preferably on the day of the last tablet 
intake.
4.
The safety follow-up visit will be performed 30 (±5) days after intake of the last tablet.
5.
To assure timely drug supply to each study site, the recording of randomization must be completed at least 1 day but not later than 4 days after Visit 1
(before Visit 2).
6.
The recording of randomization in IWRS of a participant who is eligible for intervention must be repeated on the day of the planned start of 
intervention. This will be considered as confirmation of randomization and will trigger the notification to the site about the study medication 
assignment.   
7.
The first dose of study intervention will be administered only after the 24h cough recording has been completed and the eligibility of the participant has 
been confirmed.
8.
PK sampling timing: at Visit 2 and Visit 6: pre-dose, 2 hours and 4 hours post-dose; at Visit 4 and Visit 5: 6 hours post-dose (±15 min time window 
allowed for all samples). More details on PK sampling and collection of information about the type of meal taken in timely relation to PK sampling and 
drug intake are provided in Section 8.5.
9.
At TV, sparse PK sampling will not be conducted.
10. The sample has to be taken prior to the start of study intervention.
11. At TV, biomarker sampling will not be conducted.
12. Blood sampling for genetics will have to be taken on Day 0 of Visit 2.
13. Height will be measured at Visit 1 only.
14. Blood pressure measurements can be repeated once during the screening visit if medically justified (e.g. in order to avoid suspected “white-coat 
hypertension”).
15. Hematology, chemistry and coagulation tests are to be conducted at a central laboratory every 4 weeks.
16. An oropharyngeal swab sample must be collected for quantitative measurement of the virus and a serum sample for the measurement of antibodies. 
17. Pregnancy testing will be only applicable for women of childbearing potential. A serum test will be performed at screening and urine testing will be
performed at all other site visits.
18. Spirometry results must not be older than 3 months prior to screening.
19. Adverse events will be collected from signing the informed consent until the follow-up visit at the time points specified in the SoA.
20. If a participant does not show up at the site for the planned safety follow-up visit, the survival status has to be checked. 
21. Recording of cough with the cough recording device worn by participant for 24 hours.
22. Recording of data about cough severity on SCCD by participant every day on a handheld device.
23. Cough Severity VAS will be completed by the participant every day on a handheld device.
24. LCQ, EQ-5D-5L, PGI-S, and PGI-C will be completed by the participant on a tablet device during the study visits.


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2.
Introduction
Cough is one of the symptoms for which patients most frequently seek medical attention. In 
most patients, cough manifests itself as an acute cough, e.g., due to an upper respiratory 
infection, lasts a few days to weeks, and is usually self-limiting, thus resolves without any 
medical treatment. In general, cough is classified, on the basis of its duration, into acute (< 3 
weeks), sub-acute (3-8 weeks) and chronic (> 8 weeks). The prevalence of chronic cough, i.e., 
a cough that is not self-limiting, is estimated to be around 10% in the adult population.
Chronic cough is a feature of many common respiratory diseases (e.g., chronic obstructive 
pulmonary disease, asthma) and some non-respiratory conditions (e.g., gastroesophageal 
reflux and rhinosinusitis) (1, 2), and it may be the presenting symptom of patients with some 
rarer conditions (e.g., idiopathic pulmonary fibrosis and eosinophilic bronchitis). In up to 50% 
of the chronic cough cases, the cough is refractory despite extensive investigation and 
treatment trials. In other patients with chronic cough, no potential underlying etiology is 
found – those are patients with a so-called idiopathic (or unexplained) chronic cough.
Despite the distinction above, publications often summarize both refractory and idiopathic 
chronic cough simply as refractory chronic cough. In this study protocol, both will be jointly 
referred to as refractory and/or unexplained chronic cough (RUCC).
In the majority of patients with RUCC, it has been postulated that sensitized nerve fibers play 
a prominent role after they fail to return to a normal quiescent state. This situation has been 
described in the literature as “cough hypersensitivity syndrome.” Patients with RUCC 
typically present with a mean age of about 65 years, and about two thirds of these patients are 
female (3, 4).
In a normal physiological state, noxious stimuli lead to a protective cough, while innocuous 
stimuli are not recognized by the cough receptors. In patients with cough hypersensitivity 
syndrome, however, even small, innocuous stimuli lead to the urge to cough. In fact, it was 
shown, in the experimental set-up of cough challenges, that the concentration of the tussive 
agent capsaicin, required to elicit 5 coughs within 15 seconds, is about 100 times lower in 
patients with RUCC than in healthy individuals (5). The underlying nerve damage usually 
occurs after an initial injury (often a viral infection) and is thought to be associated with a 
local neuropathy leading to throat-clearing among other responses.
While cough is a key protective reflex preventing aspiration and promoting airway clearance,
cough in patients with RUCC is mainly pathologic, does not serve as an airway-protective 
mechanism and has a major impact on physical and psychological aspects of quality of life.
Among the physical complications reported by a large proportion of patients with RUCC are 
exhaustion/fatigue, insomnia, breathlessness, vomiting and urinary incontinence (the latter 
predominately reported by women). Psychological complications with a high prevalence in 
patients with RUCC are depression, anxiety and embarrassment as well as interference with 
social life. Most patients with RUCC are able to identify the triggers of their cough, such as 
talking, singing, laughing, strong odors, strong foods or change in air temperature or quality.
A well-established expert panel have proposed a chronic cough algorithm for the management 
of patients > 15 years of age with cough lasting > 8 weeks, as clearly outlined by Irwin et al. 
2006 (Figure 3) (6).
The evaluation of chronic cough is largely based on anatomic diagnostic protocols focused on 
the most common causes. The evidence supporting such protocols is limited and etiologic 


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work-up can occasionally be extensive, costly, and low yield. Sequential empiric therapy for 
the most common causes of chronic cough has thus been recommended instead. Identifying 
the specific patient concern allows individualization of the extent of the diagnostic evaluation 
and treatment as described by Achilleos et al. 2016 (Table 1) (7).
2.1
Study Rationale
The objective of this study is to identify the optimal dose of the P2X3 receptor antagonist 
BAY 1817080 in patients with RUCC and to further assess efficacy and characterize the 
safety and tolerability profile of BAY 1817080 following a 12-week twice daily oral 
treatment
2.2
Background
There are currently no specifically approved drugs for the treatment of RUCC. Current 
guideline-approved treatment options for the management of patients with RUCC include 
only empiric treatments than cause-directed therapies. The ERS 2019 guidelines on the 
diagnosis and treatment of chronic cough in adults and children incorporate all recent 
advances in chronic cough pathophysiology, diagnosis and treatment (8).
P2X3 ion channel receptors are expressed by airway vagal afferent nerves and contribute to 
the ATP-driven hypersensitization of sensory neurons, thus contributing to the induction of 
pathologic cough. Recently developed P2X3 receptor antagonists that block these receptors 
have been investigated in improved animal models of cough using validated cough frequency 
measurement tools and demonstrated a therapeutic promise. Extrapolating from the guinea pig 
cough model, and with a better understanding of neuronal activation and sensitization together 
with their signal processing in the brain, P2X3 antagonism mode of action has been further 
validated in Phase 2 clinical trials for the treatment of RUCC (9).
Bayer has proposed a clinical development plan intended to provide an efficacious and safe 
treatment option indicated for patients diagnosed with RUCC. The implementation of this
clinical development plan, within an efficient time and resources frame, aims to generate 
strong scientific and clinical evidence and recommendations supporting the use of this 
medication.
The present Phase 2b clinical study intends to evaluate three different twice daily oral doses 
of a selective P2X3 receptor antagonist (BAY 1817080) and compare them to placebo during
a period of 12 weeks aiming to identify the most efficacious, tolerable and safe dose to 
advance the drug into a Phase 3 of development.
2.3
Benefit/Risk Assessment
2.3.1
Summary
Chronic cough is a common and disabling disorder affecting approximately 5-10% of the 
adult population (10). Currently, there is no approved treatment for refractory chronic cough. 
Medicines, such as gabapentin and morphine, are used off-label in patients with refractory 
chronic cough, however they have limited efficacy and lead to a high rate of side effects. The 
burden of the disease and the limitations of currently available off-label use treatment 
modalities cause a serious unmet medical need. 
The P2X3 antagonist gefapixant and other compounds are currently in clinical development 
for refractory chronic cough. Blocking of P2X3 counteracts purine ATP-evoked hyper-
sensitization of afferent nerves, leading to a cessation/reduction of pathological coughing. Of 
note, an effect of P2X3 antagonism (gefapixant) on capsaicin- or citric-acid-evoked cough for 


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either healthy volunteers or refractory chronic cough patients was not observed, thus 
suggesting that the protective cough reflex remains unaffected by this mode-of-action, and 
only the pathological cough hypersensitivity syndrome is the therapeutic target for this 
mechanism (11).
BAY 1817080 is a potent and selective P2X3 antagonist, which preferentially blocks the 
homomeric P2X3 channel. BAY 1817080 showed a strong effect on airway sensory afferent 
activation by inhibition of depolarization of the human and guinea pig vagus nerve prepared 
from lung tissues. Beneficial effects of BAY 1817080 on cough frequency and severity were 
demonstrated in a Proof-of-Mechanism/Proof-of-Concept Phase 2a clinical trial with 
refractory chronic cough patients (9). 
Benefit/risk ratio for BAY 1817080 is considered favorable for the planned study.
2.3.2
Potential Benefits
Administration of BAY 1817080 may be associated with the following benefits for patients 
with refractory chronic cough:

Reduction in cough frequency, severity and urgency, which is expected to be 
associated with increased quality-of-life (QoL) and social functioning

Relief from physical and psychological complications of cough, such as 
exhaustion/fatigue, insomnia, breathlessness, urinary incontinence, difficulties in 
speaking, depression and anxiety.
Recently generated evidence from a Proof-of-Mechanism/Proof-of-Concept Phase 2a clinical 
trial corroborates the potential benefit of this mode-of-action and is supportive of further 
developing BAY 1817080 as a therapeutic option for patients with refractory chronic cough
(9). During the aforementioned Phase 2a study, BAY 1817080 was tested in four different 
doses of formulation A in patients with RUCC. Twice daily administration of 50 mg, 200 mg
and 750 mg (formulation A) resulted in a 24-hour cough count reduction with -18.4%, -22%
and -25%, respectively (placebo-corrected values). Of note, formulation B will be 
administered in the current Phase 2b dose-finding study as outlined in this protocol.
2.3.3
Risks and Undesirable Effects
2.3.3.1
Taste-Related AEs
Taste-related AEs have been observed dose-dependently in up to about 20% of study 
participants at a dose of 750 mg twice daily (BID; formulation A). This highest dose of 
750 mg BID (formulation A) is expected to correspond to approximately 150 mg BID of
formulation B as described thoroughly in the latest available version of the Investigator’s 
Brochure (IB) and throughout this protocol. Taste-related AEs have also been reported for the 
P2X3 antagonist gefapixant (12). 
To date, the influence of BAY 1817080 on taste perception has been investigated in a limited 
number of study participants only. In these studies, the change in taste perception was 
reported as being non-serious and mild. Changes were fully reversible after the end of 
treatment with BAY 1817080. No participants discontinued the treatment because of taste 
disturbances.
Study 18184 (9) was a two-part study, investigating safety and pharmacokinetics (PK) of 
BAY 1817080 in healthy volunteers (Part 1) and safety, efficacy and PK in patients with 
refractory chronic cough (Part 2). In Part 1, the frequency of the taste-related AEs was evenly 


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distributed between participants receiving active treatment with BAY 1817080 (3 
participants; 8.6%) and participants receiving placebo (1 participant; 8.3%). In Part 2 of study 
18184, overall 10 out of 40 participants treated reported a taste-related AE. Some of the AEs
lasted for two or more consecutive treatment intervals with different doses. If evaluated by 
dose, 5.1% of participants had a taste-related AE starting or ongoing at the 10 mg dose, 10.3% 
at the 50 mg dose, 15.4 % at the 200 mg dose, and 20.5% at the 750 mg dose. When
extrapolated to doses of formulation B, 50 mg, 200 mg and 750 mg BID of formulation A are 
expected to correspond to approximately 25 mg, 75 mg and 150 mg BID of formulation B,
which are to be assessed in the current Phase 2b study.
Under placebo, 2.5% of participants reported a taste-related AE. The changes in taste 
perception were reported as being mild in all participants, and all participants had recovered 
from the taste-related AEs at the end of the study.
At the highest dose of 150 mg BID (formulation B; corresponding to a target dose of 
approximately 750 mg BID of formulation A), taste-related AEs are expected at rates of equal 
or less than 20%. 
In this study, the frequency of taste-related AEs will be evaluated, including the assessment of 
how bothersome the AEs were perceived to be.
At this stage of clinical development, taste disturbance is regarded an identified risk.
2.3.3.2
Antithrombin III Activity Increase
In study 18184 (9) (Part 1), antithrombin III (ATIII) activity increases were observed in 
healthy participants treated with 200 mg and 750 mg BID of BAY 1817080 (formulation A). 
Effect was first observed 3 days after the first dose. Increase was up to ~20% above baseline 
in the 200 mg BID group, and up to ~30% above baseline in the 750 mg BID group (200 mg 
and 750 mg BID of formulation A are expected to correspond to approximately 75 and 
150 mg BID of formulation B). 
In study 18184 (Part 2), in patients with refractory chronic cough, there were similar time and 
dose-dependent increases of ATIII activity observed as in the healthy volunteers in Part 1 of 
the study.
No changes in coagulation parameters were observed and no signs of bleeding/bruising 
related to BAY 1817080 were observed in study 18184 or other studies, to date, with BAY 
1817080.
Furthermore, there is no established clinical relevance linked to increased ATIII activity in 
medical literature. Therefore, it is concluded that at this stage of development, the increase in 
ATIII activity can be considered as not clinically relevant.
ATIII activity will be measured in this study. Coagulation parameters (prothrombin time 
(Quick), activated partial thromboplastin time (aPTT), fibrinogen, international normalized 
ratio (INR)) will be monitored regularly during the study as part of safety laboratory 
assessments.
Increased ATIII activity at this stage of development is regarded a potential risk.
2.3.3.3
Potential Decrease in Heart Rate and Diastolic Blood Pressure
In study 18184, a decrease in diastolic blood pressure (DBP) (4-7 mmHg) and heart rate (HR) 
(5-11 bpm) was observed in the highest dose group (750 mg BID formulation A 
corresponding to approximately 150 mg BID of formulation B) in healthy participants (Part 1; 


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mainly in 2-3 participants with high baseline values). The decrease in DBP and HR was not 
observed in patients with refractory chronic cough (Part 2). 
In the absence of AEs related to the changes in DBP and HR, such as dizziness or syncope, 
this observation was considered as not clinically significant.
Decrease in HR and DBP at this stage of development is regarded as potential risk. HR and 
blood pressure will be monitored in this study.
2.3.3.4
Potential Changes in Liver Function Laboratory Parameters
In one of two in vitro assays, BAY 1817080 was found to be an inhibitor of bile salt export 
pump (BSEP). No other risk factors have been identified pre-clinically at relevant exposures, 
including absence of signals for mitochondrial toxicity. In GLP animal toxicology studies, no 
changes in liver function laboratory parameters have been observed.
To date, clinically no changes in total bile acids or liver function laboratory parameters related 
to BAY 1817080 have been observed. 
Changes in liver function values at this stage of development are regarded as a potential risk.
Liver-specific exclusion criteria and discontinuation rules have been defined. Liver function 
laboratory parameters will be assessed at 4-weekly intervals, i.e., at every visit. Investigators 
and participants should be alerted regarding non-specific symptoms which may be associated 
with liver dysfunction, including anorexia, nausea, fatigue, right upper abdominal discomfort, 
vomiting, malaise, jaundice, fever, and rash. Information on these symptoms should be asked
for in case of abnormal liver laboratory values (see Section 8.3.6) or any other suspicion of 
liver dysfunction. The study participants should be reminded to contact the study site 
immediately, if they are concerned about such symptoms and unscheduled liver laboratory 
assessments should be considered.
2.3.3.5
Reproductive Toxicity
Studies on reproductive and developmental toxicity of BAY 1817080 were conducted in rats 
and rabbits. No effects of BAY 1817080 on male/female reproduction, fertility or 
developmental toxicity have been detected with multiples of exposures relative to the 
anticipated human therapeutic exposures of about 6-fold (rats) and 0.8-fold (rabbits). 
Women of childbearing potential must use an acceptable effective contraceptive method when 
receiving BAY 1817080. The use of highly effective methods of contraception will be 
allowed for women of child bearing potential (WOCBP) during the conduct of this Phase 2
study.
2.3.3.6
Potential Phototoxicity
BAY 1817080 was weakly phototoxic (Photoirritation factor, PIF = 17.7) in an in vitro 
phototoxicity assay at concentrations clearly exceeding the expected human maximum plasma 
concentration. In addition, reversible affinity to pigmented tissues (eye, skin) was seen in rats. 
In study 18184 (9), no AEs potentially linked to phototoxicity were observed.
Based on literature data (13), a PIF <25 derived from the in vitro assay is very unlikely to 
translate into in vivo phototoxicity. Nonetheless, as a precautionary measure, excessive 
exposure to sunlight should be avoided during the intervention period. Participants will be 
advised to use conventional ultraviolet (UV) sunscreens, to avoid prolonged sunbathing 
especially when traveling to a different geographical area with greater sunshine, and also to 


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avoid the use of solarium. They are also advised to use sunglasses if exposed to direct or 
excessive sunlight.
2.3.3.7
Risk of contracting SARS-CoV-2 infection during study participation
As long as the COVID-19 pandemic situation is ongoing, there is a risk of contracting a 
SARS-CoV-2 infection during the time period of study participation. Only SARS-CoV-2 
virus RNA and IgG tests negative participants without any symptoms suggestive of COVID-
19 infection will be included into this study. Given the global setting of the PAGANINI 
clinical trial, testing, as well as obtaining further information regarding symptoms suggestive 
of COVID-19 infection 1 , will be part of the screening visit and subsequent visits (as 
applicable in accordance with guidance from the relevant regional and local public health 
authorities). Both quantitative detection and viral load analysis of SARS-CoV-2 through 
quantitative reverse transcription polymerase chain reaction (qRT-PCR) will be performed 
throughout the study. If a participant becomes SARS-CoV-2 virus RNA test positive during 
study participation, the investigator will have to decide whether remaining in the study is 
compatible with participant’s and site personnel’s safety and well-being.
                                                
1 Common COVID-19 related symptoms could include (but are not limited to): fever over 38°C in the past 4
weeks; persistent chronic cough that exacerbated further in the past 4 weeks; chills; body aches; loss of smell
and/or taste; headache; sore throat; fatigue.


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3.
Objectives and Endpoints
The objective of this study is to identify the optimal dose of P2X3 receptor antagonist BAY 
1817080 in patients with RUCC and further assess efficacy and characterize safety and 
tolerability profile of BAY 1817080 
Objectives
Endpoints
Primary
Primary Efficacy Endpoint

Assess the efficacy of P2X3 
receptor antagonist 
BAY 1817080 as compared 
with placebo in terms of 
change in 24-hour cough 
count from baseline to week 
12 

Change from baseline in 24-hour cough count 
(measured by cough recording digital wearable 
monitoring device) after 12 weeks of intervention
Secondary
Secondary Endpoints

Further assess efficacy of 
BAY 1817080
Secondary Efficacy Endpoints

Percentage of participants with a ≥30% reduction 
from baseline in 24-hour cough count after 12 weeks 
of intervention (measured by cough recording digital 
wearable monitoring device)

Change from baseline in 24-hour cough count after 
2, 4, and 8 weeks of intervention (measured by 
cough recording digital wearable monitoring device)

Change from baseline in awake cough frequency per 
hour after 2, 4, 8 and 12 weeks of intervention
(measured by cough recording digital wearable 
monitoring device)

Change from baseline in cough related quality of life 
(measured by Leicester Cough Questionnaire [LCQ]) 
after 12 weeks of intervention

Change from baseline in cough severity after 12
weeks of intervention (measured by Cough Severity 
Visual Analogue Scale [VAS])

Percentage of participants with a ≥30 scale units 
reduction from baseline after 12 weeks of 
intervention (measured by cough Severity VAS)

Percentage of participants with a ≥1.3-point increase 
from baseline after 12 weeks of intervention
(measured with LCQ Total Score)

Further characterize safety 
and tolerability profile of BAY 
1817080
Safety and Tolerability Evaluation

Frequency and associated severity of treatment-
emergent adverse events (TEAEs)


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Objectives
Endpoints
Other Pre-specified
Exploratory Endpoints

Further describe the efficacy 
profile of BAY 1817080 
through the impact of 
intervention as patient 
reported outcomes

Assess psychometric and 
other measurement properties 
of the newly developed SCCD

Change from baseline in daily cough severity after 
12 weeks of intervention (measured by the Severity 
of Chronic Cough Diary [SCCD])

Change from baseline in night cough frequency per 
hour after 2, 4, 8, and 12 weeks of intervention
(measured by cough recording digital wearable 
monitoring device)

Percentage of participants with a ≥50% and ≥70% 
reduction from baseline in 24-hour cough count after 
12 weeks of intervention

Change from baseline in daily cough severity after 2, 
4, and 8 weeks of intervention (measured by SCCD)

Change from baseline in cough severity after 2, 4, 
and 8 weeks of intervention (measured by Cough 
Severity VAS)

Change from baseline in cough related quality of life 
after 2, 4, and 8 weeks of intervention (measured by 
LCQ)

Patient Global Impression of Change (PGI-C) and 
change from baseline in Patient Global Impression of 
Severity (PGI-S), after 2, 4, 8 and 12 weeks of 
intervention.

Change from baseline in Health-related quality of 
Life (HrQoL) after 2, 4, 8 and 12 weeks of 
intervention (as measured by EQ-5D-5L)

To investigate the 
pharmacokinetics of 
BAY 1817080 over the dose 
range of 25-150 mg BID in 
patients with RUCC

Systemic exposure of BAY 1817080 in patients with 
RUCC

To further investigate the 
study intervention and similar 
drugs (i.e., mode-of-action-
related effects and / or safety) 
and to further investigate 
pathomechanisms deemed 
relevant to pulmonary
diseases and associated 
health problems

Blood biomarkers (e.g., diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers) at baseline, week 4, and 
week 12


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Objectives
Endpoints

To evaluate potential 
associations between 
disease-associated genotypic 
information and clinical 
efficacy and / or 
pharmacodynamics effects

To further evaluate the impact 
of the disease and associated 
comorbidities 

Evaluation of clinical efficacy parameters by 
repertoire or frequency of genetic alterations in the 
relevant pathways

Sleep disturbance (prevalence and impact) 
associated with cough in patients with RUCC

Frequency of urinary incontinence associated with 
cough in patients with RUCC

Other pre-specified endpoints, if any, are specified in 
the statistical analysis plan (SAP)
Estimand for the primary efficacy objective
The estimand of interest to assess the primary efficacy objective of the study is the effect of 
the intervention in those participants who tolerate the intervention, adhere to the intervention 
schedule and follow all relevant protocol procedures.
The attributes of the estimand are as follows:
A. Population: as described by the inclusion/exclusion criteria given in Section 5 and 
further by analysis population in Section 9.3
B. Variable: change from baseline in 24h cough count after 12 weeks of intervention
C. Treatment: BAY 1817080 or placebo
D. Intercurrent events: 
a.
early discontinuation of study intervention: use data until discontinuation 
(while on treatment strategy)
b. non-compliance with study intervention: use data until non-compliance (while 
on treatment strategy)
E. Population-level summary: estimated mean of change from baseline in the logarithm 
of average hourly cough count by intervention group
The estimator used for this estimand is described in detail in Section 9.4.2.


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4.
Study Design
4.1
Overall Design
Study design summary: Randomized, double-blind, parallel group, Phase 2b dose-finding, 
efficacy and safety study of 12-week twice daily oral administration of BAY 1817080 
compared to placebo in patients with RUCC.
Intervention group:
Parallel
Study duration:
Approximately 18 weeks
Intervention duration:
12 weeks
Study Periods:
Pre-intervention period (screening & randomization), 
Intervention period, and Safety follow-up period
Diagnosis group:
Patients with RUCC
The study population consists of participants with a cough that has lasted for at least 12 
months (unresponsive to treatment options) with a diagnosis of refractory chronic cough 
and/or idiopathic (unexplained) chronic cough and with persistent cough for at least the last 8 
weeks before screening.
4.1.1
Pre-Intervention Period
Written informed consent form must be obtained before any study related activities are 
performed. After providing the written informed consent, participants will undergo a 
screening evaluation to determine their eligibility. The screening evaluation will take place on
Day -14 before Visit 2.
The screening of each participant has to be recorded in the IWRS system. To assure timely 
drug supply to each study site, the recording of randomization must be completed at least 1 
day but not later than 4 days after Visit 1 (before Visit 2). The recording of randomization in 
IWRS of a participant who is eligible for intervention must be repeated on the day of the 
planned start of intervention. This will be considered confirmation of randomization and will 
trigger the notification to the site about the study intervention assignment.
Following screening, eligible participants will be randomized to one of four parallel 
intervention groups of BAY 1817080.
4.1.2
Intervention Period
After randomization, each participant will receive one of three doses of BAY 1817080 or 
placebo administered orally with or without food, twice daily over the course of 12 weeks
with an interval of 12 hours.
4.1.3
Post-Intervention Period
After last intake of study intervention, participants will enter an observational safety follow-
up period of 30±5 days. During this period, AEs will continue to be collected. At the end of 
this observational period, a safety follow-up (SFU) visit will be performed at site.
For an overview of activities and procedures to be performed at each visit, see SoA.


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4.2
Scientific Rationale for Study Design
This Phase 2b dose-finding study with BAY 1817080 administered twice daily for 12 weeks 
will provide further data to support the determination of a dose with the highest potential for 
efficacy and with optimal risk-benefit profile for patients with RUCC. Twelve weeks on 
intervention is considered sufficiently long to identify optimal dose and explore whether 
BAY 1817080 has superior efficacy over placebo.
The inclusion of a placebo-controlled arm is regarded as fundamental to minimize bias on the 
part of participants and investigators. Randomization is designed to prevent assignment or 
selection bias. RUCC is a condition with a known behavioral component, potentially 
susceptible to a placebo effect. 
Rationale for the primary efficacy endpoints
Cough is associated with significant physical and psychological morbidity (14). In the 
research environment, the ability to measure relevant cough parameters is necessary for 
understanding its mechanism and developing new treatments (15).
Coughing can be assessed either from the perspective of the patient or from that of the 
clinician or researcher. Both approaches are very useful and complementary, therefore 
combined subjective and objective assessment is necessary for more comprehensive 
evaluation. An objective measure of cough is of use in clinical practice, clinical research and
the assessment of novel therapies. It permits validation of the presence of cough, grading of 
severity and monitoring of response to treatment (16).
The assessment of cough severity is considered the most important parameter for evaluating 
the efficacy of therapy and it can be measured by symptom severity, frequency, intensity and 
impact on quality of life, with the validated tools available. There is a general consensus that 
cough frequency monitoring is the gold standard for the objective assessment of cough and it
has been increasingly used as primary endpoint in clinical trials, although there is currently no 
standardized method for measuring cough frequency (3).
An objective measure of cough would permit validation of the presence of cough, grading of 
severity and monitoring of responses to therapeutic intervention. Therefore, our primary 
efficacy endpoint is the assessment of change from baseline in 24-hour cough count 
(measured by cough recording digital wearable monitoring device) after 12 weeks of 
intervention.


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4.3
Justification for Dose
In this study, the doses were selected based on the following:

The selected dose should result in sufficiently high exposures that block the target to 
an extent which allows to conclusively determine the optimal dose to be tested in 
subsequent confirmatory Phase 3 trials in RUCC.

The safety/ tolerability profile based on clinical evidence gathered to date will ensure 
participants’ safety during trial participation and reduce the risk of early 
discontinuations due to adverse events (AEs) or perceived lack of efficacy.
For BAY 1817080, the above-mentioned criteria are fulfilled for the selected doses of 75 and 
150 mg BID2:

Based on current dose predictions from preclinical studies and data from the proof of 
concept study in patients with refractory and/or unexplained chronic cough (study 
18184), the lowest fully effective dose was observed at a dose of 200 mg BID with 
formulation A3. Exposures after dosing of 200 mg BID with formulation A correspond 
to exposures expected with ~75 mg BID with formulation B. In this study, formulation 
B is used. 

The doses of 25, 75 and 150 mg BID were chosen in order to allow investigating the 
full dose response in RUCC, i.e., testing one lower, partially effective dose of 25 mg 
and one higher, also fully effective dose of 150 mg BID (formulation B). The doses of 
25, 75 and 150 mg BID of formulation B are expected to be similar to the doses of 50 
mg, 200 mg and 750 mg of formulation A previously tested in Phase 2a (see Figure 4–
1). 

Participants are recommended to take the tablets at approximately the same time each 
day with or without food. Tablets are not to be broken, halved or crushed; they should 
be swallowed as a complete unit with water (see Figure 4–1 and the latest available 
version of the IB for further details).

In summary, expected exposures after administration of 25, 75 and 150 mg BID of 
BAY 1817080 are believed to be sufficient to conclusively investigate the dose 
response in patients with RUCC.  

In study 18184, the highest exposure (after multiple doses of 750 mg of formulation 
A) was found to be well tolerated and safe (see the latest available version of the IB
for further details)4. 750 mg BID of formulation A translates into approximately 150
mg BID of formulation B. Accordingly, exposures following administration of 25, 75 
                                                
2 Formulation B
 
[see the latest available version of the IB for further details])
3 Clinical proof of target engagement is derived from the proof of concept study with BAY 1817080 in patients 
with refractory and/or unexplained chronic cough (study 18184; see the latest available version of the IB). For 
patients who had received the maximum technically feasible dose of 750 mg BID or the next lower dose of 200
mg BID, awake cough counts were reduced on top of placebo by 26.1% and 24.4%, respectively.
4 Patients who had received the maximum technically feasible dose of 750 mg BID or the next lower dose of 200 
mg BID experienced taste-related adverse events at a rate of 15.4% and 20.5%, respectively. Such AEs were 
also observed after administration of a different P2X3 antagonist (gefapixant) (12).
CCI


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and 150 mg BID of formulation B are expected to be similar to the concentrations 
covered in the multiple dose study 18184 (see the latest available version of the IB and 
Figure 4–1 below; applies to both fasted and fed state). 

Additionally, in study 19519, a 400 mg single dose of formulation B was found to be 
safe.
Therefore, there are no anticipated safety concerns with the selected doses of 25, 75 and 
150 mg BID (formulation B) of BAY 1817080 in study 20393. Tolerability is expected to 
facilitate completion of the study by the required number of participants and accordingly 
interpretation of study results (i.e., rate of early discontinuations within expectations). 


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Figure 4–1: Model-Based Predicted Average Concentrations After Administration of 
25, 75 and 150 mg BID of BAY 1817080 Formulation B
A)
Model-based predicted average concentrations (including 95% confidence interval) after multiple dose 
administration (BID) of 25 mg, 75 mg and 150 mg of BAY 1817080 formulation B given fasted, in comparison to 
the geometric mean concentrations (steady-state, BID) observed in study 18184 Part 2 with 50 mg, 200 mg and 
750 mg of formulation A (black circles & black lines). 75 mg: based on 25 mg fasted model.
B)
Model-based predicted average concentrations (including 95% confidence interval) after multiple dose 
administration (BID) of 25 mg, 75 mg and 150 mg of BAY 1817080 formulation B given fed (high fat, high calorie 
meal), in comparison to the geometric mean concentrations (steady-state, BID) observed in study 18184 Part 2 
with 50 mg, 200 mg and 750 mg of formulation A (black circles & black lines). 75 mg: based on 100 mg fed 
model.
Abbreviations: BID = bis in die (twice daily); HFHC = high fat, high calorie; RO = receptor occupancy


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4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit (SFU).
The primary completion is defined as the date of Visit 6 of the last participant for the primary 
outcome.
The end of the study is defined as the date of the last visit (SFU) of the last participant in the 
trial globally.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Adults ≥ 18 years of age at the time of signing the informed consent.
2. A cough that has lasted for at least 12 months (unresponsive to treatment options) with 
a diagnosis of refractory chronic cough and/or idiopathic (unexplained) chronic cough.
3. Persistent cough for at least the last 8 weeks before screening.
4. Cough severity as measured by VAS ≥40 scale units at screening.
5. Women of childbearing potential must agree to use acceptable effective or highly 
effective birth control methods during the study and for at least 30 days after the last 
dose. For more details on contraception (and highly effective birth control methods),
see Section 10.4. 
6. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
RUCC-related Medical Conditions
1. Smoking history within the last 12 months before screening (all forms of smoking, 
including e-cigarettes, cannabis and others), and any former smoker with more than 20 
pack-years.
2. Ongoing or previous exposure to inhalational toxic fumes (e.g., ammonia, chlorine, 
nitrogen dioxide, phosgene and sulfur dioxide) within the last 12 months before 
screening.
3. Chest radiograph or CT within the last 24 months before screening and subsequent to 
the onset of chronic cough with presence of any obvious lung disease that could be 
responsible or contributing for the cough (e.g., bronchiectasis, cavitary lesions, 
interstitial pulmonary fibrosis, pneumothorax, pleural disease, unstable rib fracture, 
tuberculosis).


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4. Forced expiratory volume in 1 second (FEV1)/ Forced vital capacity (FVC) ratio 
< 60% or a history of frequent exacerbations of chronic obstructive pulmonary disease 
(COPD).
5. Respiratory tract infection within 4 weeks before screening.
6. History of chronic bronchitis.
7. Active state of massive hemoptysis5 or pulmonary hemorrhage, including those events 
managed by bronchial artery embolization or any history of bronchial artery 
embolization or massive hemoptysis within 3 months prior to screening.
Hepatic-related criteria
8. Moderate-to-severe hepatic impairment defined as Child-Pugh Class B or C.
9. ALT >2xULN, or AST >2xULN, or total bilirubin greater than ULN, or alkaline 
phosphatase (AP) >2x ULN, or INR greater than ULN (unless related to 
anticoagulation treatment).
Renal-related criteria
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 calculated by 
Modification of Diet in Renal Disease (MDRD) formula.
Different eGFR formulas will be used for participants enrolled at sites in Japan in this 
study (for more details, see Section 10.6).
General Medical Conditions
11. Systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at 
screening visit.
12. Any other diseases or conditions that according to the investigator can compromise the 
function of the body systems and could result in altered absorption, excessive 
accumulation, impaired metabolism, or altered excretion of the study intervention 
(e.g., chronic bowel disease, Crohn’s disease and ulcerative colitis).
13. Esophageal achalasia.
14. Any serious or unstable diseases or conditions including psychiatric disorders that 
might interfere with the conduct of the study or the interpretation of the results.
15. Concurrent malignancy or history of cancer (exception of basal cell or squamous cell 
carcinoma of the skin) within the last 5 years prior to screening.
Prior/Concomitant Therapy
16. Intention to start new treatment for RUCC during the study.
17. Intake of prohibited prior or concomitant therapy as specified in Section 6.5.
                                                
5 Massive hemoptysis is a medical emergency defined as any degree of hemoptysis causing life-threatening 
clinical consequences such as but not limited to respiratory failure from airway obstruction, hypoxemia requiring 
mechanical ventilation, transfusion, hypotension, etc. (17)


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COVID-19 related criteria
18. Positive SARS-CoV-2 virus RNA and/or serology IgG tests at screening visit.  
Other exclusions
19. Body mass index (BMI) > 40 kg/m2.
20. Hypersensitivity to any ingredient of the study intervention (see the latest available 
version of the IB).
21. Wish for pregnancy during the study, current pregnancy or lactation.
22. Major surgery scheduled during the study period.
23. Inability to cooperate with the study procedures for any reason, including the 
following examples: language comprehension, inability to get to the study site.
24. Abuse of alcohol or medicines, or use of recreational/illicit drugs, as evaluated by the 
investigator.
25. Previous assignment to treatment (e.g., randomization) during this study.
26. Simultaneous participation in another clinical trial with investigational medicinal 
product(s).
27. Participation in another P2X3 trial within 3 months prior to screening.
28. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person (e.g., employee or student of investigational site, or sponsor’s staff).
29. Otherwise vulnerable patients. Patients who are in custody by order of an authority or 
a court of law.
5.3
Lifestyle Considerations
All forms of smoking, including e-cigarettes, cannabis and others, are not allowed. Use of 
tobacco products will not be allowed from screening until after the final SFU visit.
As a precautionary measure, excessive exposure to sunlight should be avoided during the 
intervention period. Participants will be advised to use conventional ultraviolet (UV) 
sunscreens, to avoid prolonged sunbathing especially when traveling to a different 
geographical area with greater sunshine, to avoid the use of solarium and also to wear 
sunglasses if exposed to direct or excessive sunlight (see Section 2.3.3.6).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 

Demography, 

Reason for screen failure, 

Eligibility criteria, and 

Date of last visit.


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A participant who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”.
Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed.
Dropout
A participant who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the participant has already been randomized to study intervention. Dropouts will 
not be replaced.
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered

Each participant will be randomized to receive one of three oral doses of BAY 
1817080 or placebo, administered twice daily 

Participants should be instructed to take the morning dose of study intervention at 
approximately the same time of day, every day over the course of 12 weeks. The 
interval between the application of the morning and the evening dose should be with 
an interval of approximately 12 hours.

The morning dose should be taken at the site on the second day of Visit 6 (see also 
Section 8.5)

Tablets are not to be broken, halved or crushed; they should be swallowed as a 
complete unit with water.

Tablets can be taken with or without food. See Section 8.5 for detailed instructions 
regarding recording of the drug intake and the food intake before or after the drug 
intake in relation to blood sampling for PK.

Participants will have to confirm the tablet intake twice per day by reporting this on 
the handheld device. In addition, the time of the tablet intake will be collected.

If a dose of study intervention has been missed: 
o
If ≤ 6 hours has passed since the dose was due, it should be taken immediately 
o
If > 6 hours have passed since the dose was due, the dose should be skipped 
and the next dose should be taken according to the regular schedule.


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Table 6–1: Study Interventions Administered
BAY 1817080
Placebo
Intervention 
Name
BAY 1817080 
Placebo for BAY 1817080 
Type
Drug
Placebo
Dose formulation
Tablet
Tablet
Unit dose 
strengths
25 mg and 100 mg
NA (Placebo for BAY 1817080 25 mg 
and BAY 1817080 100 mg)
Dosage Levels
25 mg or 75 mg or 150 mg BID
NA (Placebo)
Route of 
Administration
Oral
Oral
Packaging and 
Labeling
Tablets will be provided in blisters. Study intervention will be labeled as 
required per country requirement.
Abbreviations: BID = twice daily; NA = not applicable
6.1.1
Medical Device
A commercially available cough recording device (VitaloJAKTM; Vitalograph GmbH) will be 
used for the 24-hour ambulatory measurements. For further information, see the handling 
instruction and the instruction manual as provided with the device by the legal manufacturer.
6.2
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm that appropriate temperature conditions, if 
applicable, have been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive the study intervention and only authorized 
site staff may supply or administer the study intervention. 
All study interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Investigator Site File. 
Study interventions will be dispensed at the visits summarized in SoA. Returned study 
interventions must not be re-dispensed to the participants.
6.3
Measures to Minimize Bias: Randomization and Blinding
Participants will be identified by a unique participant number with 9 digits once the ICFs are 
signed. The first 5 digits will identify the country and study site, the last 4 digits are assigned 
to the participant of the specific site in increasing order.


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Following the screening visit (Visit 1), all participants who meet all eligibility criteria will be 
centrally randomized in a 1:1:1:1 allocation ratio and stratified by region (Japan, Europe 
[Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Slovakia, 
Spain, United Kingdom], ROW [Argentina, Australia, Canada, Russian Federation, Taiwan, 
Turkey, United States]) to receive either BAY 1817080 or placebo by using IWRS. 
Once a randomization number has been assigned, it must not be re-assigned.
To accomplish randomization assignments, a computer-generated randomization list will be 
prepared by Randomization Management at the study sponsor. The randomization list is
provided to the IWRS vendor. Before the study is initiated, the login information & directions 
for the IWRS will be provided to each site.
After randomization, participant, investigator and sponsor will be blinded for the intervention
participant receives. 
To maintain blinding, tablets containing BAY 1817080 and corresponding placebo are 
identical in appearance (size, color, shape). BAY 1817080 25 mg, 75 mg, and 150 mg, and 
matching placebos will be packaged in blisters labeled with a unique number. For regulatory 
reporting purposes, drug safety personnel of the sponsor are permitted to unblind individual 
cases. In compliance with applicable regulations, in the event of a suspected unexpected 
serious adverse reaction (SUSAR), the randomization code of the participant will usually be 
unblinded before reporting to the health authorities.
Bioanalytical staff will be unblinded according to the corresponding Bayer standard operating 
procedure (SOP). Pharmacometrics staff may also be unblinded according to Bayer SOPs. 
Pharmacokinetic (PK) and exposure-response analysis might be performed using population 
approaches (popPK and popPK/PD, e.g., by non-linear mixed effect modeling). Analysis and 
report will be done under a separate cover. This evaluation might be started prior to database 
lock. If this is applicable, appropriate measures will be taken to maintain blinding of the study 
team, e.g., data will be stored separately, and members of the study team will neither have 
access to the randomization list nor to individual data.
Emergency unblinding can only be performed in the IWRS system. The IWRS will be 
programmed with blind-breaking instructions. In case of an emergency, the investigator has 
the responsibility for determining if unblinding of a participant’s intervention assignment is 
warranted when knowledge of the actual intervention is absolutely essential for further 
medical management of the participant. If the investigator is unavailable, and a treating 
physician not associated with the study requests emergency unblinding, the emergency
unblinding requests are forwarded to the study specific emergency medical advice 24 hours/7-
day service (country-specific emergency contact information provided in the participant card). 
Participant safety must always be the first consideration in making such a determination. If 
the investigator decides that unblinding is warranted, the investigator should contact the 
sponsor prior to unblinding a participant’s intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s intervention assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and case 
report form (CRF), as applicable. The actual allocation must NOT be disclosed to the 
participant and/or other study personnel, including monitors, or sponsors staff; nor should 
there be any written or verbal disclosure of the code in any of the corresponding participant 
documents.


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6.4
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance will 
be assessed by direct questioning and counting returned tablets. Deviation(s) from the 
prescribed dosage regimen should be recorded in the electronic case report form (eCRF).
To monitor compliance, the investigator will be required to document intervention dispensing 
and return for each participant. The date of dispensing the study intervention to the participant 
will be documented.
Study intervention will be dispensed according to the schedule provided in SoA. Participants 
should be instructed to bring all unused study intervention and empty packages at every 
scheduled/unscheduled visit for accountability purposes. Any discrepancies between actual 
and expected amount of returned study intervention must be discussed with the participant at 
the time of the visit, and any explanation must be documented in the source records.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
When participants self-administer study intervention at home, compliance with study
intervention will be assessed at each visit. 
6.5
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment up to 12 
weeks prior to screening or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
A list of prohibited prior and concomitant medications, along with the timeframe is provided 
in Table 6–2.
Medications that are allowed only if the participant is on stable treatment (prior to and at 
enrollment) are described in Table 6–3. Other treatment considerations are described below.


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Table 6–2: Prohibited Prior and Concomitant Therapy
Therapy
Timeframe
Angiotensin converting enzyme inhibitor (ACEI)
From 12 weeks prior to screening until EoI
Opioids, including codeine
From 2 weeks prior to screening until EoI
Digoxin
From 2 weeks prior to screening until 2 
weeks after EoI
Dabigatran 
From 2 weeks prior to screening until 2 
weeks after EoI
Apixaban
From 2 weeks prior to screening until 2 
weeks after EoI
Edoxaban 
From 2 weeks prior to screening until 2 
weeks after EoI
Gabapentin/pregabalin (for chronic cough)
From 2 weeks prior to screening until EoI
Tricyclic antidepressants (i.e., amitriptyline, 
nortriptyline) (indication RUCC)
From 4 weeks prior to screening until EoI
Interferon alpha-2b and alpha-2a
From 2 weeks prior to screening until EoI
Mycophenolate mofetil
From 1 week prior to screening until EoI
Methotrexate
From 4 weeks prior to screening until EoI
Ribavirin
From 2 weeks prior to screening until EoI
Non-narcotic cough medicine (including 
over-the-counter and herbal)
From 1 week prior to screening until EoI
Strong cytochrome P450 isoenzyme 3A4 (CYP3A4) 
inhibitors including: 

antivirals (e.g., viekira pak, telaprevir, 
boceprevir), 

protease inhibitors (e.g., ritonavir, lopinavir, 
indinavir, nelfinavir, saquinavir)

antifungals (e.g., itraconazole, voriconazole, 
posaconazole) 

antibiotics (e.g., clarithromycin, telithromycin)
grapefruit and any grapefruit containing food products 
(e.g., grapefruit juice)
From 2 weeks prior to screening until EoI
Strong CYP3A4 inducers, e.g., rifampicin, 
carbamazepine, phenytoin, St John´s Wort
From 2 weeks prior to screening until EoI
Non-drug treatment for RUCC
Speech Therapy 
From 4 weeks prior to screening until EoI
Chinese medicine
From 4 weeks prior to screening until EoI
Abbreviations: EoI = end of intervention; RUCC = refractory and/or unexplained chronic cough
A list of permitted medication only on stable dose is provided in Table 6–3. It is not permitted
to change the daily dose of these medications within the timeframe described below (prior to 
and screening).


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Table 6–3: Medication Permitted on Stable Dose
Therapy
Timeframe of stable treatment
Benzodiazepines
From 4 weeks prior to screening until EoI
Paroxetine
From 4 weeks prior to screening until EoI
Baclofen 
From 4 weeks prior to screening until EoI
Memantine
From 4 weeks prior to screening until EoI
Azithromycin and erythromycin
From 4 weeks prior to screening until EoI
Antihistamines (Chlorphenamine) for chronic cough
From 4 weeks prior to screening until EoI
Gabapentin/pregabalin (other indications e.g., diabetic 
neuropathy, neuropathic pain)
From 4 weeks prior to screening until EoI
Tricyclic antidepressants (i.e., amitriptyline, 
nortriptyline) (other indications)
From 4 weeks prior to screening until EoI
Asthma medications (e.g., inhaled corticosteroids, 
leukotriene modifiers, log-acting beta agonists, 
theophylline)
From 4 weeks prior to screening until EoI
Proton-pump inhibitors
From 8 weeks prior to screening until EoI
Abbreviations: EoI = end of intervention
Dose changes in these medications should be avoided during the study. Dose changes 
considered clinically necessary by the investigator need to be documented in the eCRF and 
the clinical condition / diagnosis that led to this dose modification should be captured as AE.
6.5.1
Other Treatment Considerations
Apixaban, dabigatran, edoxaban, digoxin: prohibited within the last 2 weeks prior to 
screening visit and until 2 weeks after end of intervention period of this study.
Based on preclinical data, an increase in exposure of drugs that are sensitive substrates of 
OATP1B1/1B3, P-gp or BCRP during co-administration of BAY 1817080 due to inhibition 
of those transporters by BAY 1817080 cannot be excluded.
•
Typical OATP1B1, OATP1B3, BCRP or P-gp substrates include but are not limited to 
the following: fexofenadine, sulfasalazine, rosuvastatin, atorvastatin, cerivastatin, 
glyburide, pravastatin, repaglinide, simvastatin.
•
Participants receiving a combination of BAY 1817080 and OATP1B1/1B3, BCRP and 
P-gp substrates should be closely monitored for signs and symptoms of adverse events 
due to increased exposure of co-administered OATP1B1/1B3, BCRP or P-gp 
substrates. Dose modification of sensitive OATP1B1/1B3, BCRP or P-gp substrates 
should be considered based on the prescriber information or such compounds should 
be avoided. 
A clinical DDI study investigating the effect of BAY 1817080 on the sensitive 
OATP1B1/1B3 and BCRP substrate rosuvastatin is ongoing. 
According to the risk assessment based on the FDA Drug Development and Drug Interactions
(DDI) guidance (18), the potential increase in exposure (AUC) due to inhibition of 
OATP1B1, the transporter with the lowest measured IC50 is estimated to be up to 2.85-fold 
with the highest dose of 150 mg BID of BAY 1817080 (simulated steady state exposure of 
formulation B was used for DDI predictions). The parameters used for this calculation are 


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entirely based on IC50 values determined in in vitro assays reflecting the maximum possible 
effect. The clinical relevant interaction will be assessed in the ongoing clinical DDI study 
investigating the effect of BAY 1817080 on the sensitive OATP1B1/1B3 and BCRP substrate 
rosuvastatin. Please refer to the current version of the IB for further information. 
Additional information regarding other OATP1B1, OATP1B3, BCRP and P-p substrates can 
be found in Table 5-1 of the FDA DDI guidance (19).
Ketoconazole and other triazole antifungal drugs are allowed for topical/local use (including 
vaginal application) at any time during the study.
Occasional intake of proton-pump inhibitors as treatment for concomitant AE, at the 
discretion of the investigator is allowed, but not recommended. Alternative treatment options 
are strongly suggested to be considered.
6.6
Dose Modification
Dose modification is not allowed within the study.
6.7
Intervention after the End of the Study
Participants completing the intervention period will not be given further access to study 
intervention. The investigator will decide in consultation with the individual participant if 
additional treatment is required and choose from existing treatment options.
It will be up to the investigators discretion to provide follow-up medical care for all 
participants who complete the study or who are prematurely withdrawn from the study or 
refer them for appropriate ongoing care as required.
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Unnecessary withdrawal of participants from the study should be avoided and all efforts 
should be taken to motivate participants to adhere to all study procedures until the end of the 
trial.
In case a participant premature discontinues the study intervention, the participant will remain 
in the study to be evaluated for the procedures planned at EoI and SFU visits before the 
participant leaves the study. See the SoA for data to be collected at the time of discontinuation 
of study intervention.
7.1
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Such 
events are expected to be rare.
If study intervention is discontinued, a participant who is still in the intervention period 
should have the EoI visit (Visit 6) assessments performed as soon as possible. Following Visit 
6, the participant continues to the follow-up period and the end of study visit (i.e., the SFU 
visit) assessments thereafter according to the SoA.
Participants must discontinue study intervention if any of the following occurs:


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
In the investigator's opinion, continuation of the study intervention would be harmful 
to the participant's well-being

Liver safety-related discontinuation criteria are met as described in Table 7–1.

Pregnancy (see Sections 8.3.5 and 10.4).
Table 7–1: Liver Safety-Related Monitoring and Discontinuation Criteria
Lab result
Measures
ALT or AST >3 x ULN 

Repeat testing of ALT, AST and TBL 2-3 times a 
week

Withdraw study intervention if the participant 
cannot come for a repeat testing*

’Close observation’ as defined in Section 8.3.6
ALT or AST >3 x ULN and TBL >2 x 
ULN 
Withdraw study intervention and initiate close 
observation as outlined in Section 8.3.6
ALT or AST >3 x ULN and INR >1.5 x 
ULN**
Withdraw study intervention and initiate close 
observation as outlined in Section 8.3.6
ALT or AST > 3 ULN with appearance of 
fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, 
fever, rash and/or eosinophilia (>5%)
Withdraw study intervention and initiate close 
observation as outlined in Section 8.3.6
ALT or AST >5 x ULN for more than 2 
weeks
Withdraw study intervention and initiate close 
observation as outlined in Section 8.3.6
ALT or AST >8 x ULN
Withdraw study intervention and initiate close 
observation as outlined in Section 8.3.6
*i.e., in case no visit for a repeat testing could be arranged within a reasonable time frame despite efforts to 
contact the participant
**Relevant only if the participant is not on Vitamin K antagonist or heparin
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international 
normalized ratio, TBL = total bilirubin, ULN = upper limit of normal (all referring to serum)
In participants fulfilling one of the criteria listed in Table 7–1, investigators and participants
should be alerted regarding non-specific symptoms which may be associated with liver 
dysfunction, including anorexia, nausea, fatigue, right upper abdominal discomfort, vomiting, 
malaise, jaundice, fever, and rash. Information on these symptoms should be asked for in case
of abnormal liver laboratory values (see Table 7–1) or any other suspicion of liver 
dysfunction. The study participants should be reminded to contact the study site immediately, 
if they are concerned about such symptoms, and unscheduled liver laboratory assessments
should be considered.
A close observation has to be initiated if any of the criteria listed in Table 7–1 occurs.
7.1.1
Rechallenge
Study intervention may be restarted after a temporary interruption if deemed clinically 
appropriate by the investigator in collaboration with the Bayer Medical Monitor.


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7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
he/she may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. The participant will not suffer any 
disadvantage as a result. Withdrawals from the study are expected to be rare. 

If a participant becomes SARS-CoV-2 virus RNA test positive while on study, the 
investigator will have to decide whether staying in the study is compatible with 
participant and site personnel safety and wellbeing. The decision should also take into 
account possible interaction between the test drug and potential antiviral medication 
(for details on concomitant therapy see Section 6.5).

At the time of withdrawal from the study, the participant must discontinue study 
intervention and complete the following visits as soon as possible:
o
For withdrawal during intervention phase, the participant should undergo 
assessments scheduled for the end of intervention visit (Visit 6) and return 
supplies.
o
In addition, the participant should undergo the assessments scheduled for end of 
study visit (the SFU visit).

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
Data already captured at the time of withdrawal will not be removed.
7.3
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
No screening procedures may be performed unless written informed consent has been 
obtained. If the (first) screening procedures already start on the same day (same date) as the 
participant signs the ICF, confirmation that ICF was signed prior to any screening procedures 
being initiated, must be recorded in the source documents.
Information on smoking history and a detailed history of symptoms and complications as a 
result of cough (type, onset, duration and time of resolution) will be recorded at screening 
visit via a series of questions reflected on individual eCRF page as part of the participant’s 
medical history. Worsening of any of the conditions listed on the aforementioned eCRF page 
or their first occurrence after signing the informed consent will be recorded as AEs.
8.1
Efficacy Assessments
Planned time points for all efficacy assessments are provided in the SoA (see Section 1.3).
8.1.1
Cough Count Measurement
Objective 24-hour cough monitoring will be performed with the VitaloJAK cough recorder 
(VitaloJAK, Vitalograph), a non-invasive, battery operated and custom-built validated 
recording device and microphone intended to acquire, record and store ambulatory cough 
sounds from participants for 24 hours at six time points (see the SoA). Briefly, this consists of 
a digital data logger recording sounds at a sample rate of 8 kHz, with 16-bit resolution and in 
WAV format, which is a commonly used uncompressed sound file format. Recordings will be
transferred to a personal computer; silences and background noise will be removed by using 
validated, custom-written software, and cough sounds will be counted by using an audio 
editing package (Vitalograph). The number of coughs will be expressed as coughs per hour 
and added up to give a cough count for a 24-hour period. Cough monitoring with the 
VitaloJAK recorder will be started at approximately the same time of day on each of the 
assessment days.
8.1.2
Electronic Patient Reported Outcomes (ePROs)
Patient reported outcomes (PROs) are self-administered questionnaires to be completed by the 
study participants themselves. All questionnaires will be available in the participant’s local 
language. 
For standardization purposes, in this study all PROs will be collected using electronic devices: 
either (e)PRO/electronic handheld device to be responded to at home for daily entries or tablet 
devices for entries at the study site during the entire study duration.
PROs collected daily on the handheld device 


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The following PROs will be collected daily on the handheld device in the following sequence:

SCCD

Severity of Cough VAS
The estimated time for completion is approximately 5 minutes, calculated using a 
conservative approach (30 seconds per item).
PROs collected during study site visits at the study site using a tablet device:
The following PROs will be collected on the tablet device in the following sequence:

LCQ

PGI-S

PGI-C

EQ-5D-5L
The estimated time for completion is approximately 6 minutes, calculated using a 
conservative approach (30 seconds per item).
Dispensation of the handheld device, data entry into the handheld device and the tablet 
device and transmission:
Following training on the use of the handheld device and the tablet device during Visit 1, the
participants will be asked to confirm their understanding on the use of the devices and the 
completion of the PROs before the devices are activated and dispensed to the study 
participants for recording.
The specific time window for data entry into the handheld device is PRO-specifically 
technically regulated and alarms will be set as appropriate to remind the study participant to 
complete the SCCD, the Cough Severity VAS (and the study intervention intake),
respectively. The study participants will be asked to fill in the daily (every day at the same 
time). Alarms will be set to remind the study participants to complete the PROs at the same 
time every day. This alarm will be set at a certain time per day and will sound in general only, 
if the PROs have not already been completed. 
The PROs on the tablet device will be responded to by the study participants at the selected 
visits (see SoA) prior to any other assessment and procedures.
Training of study participants:
Study participants will be educated regarding the importance of their in-time correct 
completion of the ePROs during the study. Standardized technical training for the use of the 
handheld device and the tablet device during the screening visit and ongoing technical support 
during the entire study duration will be provided by the study site staff to prevent missing data 
entry to the extent possible. Beyond this technical support, no other help should be given to 
study participants regarding the completion of the ePROs and the study participant will be 
instructed to complete the ePROs on their own, in a quiet place in one sitting at the pre-
specified time points, following the instructions on the tablet device, without any input from 
others. 
Training of and by site staff, 24-hour help desk
Study site staff will be instructed to explain to the study participants at each visit the 
importance of completing the records on the handheld and tablet devices. The study site staff 
will be trained regarding the use of the handheld device, and in resolving technical issues with 


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the handheld device and the tablet device. The study site staff will provide a standardized 
technical training on the handling of the handheld-device and the tablet device to the study 
participants during the screening visit and will assist the study participants in case of any 
technical queries during the entire study duration.
In addition to the technical support by the study site staff, a 24-hour help desk by the ePRO 
provider will be available during the entire study duration to respond urgent technical 
questions of the site staff.
Measures to prevent missing data entry
In case a warning due to missing data entry is received at the study site, the study site staff 
will directly contact the study participant immediately and ask for reasons for failure in data 
entry and transfer. The study site staff will remind the study participant again regarding the 
importance of the daily records.
The handheld device will be returned to the site upon study participant discontinuing or 
completing the study.
8.1.2.1
Severity of Chronic Cough Diary (SCCD)
Study participants’ assessment of frequency, severity of cough, disruption due to cough and 
disruptions of sleep will be recorded electronically every day from screening until the end of 
the intervention period using the SCCD.
The SCCD is a novel 14-item PRO questionnaire, asking the participant to assess experiences 
with their cough during the past 24 hours. Study participants will rate the frequency (items 1-
4), severity (items 5-8), disruptions due to cough (items 9-11 and 14) and disruptions of sleep 
(items 12-13) using verbal rating scales (VRS) and are asked to enter their daily assessments 
directly into the handheld device at home. The completion of the SCCD takes approximately 
5 minutes.
The daily recording of the SCCD will start at Visit 1 and will be continued daily until the SFU 
visit or at early termination for those study participants discontinuing the study before 
completion.
SCCD scores will be calculated based on study participants’ responses to single items. 
The SCCD is a PRO, which has been newly developed by Bayer. The SCCD underwent 
cognitive interviews (CIs) confirming the content validity, the ease of comprehension, 
interpretation and completion prior to initiation of this study. Psychometric and other 
measurement properties of the SCCD are planned to be assessed using data from this trial. 
Results from the CIs and the psychometric analyses are aimed to confirm the appropriateness 
of the instrument for use in clinical Phase 3 in potential support of label claims.
Training and instructions will be provided to participants in terms of how to complete the 
questionnaire.
8.1.2.2
Cough Severity Visual Analog Scale
Study participant assessment of cough severity will be recorded electronically daily using the 
Cough Severity Visual Analogue Scale (VAS).
The Cough Severity VAS is a single item instrument, asking the study participant to assess 
the severity of his/her cough using a 0-100 VAS. This is a vertically oriented line ordered 
from 0–100, on which the study participants indicate the severity of their cough by crossing 
the line at the point that that best reflected the perception of the severity of their cough on 


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their handheld device. The completion of the Cough Severity VAS will take less than 1 
minute.
The daily recording of the Cough Severity VAS will start at Visit 1 and will be continued 
daily until the SFU visit or at early termination for those study participants discontinuing the 
study before completion.
The Cough Severity VAS response option is known for its simplicity and practicality and is 
commonly used in clinical research for the measurement of a variety of clinical phenomena 
(20), including for the assessment of cough (16). The scale response range is from ("No 
Cough") to 100 ("Extremely Severe Cough"). A change of 17 scale units on a VAS has been 
reported to be perceived as important to subjects with acute cough (21). Clinical trial 
endpoints evaluating treatments for chronic cough include an endpoint of  ‘≥30 scale units 
Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score’(22).
In this trial, the Cough Severity VAS will assess key secondary and other efficacy endpoints. 
Scores from the Cough Severity VAS will also be used to investigate psychometric properties 
of the SCCD.
8.1.2.3
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C)
PGI-S and PGI-C will be assessed on the tablet device at predefined visits according to the 
SoA or at earlier termination for those study participants discontinuing the study before 
completion.
PGI-S
Study participants rate the severity of cough using the PGI-S scale experienced at the time
point of the assessment (no recall period). 
The PGI-S is a single item instrument. Study participants respond to the PGI-S using a 5-point 
verbal rating scale: a score of 0 = “No cough”, 1 = “Very mild”, 2 = “Mild”, 3 = “Moderate”,
4 = “Severe”, 5 = “Very severe” and will enter their assessment on a tablet device during 
study visits. The PGI-S is being included in the trial as a reference measure for assessment of 
psychometric and other measurement properties of the newly developed SCCD.
PGI-C
Study participants rate the change in the severity of their cough using the PGI-C scale since 
starting study intervention at the different assessment time points respectively. Study 
participants respond using a 7-point verbal rating scale: a score of 0 = “Very much better”,
1 = “Much better”, 2 = “A little better”, 3 = “No change”, 4 = “A little worse”, 5 = “Much 
worse” and 6 = “Very much worse”. The PGI-C is being included in the trial as a reference 
measure for assessment of psychometric and other measurement properties of the newly 
developed SCCD.
8.1.2.4
Leicester Cough Questionnaire
Study participants assessment of health related quality of life will be recorded electronically 
using the Leicester Cough Questionnaire LCQ (23).
The LCQ is a 19-item instrument that asks about the impact of chronic cough on various 
aspects of participants’ lives using a recall period of two weeks. The 8 items: 1, 2, 3, 9, 10, 


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11, 14, 15 build the physical domain. 7 items: 4, 5, 6, 12, 13, 16, 17 build the psychological 
domain. Further 4 items: 7, 8, 18 and 19 build the social domain.
Study participants respond to the items using a 7-point Likert scale from 1 (all of the time) to 
7 (none of the time) and will enter their assessments on a tablet device during study visits 
according to the SoA or at earlier termination for those study participants discontinuing the 
study before completion. Completion of the LCQ takes approximately five minutes.
The LCQ total score is calculated as a mean score for each of the three domains ranging from 
1 to 7, with the LCQ total score ranging from 3 to 21. A clinically significant improvement in 
cough-specific quality of life (QoL), is indicated by a ≥1.3-point increase in the LCQ total 
score from baseline (24).
In this trial, the LCQ will assess key secondary and other efficacy endpoints. Scores from the 
LCQ will also be used to investigate psychometric properties of the SCCD. The LCQ version 
used in this trial is 2001. S. Birring, UK.
8.1.2.5
EQ-5D-5L
The EQ-5D-5L will be filled in on the tablet device during study visits according to the SoA 
or at earlier termination for those study participants discontinuing the study before 
completion. Completion of the EQ-5D-5L takes approximately 3 minutes.
The EQ-5D-5L is a self-administered generic and widely used measure of health status with 
well-documented reliability, validity and responsiveness in the general population as well as 
in various diseases. Use of this instrument will enable a comparison of effects of RUCC on 
health-related quality of life with an age-matched normative sample. The instrument 
comprises 5 dimensions and an overall assessment of health status on a VAS. The 5 
dimensions include: mobility, self-care, usual activities, pain and discomfort, and anxiety and 
depression where the scores 1 to 5 indicate: having no problems, having slight problems, 
having moderate problems, having severe problems and being unable to do/having extreme 
problems. In addition, patients are asked to self-rate their own health today on a vertical 0-100 
unit VAS, with 0 corresponding to "the worst health you can imagine", and 100 
corresponding to "the best health you can imagine".
Descriptive assessment will be done on the basis of the VAS and on dimension level 
assessment basis. The EQ-5D-5L version used in this trial is "EQ-5D-5L Tablet" © 2009 
EuroQol Group EQ-5D™.


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8.2
Safety Assessments 
8.2.1
Physical Examinations
A comprehensive physical examination should be performed by the investigator at Visit 1
(screening), Visit 2 (Day 0) and Visit 6 (Day 84 ±2). Any abnormal findings are to be 
recorded and reported as an AE/SAE (see Section 8.3.1).
8.2.2
Vital Signs
Vital signs will be assessed at the site visits as specified in SoA table. This will include blood 
pressure (BP) and heart rate (HR) measurements. BP will be measured by using a standard 
sphygmomanometer with an appropriate size cuff in the sitting position after 5 minutes of 
rest, in a quiet setting. Blood pressure measurements can be repeated once during the 
screening visit if medically justified (e.g. in order to avoid suspected “white-coat 
hypertension”.)
8.2.3
Electrocardiograms
ECGs in supine position will be assessed locally as safety measures: standard 
electrocardiograms (12-lead ECG) according to Goldberger / Einthoven and Wilson will be 
recorded after resting for at least 5 minutes at Visit 1 (screening), Visit 6 (Day 84 ±2) and 
SFU visit, as outlined in the SoA. The following parameters will be recorded in the eCRF: 
VR, PR interval, QRS duration, QT interval (corrected QT calculated according to the 
formulas of both Bazett and Fridericia will be automatically calculated in Rave).
(1) Fridericia´s correction: QTc = QT/RR0.33
(2) Bazett´s correction: QTc = QT/RR0.5
All ECG printouts will be identified with the SID as well as the date and time of recording 
and will be attached to participant´s file.
ECG printouts must be reviewed and evaluated locally by the investigator or clinicians with 
experience in ECG interpretation on the day of recording for safety and quality.
An overall investigator assessment of ECG will be provided (categories: “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”). All ECG 
findings will be reported in the eCRF and any clinically relevant abnormality will be 
documented as an AE.
8.2.4
Spirometry (Lung Function Test)
Lung function testing (spirometry) will be conducted at Visit 1 (screening) in accordance with 
Guidelines from ATS/ERS Task Force (25), which is a standard method of the practice in 
pneumology. Available lung function testing results will be considered as baseline if they are 
not older than 3 months prior to screening.


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Lung function measurements and predicted parameters calculated by the device include but 
are not limited to the following:

Date

Forced vital capacity (FVC) (L)

Forced expiratory volume in one second (FEV1) (L)

FEV1/FVC ratio (%)

Forced expiratory flow (FEF) (L/sec)6

Peak expiratory flow (PEF) (L/sec)

Total lung capacity (TLC) (L)

Vital Capacity (VC) (L)

Inspiratory Capacity (IC) (L)

Tidal volume (TV) (L)

Residual volume (RV) (L)
All measured parameters that are listed above have to be transferred into the eCRF. The 
FEV1/FVC ratio is the ratio of the forced expiratory volume in the first one second to the 
forced vital capacity of the lungs. If not provided automatically by the available spirometer on 
site, the following formula or online tools should be applied for manual calculation (25):
FEV1/FVC ratio (FEV1%)
 1	
 =  1
 ∗100 
8.2.5
Clinical Safety Laboratory Assessments
The clinical laboratory tests detailed in Section 10.2 will be performed by the central 
laboratory.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study and after start of intervention in the AE 
section of the eCRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator. Participants in close liver observation should be followed up as described in 
Section 8.3.6.
                                                
6 The following FEF readouts during some fixed intervals will be recorded as part of the eCRF:

Forced Expiratory Flow 25-75%

Forced Expiratory Flow 50%


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
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 

If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator then the results must be recorded in 
the eCRF in the AE page (e.g., AE or SAE) 

Details on the collection, processing, shipment and storage of samples for safety 
laboratory assessments will be provided in separate documents (e.g., sample handling 
sheets or lab manual). 
The name and address for the central laboratory service provider can be found in the 
documentation supplied by the vendor. 
Hematology and chemistry tests are to be conducted every 4 weeks. Coagulation tests will be 
done every 4 weeks. Prothrombin time (PT) (Quick and INR) will be determined using 
standard methods. Activated partial thromboplastin time (aPTT) will be measured via clotting 
assay.
Quantitative reverse transcription polymerase chain reaction (qRT-PCR) for SARS-CoV-2 
nucleic acid detection (oropharyngeal swabs) and immunoassay for qualitative detection of 
IgG antibodies against SARS-CoV-2 antigen (serum) are to be performed at specified visits at 
the site (see Section 1.3 for details).
Since there is no established clinical relevance linked to increased ATIII activity in medical 
literature, it is concluded that at this stage of development, the increase in ATIII activity can 
be considered as not clinically relevant. In addition, given the potential for unblinding
participants receiving active treatment with BAY 1817080, the results of ATIII measures at 
the other visits will not be communicated to study teams nor investigators until after 
unblinding of the study.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g., clotted or hemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
AE will be reported by the participant (or, when appropriate, healthcare professional not 
involved in the study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study intervention. 
8.3.1
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
the follow-up visit at the time points specified in the SoA (Section 1.3).
A detailed history of symptoms and complications as a result of cough (type, onset, duration 
and time of resolution) will be recorded at screening via a series of questions reflected on an 


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individual eCRF page as part of the participant’s medical history. Worsening of any of the 
conditions listed on the aforementioned eCRF page or their first occurrence after signing the 
informed consent will be recorded as AEs.
Additional details on smell and taste related AEs will be collected.   
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstances should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in Section 10.3. 
8.3.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.


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8.3.5
Pregnancy
Details of all pregnancies in female participants and, female partners of male participants will 
be collected after the start of study intervention and until last safety follow up (SFU) visit in 
the study.
If a pregnancy is reported, the investigator should inform the sponsor no later than 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6
Liver-Related AEs
Investigators and participants should be alerted regarding non-specific symptoms which may 
be associated with liver dysfunction, including anorexia, nausea, fatigue, right upper 
abdominal discomfort, vomiting, malaise, jaundice, fever, and rash. Information on these 
symptoms should be asked for in case of abnormal liver laboratory values (see Table 7–1) or 
any other suspicion of liver dysfunction. The study participants should be reminded to contact
the study site immediately, if they are concerned about such symptoms and unscheduled liver 
laboratory assessments should be considered.
A ‘close observation’ has to be initiated in case of ALT or AST >3ULN after start of 
study intervention (see Table 8–1) (26).
Abnormal laboratory results and clinical signs and symptoms resulting in close liver 
observation (CLO) should be promptly reported as adverse event if an overarching diagnosis 
is not yet available.
All events of ALT >3 × upper limit of normal (ULN) and bilirubin >2 × ULN or ALT >3 × 
ULN and international normalized ratio (INR) >1.5, if INR measured which may indicate 
severe liver injury (possible Hy’s Law), must be reported as an SAE.
Close observation includes:

Repeat serum chemistry panel (including serum transaminases [AST and ALT] and 
serum bilirubin) 2 to 3 times per week. Frequency of retesting can decrease to once a 
week or less if laboratory abnormalities decrease and participant is asymptomatic.

Obtaining a more detailed history of the symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Ruling out acute viral hepatitis; autoimmune or alcoholic hepatitis; nonalcoholic 
steatohepatitis (NASH); hypoxic/ischemic hepatology and biliary tract disease. This 
may require performing additional procedures, e.g., ultrasound examinations. If 
requested, tests will be done retrospectively using residual blood/serum samples 
collected at visits before laboratory abnormalities occurred.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function as required, (e.g, international 
normalized ratio [INR], direct bilirubin measurements).


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Stopping criteria for close observation: 

2 consecutive normal/baseline results for liver enzymes in addition to availability of 
results from detailed CLO lab panel, related procedures, relevant medical and 
medication history and the reporting of signs and symptoms related to elevated liver 
enzymes, or

a confirmed clinical diagnosis explaining the elevated liver enzymes.
Table 8–1: Close Observation Liver Safety Required Laboratory Assessments
Initial serum chemistry 
and coagulation panel
Albumin
First sample after AST or ALT 
> 3 X ULN
Alkaline phosphatase
Alanine-aminotransferase (ALT / GPT)
Differential blood count
Cholinesterase
Conjugated (direct) bilirubin
Creatinine kinsase
γ-GT (gamma-GT)
LDH
Total bilirubin
INR, aPTT
Hepatitis serology 
Anti-Hepatitis A virus IgM antibodies
-
Hepatitis B virus surface antigen
-
Anti-Hep. B surface antibodies
-
Anti-Hep. B core total antibodies
-
Anti Hep. B IgM antibodies
-
Hepatitis B PCR (viral copies)
Anti-Hepatitis C virus antibodies
-
Hepatitis C PCR (viral copies)
-
Anti-Hepatitis D virus antibodies (if 
positive, automatically test HDV RNA)
-    Anti-Hepatitis E virus IgM (if positive, 
automatically test HEV RNA
Anti-Cytomegalovirus (CMV) IgM Antibodies
Anti-Epstein-Barr Virus (EBV) IgM Antibodies
Herpes simplex IgM (anti HSV IgM)
Autoimmune serology
IgG level (gamma globulins)
Anti-mitochondrial antibodies
Anti-nat DNA Antibodies
Anti-sm Antibodies
Metabolic and genetic 
etiology
A1AT level
Ceruloplasmin
Ferritin
Iron
Total iron binding capacity (TIBC)
Follow-up samples 
during close 
observation:
Albumin
To be repeated 2 to 3 times 
per week until normalization of 
ALT or AST
Alkaline phosphatase
Alanine-aminotransferase (ALT/ GPT)


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Aspartate-aminotransferase (AST/ GOT)
Blood count, full (including eosinophils)
Cholinesterase
CK
Conjugated (direct) bilirubin
Total bilirubin
γ-GT (gamma-GT)
Hemoglobin
LDH
Further laboratory tests 
to be considered*
Brucellosis, Leptospirosis (to be analysed 
from EDTA-blood sample), Toxoplasmosis  
*Additional further tests to be performed on case-by-case decision among Investigator, Medical Monitor and Lab 
Physician.
Abbreviations: A1AT = alpha-1 antitrypsin; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; CK = creatine kinase; DNA = deoxyribonucleic acid; 
EDTA = ethylenediaminetetraacetic acid; GOT = glutamic oxaloacetic transaminase GPT = glutamic-pyruvic 
transaminase; GT = glutamyl transferase; HSV = Herpes simplex virus; IgG = immunoglobulin G; IgM = 
immunoglobulin M; INR = international normalized ratio; LDH = lactate dehydrogenase; PCR = polymerase 
chain reaction
8.4
Treatment of Overdose

In this study, an overdose is defined as an intentional or accidental administration of 
investigational drug, to or by a study participant, at a dose which is higher than the 
dose assigned to that individual participant according to the study protocol 

There is no known specific treatment for an overdose with BAY 1817080 (no 
antidote)

An overdose should be treated as clinically indicated based on signs and symptoms 

Overdose per se will not be reported as an AE and/or SAE unless it is associated with 
clinically relevant signs and/or symptoms, or an intentional overdose taken with 
possible suicidal and/or self-harming intent (see Sections 10.3.1 and 10.3.2). In these 
cases, if feasible, a plasma sample for PK analysis may be obtained, ideally as soon as 
possible after the overdose, with recording of date and time of sampling.  
8.5
Pharmacokinetics
Blood samples will be collected for measurement of plasma concentrations of BAY 1817080 
as specified in the SoA. Samples collected at additional time points during the study will be 
measured too. Timing of samples collection at randomization visit (Visit 2) and EoI visit 
(Visit 6) is provided in Table 8–2. Timing of samples collection at week 4 (Visit 4) and week 
8 (Visit 5) is provided in Table 8–3. At Visits 2 and 6, pre-dose as well as 2 hours and 4 hours 
post-dose samples will be collected. At Visits 4 and 5, only 6 hours post-dose samples will be 
collected. A ±15 min time window is allowed for all samples. 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sample, as well as the time of the last 
dose and the closest meal before or after that last dose will be recorded.
Samples will be used to evaluate the PK of BAY 1817080. In addition, it is planned to 
optionally perform an explorative metabolite analysis in human plasma. Results will be 
reported under separate cover, if applicable.


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Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g., sample handling sheets or laboratory manual).
Baseline (Visit 2) 

Up to 1 hour before administration of the morning dose of study intervention (trough)

2 hours after administration of the morning dose of study intervention

4 hours after administration of the morning dose of study intervention
Table 8–2: PK Sampling (Visit 2)
Visit 2 
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
2h
4h
Blood sample for PK
X
Recording of the time and type of meal before dosing
X
Administration of morning dose of study intervention
X
Blood sample for PK
X
Recording of the time and the type of meal closest to
the tablet intake during the visit
X
Blood sample for PK
X
Recording of the time and the type of meal closest to 
tablet intake during the visit
X
Abbreviations:  h = hours; PK = pharmacokinetic
Visits 4 and 5

6 hours after administration of the morning dose of study intervention
Table 8–3: PK Sampling (Visits 4 and 5)
Visit 4 and Visit 5
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
00
6h
Administration of morning dose of study intervention
X
Blood sample for PK
X
Recording of the time and the type of meal closest to 
tablet intake in the morning
X
Abbreviations:  h = hours; PK = pharmacokinetic


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End of Intervention (Visit 6)

Up to 1 hour before administration of the morning dose of study intervention (trough)

2 hours after administration of the morning dose of study intervention

4 hours after administration of the morning dose of study intervention
Table 8–4: PK Sampling (Visit 6)
Visit 6 
Cycle of procedures
Order of 
procedures Starting point of procedures
Time interval (h)
1 h 00
00
2h
4h
Blood sample for PK
X
Recording of the time and the type of meal closest to the 
tablet intake in the evening before the visit
X
Administration of morning dose of study intervention
X
Blood sample for PK
X
Recording of the time and the type of meal closest to the 
tablet intake during the visit
X
Blood sample for PK
X
Recording of the time and the type of meal closest to the 
tablet intake during the visit
X
Abbreviations:  h = hours; PK = pharmacokinetic
Population pharmacokinetic (popPK) analysis
The systemic exposure of BAY 1817080, drug-related pharmacodynamic (PD) biomarker 
and/or safety and efficacy measurements collected during the trial might be analyzed using 
nonlinear mixed effects modeling.
Mixed effects models, e.g., popPK models, describe the relationship between dose and time 
and variables such as drug plasma concentrations. Both structural and random effects are 
involved in this relationship. A preliminary popPK compartmental model will be further 
developed using the concentration of the drug as the dependent variable.
The potential influence of relevant participant covariates (e.g., body weight) and optionally 
efficacy, PD biomarkers or safety laboratory parameter can be included in the PK/PD 
modeling using population approaches. A separate evaluation plan, providing details of the 
model building process and evaluation will be provided prior to the beginning of the 
popPK/PD analysis. Results obtained by popPK/PD modeling will be presented in a separate 
report that may also include PK data from other studies with BAY 1817080.
The modeling analyses might be started prior to database lock. If this is applicable, 
appropriate measures will be taken to maintain blinding of the study team, e.g., data will be 
stored separately, and members of the study team will neither have access to the 
randomization list nor to individual data.
Plasma concentration data for all participants will be listed in the clinical study report.
8.6
Pharmacodynamics
See Section 8.5 for details. 


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8.7
Genetics
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study. See Section 8.8 for details.
8.8
Biomarkers
In this study, genetic as well as non-genetic biomarkers will be investigated. Genetic 
investigations may be of any kind, except for whole genome sequencing.
Blood samples will be collected for biomarkers as indicated in the SoA.

Timing: see Section 1.3 for planned time-points of sample collection.

Sample handling and storage: details on the collection, processing, shipment and 
storage of samples will be provided in separate documents (e.g., sample handling 
sheets or lab manual). Samples may be stored for a maximum of 15 years (or according 
to local regulations) following the end of the study at a facility selected by the sponsor 
to enable further analyses.

Reporting: the results of biomarker investigations may be reported separately (e.g., in 
the Biomarker Evaluation Report).
8.8.1
Biomarkers Monitoring Disease Activity
Various factors may be involved in the pathogenesis of the syndrome of RUCC. To further 
investigate potential mechanisms affected by BAY 1817080, candidate biomarkers indicative 
of disease activity will be investigated in blood samples. Candidate monitoring biomarkers 
may include (but are not limited to), for example neurogenic and/or inflammatory markers.
8.8.2
Pharmacogenetic Biomarkers
Genetic predisposition that might be associated with treatment response to BAY 1817080 
and/or genetic determinants of cough sensitivity and/or associated comorbidities will be 
investigated.
The phenotypic heterogeneity of patients may be caused by genetic factors (27). In needs to 
be explored, whether some of the recently discussed genetic variants within neuropathic 
processing contribute to cough sensitivity and response to therapy in chronic pain. DNA 
samples will be utilized for genotyping of candidate genes suggested to play a role in cough 
syndrome, neuropathic processes and/or afferent hypersensitivity.
A blood sample will be obtained from those participants, who have signed an informed 
consent form. The sample may be used as source of germline DNA. 
Pharmacogenetic analyses may include targeted sequencing of the candidate genes and allele 
specific PCR analyses, for example. The methods will be chosen according to current state of 
the art.
Details on the collection, processing, shipment and storage of samples will be provided in 
separate documents (e.g., sample handling sheets or lab manual). Samples may be stored for a 
maximum of 15 years (or according to local regulations) following the end of the study at a 
facility selected by the sponsor to enable further analyses.
The results of genetic investigations may be reported separately (e.g., in the Biomarker 
Evaluation Report).


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8.8.3
Other Biomarkers
In addition to the biomarkers described in Sections 8.8.1 and 8.8.2, further biomarkers related 
to the mode of action or the safety of BAY 1817080 and similar drugs may be examined. The 
same applies to further biomarkers deemed relevant to pulmonary diseases and associated 
health problems. These investigations may include e.g., diagnostic, safety, PD, monitoring, or 
potentially predictive biomarkers.
8.9
Health Economics / Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9.
Statistical Considerations 
9.1
Statistical Hypotheses
The primary endpoint for this study will be the change from baseline in 24-hour cough count
after 12 weeks of intervention. The primary efficacy aim is the detection of a trend in the dose 
relationship for the primary efficacy endpoint. For detecting an overall trend, or a dose-
response signal, each of the dose-response shapes in the candidate set will be tested, i.e., the 
null hypotheses: “The response at all doses is equal” will be tested against the alternative 
“There is a dose-response-relationship”. This will be done using a single contrast test based 
on contrast coefficients, taking the actual estimated effect per intervention group into account. 
For each of the  = 4 intervention groups (i.e., the placebo group and the 3 active 
intervention groups of BAY 1817080) the response is ,  = 1, … , .
For each model ,  = 1, … , 4, in the candidate set
the null hypothesis
:    = 0 
will be tested against
the respective 1-sided alternative hypothesis
:      >  0,
where  = (, … ,  )′ is an optimized contrast vector for the doses,
 = (, … ,   )′ = (#  ($, %  ), … , #  ($&, %  ))′ and
# is the dose-response model   =  #($, %) + (.
A more detailed description of the multiple comparison procedure modelling (MCP-Mod)
approach and the models used will be given in Section 9.4.
9.2
Sample Size Determination 
Sample size calculations were performed for establishing evidence of a drug effect across the 
doses, that is, detecting a statistically significant dose response signal for the primary efficacy 
outcome in this study using the MCP-Mod approach.
Treatment effects are here presented on the log scale of average hourly counts, measured over 
24 hours (see Section 9.4.2 for calculation details and interpretation).
Assuming a true change in cough count under placebo after 12 weeks of -0.19 (17% 
reduction), a maximum cough count change of -0.35 for BAY 1817080 over placebo (30% 


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reduction relative to placebo), a common standard deviation of 0.8, a set of plausible dose-
response shapes including Emax and sigmoidal Emax models (chosen based on BAY 
1817080 effects in Study 18184 combined with literature review), random allocation of 
participants to dose groups according to a 1:1:1:1 ratio, a sample size of 50 participants per 
dose groups will have at least 85% power to demonstrate a dose- response relationship, using 
a one-sided test at a type I error rate of α=0.10. Approximately 236 participants will be 
randomized to achieve 200 evaluable participants for an estimated total of 50 evaluable 
participants per intervention group. The number of participants to be randomized might be 
increased if more participants than expected become unevaluable due to COVID-19 related 
circumstances, to maintain the goal of 50 evaluable participants per intervention group.
With this sample size, the dose-response curve is expected to be estimated with 80%
confidence bands of half-widths of 0.14 to 0.16, depending on the underlying dose-response 
relationship.
9.3
Populations for Analyses 
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Full analysis set (FAS)
All participants randomly assigned to study intervention.
Safety analysis set (SAF)
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the intervention they actually 
received.
Per protocol set (PPS)
All participants randomly assigned to study intervention, who 
have no validity findings affecting efficacy. Further details 
will be specified in the SAP, ACIR and the BRR.
Abbreviations: ACIR = Assessment Criteria and Identification Requirement; BRR = Blind Review Report; ICF = 
informed consent form; SAP = statistical analysis plan
The efficacy endpoints will be analyzed using the PPS, with analyses on the FAS serving as 
sensitivity analyses. The safety endpoints will be analyzed using the SAF. 
9.4
Statistical Analyses
9.4.1
General considerations
The statistical analysis plan (SAP) will be developed and finalized before unblinding of the 
database and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. It will provide further 
details on the planned analysis for all efficacy, safety and other endpoints.
This section is a summary of the planned statistical analyses with focus on the primary and 
secondary efficacy endpoints.
The statistical analyses will be performed using SAS; the version used will be specified in the 
SAP. There will be separate analysis plan for psychometric properties, scoring and assessment 
of SCCD.


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Continuous variables will be analyzed using at least the following descriptive statistics: 
number of non-missing observations, arithmetic mean and standard deviation, median, 
minimum and maximum. Discrete data will be analyzed using frequency tables.
The primary efficacy analysis is based on a while on treatment estimand strategy. The goal is 
to estimate the effect of the intervention in those participants who tolerate the intervention, 
adhere to the intervention schedule and follow all relevant protocol procedures. The analysis 
will be performed on the PPS population. The primary variable will be the change from 
baseline in 24-hour cough count after 12 weeks of intervention. The intercurrent events 
“discontinuation of study intervention” and “non-compliance with study intervention” will be 
handled with the while on treatment strategy, and for participants experiencing such an event, 
the last observation of the endpoint prior to the event will be carried forward. Participants 
with intercurrent events that lead to exclusion from the PPS will be excluded from the 
analysis. Handling of intercurrent events related to COVID-19 will be described in the SAP.
Other intercurrent events will be disregarded. The population-level summary will be the 
estimated mean of change from baseline in the logarithm of average hourly cough count by 
intervention group.
9.4.2
Primary Endpoints
The primary efficacy endpoint is the change from baseline in 24h cough count after 12 weeks 
of intervention. Baseline is defined as the measurement at Visit 2. The raw 24h cough count 
will be standardized to an average hourly count, and then log-transformed for the analysis due 
to the expected range and distribution of the data. After applying a log-transformation, the 
data are expected to be normally distributed.
The primary analysis will be performed on participants in the PPS who have valid cough 
count measurements both at baseline and at least one post-baseline measurement. Supporting 
analyses will be performed on the FAS. Further sensitivity analyses will be specified in the 
SAP.
The MCP-Mod method combining MCP (multiple comparison procedures) principles with 
modeling techniques will be used for the primary statistical analysis. This method allows the 
flexibility of modeling for dose estimation, while preserving the robustness to model 
misspecification associated with MCP procedures.
3 active doses of BAY 1817080 will be used in this study: 25 mg, 75 mg, and 150 mg BID, 
with an additional placebo arm, corresponding to a 0 mg dose. The measurement of the 
primary efficacy endpoint at dose * will be a normally distributed variable +, i.e., the change 
from baseline in log (average hourly cough count). For the dose-response relationship we 
assume
+ = #(*, %) + (.
It is assumed that the change from baseline after 12 weeks of intervention is -0.19 under 
placebo and -0.54 at the maximum possible dose. 
The candidate set of models for #(*, %) consists of four models, two Emax models with 
parameter ,-= 30 and ,-= 50 and two sigmoidal models with the parameters ,- = 30 
and .. = 3, and  ,- = 60 and .. = 5. All these candidate models assume a 
monotonically decreasing dose-response. The parameters of the models are based on Phase 2a 
data and literature review. The dose-response candidate models are shown in Table 9–1. 


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Table 9–1: Dose-Response Candidate Models
Model
Response as function of dose d
Emax1
-0.19 - 0.42 * d / (30 + d)
Emax2
-0.19 - 0.47 * d / (50 + d)
sigmoidal Emax1
-0.19 - 0.35 * d^3/(30^3 + d^3)
sigmoidal Emax2
-0.19 - 0.35 * d^5/(60^5 + d^5)
The corresponding dose-response relationships of the candidate models are shown in Figure 
9–1.
Figure 9–1: Candidate Set of Dose Response Curves
Based on these models and the observed data optimal contrasts  and the corresponding 
critical value will be calculated. A more detailed description will be provided in the SAP.
Based on the optimal contrast and the critical values a one-sided test with 1 = 0.1 based on 
the maximum value of the test statistics for the models in the candidate set will be performed. 
The MCP-Mod method takes multiplicity into account, and thus no further multiplicity 
adjustments have to be performed.
If at least one contrast test is statistically significant, then a dose-response signal is considered 
to be established. The best model can be selected out of the statistically significant models in 
the candidate set for the next step: modeling and estimation. The selection of the dose-
estimation model will be based on an assessment of the p value. If no candidate model is 
statistically significant, the procedure stops indicating that a dose-response relationship cannot 
be established from the observed data.


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Supportive and sensitivity analyses will include pairwise comparisons of each active dose 
with placebo, and corresponding analyses on the FAS. Further details will be given in the 
SAP.
9.4.3
Secondary Endpoints
The following table gives an overview of the secondary efficacy endpoints and outlines the 
key features of the planned analyses. Further details will be provided in the SAP.
Secondary Efficacy Based on Cough Counts

Percentage of participants with a ≥30% 
reduction from baseline in 24-hour 
cough count after 12 weeks of 
intervention (measured by cough 
recording digital wearable monitoring 
device)

Change from baseline in 24-hour cough 
count after 2, 4, and 8 weeks of 
intervention (measured by cough 
recording digital wearable monitoring 
device)

Change from baseline in awake cough 
frequency per hour after 2, 4, 8 and 12 
weeks of intervention (measured by 
cough recording digital wearable 
monitoring device)

The proportion of participants meeting 
the responder threshold will be 
compared across intervention groups 
using a Chi-square test.

The secondary efficacy endpoints of 
cough count at different time points and 
awake cough count will be analyzed 
similar to the primary efficacy endpoints
HrQoL and PRO Associated Secondary 
Endpoints

Change from baseline in cough related 
quality of life (measured by Leicester 
Cough Questionnaire) after 12 weeks of 
intervention

Change from baseline in cough severity 
after 12 weeks of intervention 
(measured by Cough Severity Visual 
Analogue Scale (VAS))

Percentage of participants with a ≥30 
scale units reduction from baseline after 
12 weeks of intervention (measured by 
cough Severity VAS)

Percentage of participants with a ≥1.3-
point increase from baseline after 12 
weeks of intervention (measured with 
Leicester Cough Questionnaire (LCQ) 
Total Score)

The change from baseline will be 
analyzed by means of a mixed-model for 
repeated measurements (MMRM). This 
will be further detailed in the SAP

The proportion of participants meeting 
VAS and LCQ responder thresholds by 
intervention group will be compared 
across intervention groups using a Chi-
square test.
The secondary endpoint of TEAEs will be analyzed by descriptive statistics, such as 
frequency tables. All TEAEs will be tabulated according to the affected system organ class 
and preferred term, as coded by the Medical Dictionary for Regulatory Affairs (MedDRA). 
Further tables will be provided for serious and/or drug related TEAEs. 
A TEAE is defined as any event arising or worsening after the start of study drug 
administration until 14 days after the last study medication intake.


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The summaries will be provided by intervention group and overall.
9.4.4
Exploratory Endpoints
The analysis of the exploratory endpoints will be described in the SAP.
9.4.5
Other Safety Endpoints
All safety analyses will be performed on the Safety Analysis set (SAF). All tabulations will be 
descriptive.
The number of participants with pre-treatment and post-treatment AEs will be also assessed.
9.4.6
Other Analyses 
Summary statistics will be presented by intervention group and overall. Frequency tables for 
qualitative data will be provided. Medical history findings will be summarized using 
MedDRA terms.
PK, PD, and biomarker exploratory analyses will be described in the SAP finalized before 
database lock, or in separate analysis plans. The population PK/PD analysis will be presented 
separately from the main clinical study report (CSR).
The psychometric properties of SCCD will be evaluated to support qualification of SCCD as 
an endpoint for RUCC. These exploratory analyses results will be presented separately from 
the CSR. 
In addition, the dose-dependency of taste-related AEs will be assessed using a logistic 
regression model.
Any other pre-specified analyses will be described in the SAP finalized before database lock.
9.5
Interim Analyses 
Not applicable to this study.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 


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The investigator may be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests prior to the start of study, and 
in case of any changes, within 1 year after completion of the study.
10.1.3
Informed Consent Process
The investigator will explain the nature of the study to the participant or his/her legally 
authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC and study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant. 
10.1.4
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5
Committees Structure
A Steering Committee will be established to ensure a proper study conduct according to the 
state of the art. The Steering Committee will be responsible for all scientific aspects of the 


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study and it will ensure that study execution and management of the study are of the highest 
quality. The Steering committee will consist of investigators and a chair.
10.1.6
Dissemination of Clinical Study Data
Result Summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3 and 4
and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers' 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States (US) and European 
Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (e.g., cough recorder data, PRO date, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically 
or electronically signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for at least 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 


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destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Cough recordings and records entered on the tablet and hand-held device are considered 
source data. All other source data will be specified on the Source Data Identification Check 
List. 
10.1.9
Study and Site Start and Closure
The study start date is the date of first patient first visit (FPFV).
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required data, documents, and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant
and should assure appropriate subject therapy and/or follow-up
10.1.10
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10–1 will be performed by the central laboratory, apart from urine 
pregnancy tests which are to be done at the trial sites. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.


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Table 10–1: Protocol-Required Safety Laboratory Assessments
Laboratory assessments
Parameters
Hematology
Erythrocytes, Hemoglobin, Hematocrit, Leukocytes, Platelets
Blood Chemistry1
Sodium, Potassium, Calcium, Magnesium, Phosphorus, Creatinine, 
Cystatin C, Total protein, Albumin, eGFR 2
Liver enzymes
Alkaline phosphatase, γ-GT (gamma GT), Alanine-
aminotransferase (ALT, former GPT), Aspartate-aminotransferase 
(AST, former GOT), Total bilirubin
Carbohydrate metabolism
Serum glucose, Hemoglobin-A1C (HbA1C)
Lipids
Total cholesterol, Triglyceride, HDL-cholesterol, LDL-cholesterol
Coagulation 
Prothrombin time (Quick), Activated partial thromboplastin time 
(aPTT), Fibrinogen, International normalized ratio (INR), 
Antithrombin III (ATIII) 3
Pancreas
Pancreatic α-amylase, Lipase
Pregnancy testing4
For women of child-bearing potential only, serum test at Visit 1, 
otherwise urine pregnancy tests every 4 weeks until the last study 
visit (SFU Visit)
COVID-19 testing5
Quantitative reverse transcription polymerase chain reaction (qRT-
PCR) for SARS-CoV-2 nucleic acid, SARS-CoV-2   
Immunoglobulin G antibodies
NOTES:
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after 
liver stopping or monitoring event are given in Section 8.3.6. All events of ALT >3 × upper limit 
of normal (ULN) and bilirubin >2 × ULN or ALT >3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), must 
be reported as an SAE .
2 Estimated glomerular filtration rate calculated by Modification of Diet in Renal Disease (MDRD) 
formula. Japan-specific formula will be applied for participants enrolled at Japan sites (see
Section 10.6).
3 Screening ATIII results will be available to the investigator/sites as soon as measured and 
reported by the central laboratory. Considering the potential for unblinding participants 
receiving active treatment with BAY 1817080, the results of ATIII measures at the following 
visits will not be communicated to study teams nor investigators until after unblinding of the 
study.
4 All study-required laboratory assessments will be performed by a central laboratory, with the 
exception of urine pregnancy tests.
5 An oropharyngeal swab will be collected for quantitative measurement of the virus and serum 
will be collected for measurement of antibodies (serology).
Abbreviations: ALT = alanine aminotransaminase; ATIII = antithrombin III; GOT = glutamic oxaloacetic 
transaminase; GPT = glutamic-pyruvic transaminase; GT = glutamyl transferase; HDL = high-density 
lipoprotein; INR = International normalized ratio; MDRD = Modification of Diet in Renal Disease; SAE = 
serious adverse event; SFU = safety follow-up; ULN = upper limit of normal


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE 
Time period and frequency for collecting AEs and SAEs can be found in Section 8.3.1.
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, 
associated with the use of study intervention, whether or not considered related to 
the study intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention (for definition of study intervention, see 
Section 6).
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or 
SAE. 


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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death
a. Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 were more severe.
b. Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
c.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
d. Is a congenital anomaly/birth defect


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e.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to sponsor in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to sponsor. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor with a copy of any post mortem findings 
(autopsy report). 

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to sponsor will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.


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
The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section).

Contacts for SAE reporting can be found in the Investigator Site File.
SAE Reporting to the Sponsor via Paper CRF

Electronic data transmission of the SAE is the preferred method to transmit this 
information to the sponsor’s Pharmacovigilance department

In rare circumstances and in the absence of email, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRFs within the designated reporting time frames

Paper SAE forms (CRFs), details and contacts for SAE reporting can be found in the 
Investigator Site File


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, confirmation with more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
acceptable effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Guidance:
(See also the Inclusion Criteria in Section 5.1.)
Acceptable effective birth control methods which may not be considered as highly
effective (as per CTFG guidelines):
Acceptable effective birth control methods that result in a failure rate of more than 1% per 
year include:

progestogene-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action


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
male or female condom with or without spermicide7

cap, diaphragm or sponge with spermicide7
Highly effective birth control methods (that can achieve a failure rate of less than 1% 
per year when used consistently and correctly) include (as per CTFG guidelines):

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral
o
injectable
o
implantable 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS) 

Bilateral tubal occlusion 

Vasectomized partner8

Sexual abstinence9
No measures are required for male participants
Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in this 
study. This applies only to male participants who have received at least one dose of
study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor as being aware of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
                                                
7 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly effective, birth control methods.
8 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner
of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the
surgical success.
9 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study interventions. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant.


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Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure.
Female Participants who Become Pregnant 

The investigator will collect pregnancy information on any female participant whose 
pregnancy is detected after the first dose of study intervention. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within of 24 
hours of learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents, unless local law or specific 
circumstances of the respective case allow otherwise, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure.

Any female participant who becomes pregnant while participating in the study must 
discontinue study intervention.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related 
to the study intervention by the investigator will be reported to the sponsor as described 
in Section 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 


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10.5
Appendix 5: Device Malfunction or Failure and Medical Device Related 
Events Reporting
A Product Technical Compliant (PTC) is any report about a potential or alleged failure of a 
product in its quality (including the identity, durability, reliability, safety, efficacy or 
performance) or suspect counterfeit. The complaint may or may not represent a potential risk 
to the participant.
Any malfunction or failure of the cough recording device (VitaloJAKTM) including use errors 
or inadequacy in the labeling will be recorded by the clinical/investigational site, including all 
relevant device information, and reported directly to the manufacturer. 
There are three different situations, in which a PTC might need to be reported by the 
investigator. 
a.
When an AE is recorded, the investigator needs to check if a device assigned and worn 
by the corresponding participant operates as intended.
b. When a device malfunction or device failure occurs, the investigator needs to assess 
whether an AE might have occurred in relation to the device complaint.
c.
When a device malfunction, device failure, or use error occurs, without any associated 
AE, this also needs to be captured in the form, especially if it classifies as a reportable 
incident, and immediately forwarded to the sponsor for PTC investigation. 
There are three different categories of medical device related events
Incident
Any malfunction or deterioration in the characteristics and / or performance of a device, as 
well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
led, might lead to or might have led to the death of a participant, or user or of other persons or 
to a serious deterioration in their state of health.
Other reportable incident
Any incident that did not lead to death or serious deterioration in health, but it might do if it 
occurred again under less fortunate circumstances or without intervention of healthcare 
personnel. This may include cases without any medical event reported.
Non-incident
Any device related case that does not fulfill all the three basic incident criteria a-c listed in the 
definition of an “incident” above. This includes reports of:

Deficiencies of a device which are always detected prior to its use

Event is caused by the participant’s condition

Service life or shelf life of the device is expired

Events which did not lead to serious deterioration in state of health or death, because a 
design feature protected against a fault becoming a hazard.

Events where the risk of a death or serious deterioration in state of health has been 
quantified and found to be negligibly small.
In case of an incident and other reportable incident, a PTC always needs to be reported.


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Serious deterioration in state of health (=serious injury) is any AE in relation to a medical 
device if it:

Resulted in a life-threating illness or injury, or

Resulted in a permanent impairment of a body structure or a body function, or

Required in-patient hospitalization or prolongation of existing hospitalization, or

Resulted in medical or surgical intervention to prevent life-threating illness, or 
permanent impairment of a body function or damage to a body structure, or

Led to fetal distress, fetal death or congenital abnormality or birth defect.
The details of the malfunction and medical circumstances will be captured by the investigator 
and then returned to the sponsor.
The processing and reporting of all reportable device events (incidents /other reportable 
incidents) to the authorities will be done by the manufacturer of the device.
10.6
Appendix 6: Country-specific Requirements 
The estimation of GFR is limited by differences in creatinine generation among ethnicities. 
Thus, the MDRD GFR equation is less accurate for Asians, with greater bias at eGFR less 
than 30 mL/min/1.73 m2. In Japan, the equation recommended by the Japanese Society of 
Nephrology (28) will be used for participants enrolled at Japan site in this study.

For men: eGFRcreat(mL/min/1.73m2) = 194×Cr-1.094×age-0.287

For women: eGFRcreat(mL/min/1.73m2) = 194×Cr-1.094×age-0.287×0.739


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10.7
Appendix 7: Abbreviations 
AE
Adverse event
AG
Aktiengesellschaft, public limited company
ALT
Alanine aminotransaminase
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransaminase
ATIII
Antithrombin III
ATP
Adenosine triphosphate
ATS
American Thoracic Society
AUC
Area under the curve
BCRP
Breast cancer resistance protein
BID
Bis in die (twice daily)
BP
Blood pressure
CFR
Code of Federal Regulations Title 21
CI
Cognitive interview
CLO
Close liver observation
COVID-19
Coronavirus disease 2019
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTFG
Clinical Trials Facilitation and Coordination Group
Ctrough
Trough concentration
CYP3A4
Cytochrome P450 3A4
DBP
Diastolic blood pressure
DDI
Drug Development and Drug Interactions
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
eGFRcreat
eGFR using the serum creatinine
EoI
End of intervention
ePRO
Electronic patient report outcome
EQ-5D-5L
European Quality of Life 5 Dimensions 5 Level Scale
ERS
European Respiratory Society
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full analysis set


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FDA
Food and Drug Administration
FEF
Forced expiratory flow
FEV
Forced expiratory volume
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good clinical practice
GFR
Glomerular filtration rate
GLP
Good laboratory practice
GOT
Glutamic oxaloacetic transaminase
GPT 
Glutamic pyruvic transaminase
GT
Glutamyl transferase
HDV
Hepatitis D virus 
HEV
Hepatitis E virus
HR
Heart rate
HrQoL
Health-related quality of life
HRT
Hormonal replacement therapy
HSV
Herpes simplex virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobin G
IgM
Immunoglobin M
IND
Investigational new drug
INR
International normalized ratio
IRB
Independent Review Board
IWRS
Interactive Web Response System
kHz
Kilohertz
LCQ
Leicester Cough Questionnaire
LDH
Lactate dehydrogenase
MCP
Multiple comparison procedure
MCP-Mod
Multiple comparison procedure modelling
MD
Medical doctor
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
OATP1B1
Organic anion transporting polypeptide 1B1


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OATP1B3
Organic anion transporting polypeptide 1B3
P2X3
Purinergic receptor P2X
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
P-gp
P-glycoprotein
PIF
Photoirritation factor
PK
Pharmacokinetic(s)
popPK
Population pharmacokinetic(s)
PPS
Per protocol set
PRO
Patient reported outcome
PT
Prothrombin time
PTC
Product Technical Complaint
QoL
Quality-of-life
qRT-PCR
Quantitative reverse transcription polymerase chain reaction
RNA
Ribose Nucleic Acid
RO
Receptor occupancy
RUCC
Refractory and/or unexplained chronic cough
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SAS
Statistical Analysis System
SCCD
Severity of Chronic Cough Diary
SFU
Safety follow-up
SoA
Schedule of Activities
SOP
Standard operating procedure
SUKL
State Institute for Drug Control (Czechia Health Authority)
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse events
TLC
Total lung capacity
TV
Termination visit
ULN
Upper limit of normal
UV
Ultraviolet
VAS
Visual Analogue Scale
VR
Ventricular rate
WAV
Waveform audio file format


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WOCBP
Woman of childbearing potential


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10.8
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
10.8.1
Amendment 1 (17 JUL 2020)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
The main purpose of this global amendment is to address COVID-19 pandemic related issues. 
Changes include additional benefit risk assessments, exclusion criteria as well as COVID-19 
testing for participants. The discontinuation criteria was also modified to explain how to 
manage participants who get infected with COVID-19 while on study.     
Other changes have also been made in this global amendment. Following are the description 
of change and a brief rationale.
These changes do not affect the design or the overall concept of the study. 
Section # 
and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA), 8.2.5 Clinical Safety 
Laboratory Assessments 
and 10.2 Appendix 2: 
Clinical Laboratory Tests
COVID-19 testing was 
added. Survival status check 
was added for participants 
who do not show up at the 
safety follow-up visit.
To address issues related to the 
COVID-19 pandemic.
2.3 Benefit/Risk 
Assessment
A new Section 2.3.3.7 Risk 
of contracting SARS-CoV-2 
infection during study 
participation was added.
5.2 Exclusion Criteria
COVID-19 related exclusion 
criteria #18 was added.
7.1.1 Rechallenge
Criteria for rechallenge was 
added.
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Withdrawal from study 
criteria added to clarify what 
to do if a participant 
becomes SARS-CoV-2 virus 
RNA positive while on study.
9.2 Sample Size 
Determination and 9.4.1 
General considerations
Statistical considerations 
adjusted for COVID-19 
related issues. 
1.3 SoA, 5.2 Exclusion 
Criteria, and 8.2.2 Vital 
Signs
Exclusion criteria #11 was 
modified to exclude 
participants with 
systolic/diastolic blood 
pressure levels 
≥160/100 mmHg at the 
screening visit.
To align with the local amendment 
for Czechia (to satisfy the request 
from Czechia Health Authority, State 
Institute for Drug Control [SUKL]).


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Section # 
and Name
Description of Change
Brief Rationale
1.1 Synopsis, 3 Objectives 
and Endpoints and 9.4.3 
Secondary Endpoints
The secondary endpoint for 
safety and tolerability 
evaluation was changed to 
“frequency and associated 
severity of treatment-
emergent adverse events 
(TEAEs)”.
To align with other studies within 
P2X3 program. 
9.4.5 Other Safety 
Endpoints
The incidence of AEs during 
pre-treatment and post-
treatment periods was added 
as other safety endpoints.
1.3 SoA and 6.1 Study 
Intervention Administered
V6/TV was changed to be a 
2-day visit. 
To clarify when cough recording 
device will be dispensed and when 
other procedures could be 
conducted at V6/TV.
2.3.1 Summary
The introduction of chronic 
cough was edited. 
To address comment from the 
Steering Committee.
2.3.3.6 Potential 
Phototoxicity
PIF value was corrected.
Correction of error.
4.1 Overall Design and 5.1 
Inclusion Criteria
Inclusion criteria #2 was 
modified for clarification.
To address potential 
misinterpretations.
6 Study Intervention
The definition of study 
intervention was added.
For clarification.
6.5 Prior and Concomitant 
Therapy
Text for Section 6.5.1 Other 
Treatment Considerations 
was adjusted.
To align with the request from FDA.
Text “up to 12 weeks prior to 
screening” was added to the 
definition of prior and 
concomitant therapy.
In Table 6-2: the prohibited 
timeframe of apixaban, 
dabigatran, edoxaban, 
digoxin was edited to reflect 
“until 2 weeks after end of 
intervention (Eol)”; over-the-
counter cough medicine was 
adjusted to include all 
non-narcotic cough 
medicine.
For clarification. 
In Table 6-2: phenobarbital 
was removed from the strong 
CYP3A4 inducers examples. 
Correction of error.
8. Study Assessments and 
Procedures
Text on cough history 
recording was copied and 
added from Section 8.3.1. 
For clarification.
8.2.1 Physical 
Examinations and 1.3 SoA
“Day 1” of Visit 2 was 
changed to “Day 0" to match 
the SoA.
Correction of error.
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE information
Added that additional details 
on smell and taste related 
AEs will be collected.
This was erroneously missed in the 
original protocol.
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE information, 
The collection of AEs was 
changed to “commence from 
signing the informed consent 
To align with other studies within 
P2X3 program. 


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Section # 
and Name
Description of Change
Brief Rationale
1.3 SoA, 8.2.1 Physical 
Examinations, and 8.2.3 
Electrocardiograms
form”.
8.3.6 Liver-Related AEs
Stopping criteria for close 
observation was added.
This was erroneously missed in the 
original protocol.
Hepatitis serology tests for 
hepatitis D and E was added 
in Table 8-1.
Hepatitis B core IgG antibody 
test was removed from Table 
8-1.
Correction of error.
8.3.6 Liver-Related AEs, 
2.3.3.4 Potential Changes 
in Liver Function 
Laboratory Parameters, 
7.1 Discontinuation of 
Study Intervention, and 
10.2 Appendix 2: Clinical 
Laboratory Tests
The criteria for liver-related 
AE and SAE reporting was 
modified.
To address the inconsistency 
throughout the document.
8.5 Pharmacokinetics
Text for explorative 
metabolite analysis was 
added.
To align with the request from FDA.
9.4.6 Other Analyses
Text for dose-dependency of 
taste-related AEs was moved 
from Section 9.4.3 to 9.4.6.
This was erroneously put under the 
analysis of the secondary endpoints 
in the original protocol.
10.2 Appendix 2: Clinical 
Laboratory Tests
“Japan-specific MDRD 
formula” corrected to be 
“Japan-specific formula” in 
Table 10-1 footnote #2.
Correction of error.
In addition, minor editorial and formatting revisions have been made throughout the 
document.


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10.9
References
1.
Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of 
causes, key components of the diagnostic evaluation, and outcome of specific therapy. 
Am Rev Respir Dis. 1990;141(3):640-7.
2.
Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 
2008;371(9621):1364-74.
3.
Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, et al. A 
worldwide survey of chronic cough: a manifestation of enhanced somatosensory 
response. Eur Respir J. 2014;44(5):1149-55.
4.
French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of 
life. Arch Intern Med. 1998;158(15):1657-61.
5.
Belvisi MG, Birrell MA, Wortley MA, Maher SA, Satia I, Badri H, et al. XEN-D0501, 
a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough 
in Patients with Refractory Cough. Am J Respir Crit Care Med. 2017;196(10):1255-
63.
6.
Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. 
Diagnosis and management of cough executive summary: ACCP evidence-based 
clinical practice guidelines. Chest. 2006;129(1 Suppl):1s-23s.
7.
Achilleos A. Evidence-based Evaluation and Management of Chronic Cough. Med 
Clin North Am. 2016;100(5):1033-45.
8.
Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Ribas CD, et al. 
ERS guidelines on the diagnosis and treatment of chronic cough in adults and 
children. Eur Respir J. 2019:1901136.
9.
NCT03310645. Repeat Doses of BAY 1817080 in Healthy Males & Proof of Concept 
in Chronic Cough Patients. Bayer. 2017. ClinicalTrials.gov.
10.
Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, et al. The global 
epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur 
Respir J. 2015;45(5):1479-81.
11.
Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, et al. The 
effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised 
placebo-controlled study. Eur Respir J. 2019;54(1).
12.
NCT02612610. A 12-Week Study to Assess the Efficacy and Safety of AF 219 in 
Subjects With Refractory Chronic Cough (MK-7264-012). Afferent Pharmaceuticals, 
Inc. 2015. ClinicalTrials.gov.
13.
Schumann J, Boudon S, Ulrich P, Loll N, Garcia D, Schaffner R, et al. Integrated 
preclinical photosafety testing strategy for systemically applied pharmaceuticals. 
Toxicol Sci. 2014;139(1):245-56.
14.
Brignall K, Jayaraman B, Birring SS. Quality of life and psychosocial aspects of 
cough. Lung. 2008;186 Suppl 1:S55-8.
15.
Turner RD, Bothamley GH. Cough hypersensitivity syndrome: clinical measurement 
is the key to progress. Eur Respir J. 2015;45(5):1507-8.
16.
Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, et al. 
ERS guidelines on the assessment of cough. Eur Respir J. 2007;29(6):1256-76.
17.
Davidson K, Shojaee S. Managing Massive Hemoptysis. Chest. 2019:S0012-
3692(19)31386-8.
18.
FDA. FDA Guidance for Industry: In Vitro Drug Interaction Studies — Cytochrome 
P450 Enzyme- and Transporter-Mediated Drug Interactions. Available on: 


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https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-
drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-
interactions. Accessed date: 03 Jul 2020. 2020.
19.
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers,Table 5-1. 14Nov2017.Available online: https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers#table5-1 Accessed date: 05Nov2019. 2017.
20.
Wewers ME, Lowe NK. A critical review of visual analogue scales in the 
measurement of clinical phenomena. Res Nurs Health. 1990;13(4):227-36.
21.
Lee KK, Matos S, Evans DH, White P, Pavord ID, Birring SS. A longitudinal 
assessment of acute cough. Am J Respir Crit Care Med. 2013;187(9):991-7.
22.
NCT03449147. A Study of Gefapixant (MK-7264) in Adult Participants With Chronic 
Cough (MK-7264-030). Merck Sharp & Dohme Corp. 2018. ClinicalTrials.gov.
23.
Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a 
symptom specific health status measure for patients with chronic cough: Leicester 
Cough Questionnaire (LCQ). Thorax. 2003;58(4):339-43.
24.
Raj AA, Pavord DI, Birring SS. Clinical cough IV:what is the minimal important 
difference for the Leicester Cough Questionnaire? Handb Exp Pharmacol. 
2009(187):311-20.
25.
Philip H. Quanjer SS, Tim J. Cole, Janet Stocks. GLI-2012 Desktop Software for 
Individual Calculations. Global Lung Function Initiative. Available from: 
https://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-
tools/desktop-individual-calculator.aspx. Dec. 2014.
26.
FDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. Available online: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation. 
Accessed date 11Nov2019. 2009.
27.
Mazzone SB, Chung KF, McGarvey L. The heterogeneity of chronic cough: a case for 
endotypes of cough hypersensitivity. Lancet Respir Med. 2018;6(8):636-46.
28.
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised Equations 
for Estimated GFR From Serum Creatinine in Japan. American Journal of Kidney 
Diseases. 2009;53(6):982-92.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
Randomized, double-blind, parallel group, phase 2b dose-finding, 
efficacy and safety study of 12-week twice daily oral administration 
of BAY 1817080 compared to placebo in the treatment of refractory 
and/or unexplained chronic cough (RUCC) 
NCT Number: 
NCT04562155  
Document Date: 
08-Jul-2021 
 


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 1 of 32
 
 
 
Title page 
Randomized, double-blind, parallel group, phase 2b dose-finding, 
efficacy and safety study of 12-week twice daily oral administration of 
BAY 1817080 compared to placebo in the treatment of refractory and/or 
unexplained chronic cough (RUCC) 
Dose-finding, efficacy and safety study of BAY 1817080 in the treatment of 
refractory and/or unexplained chronic cough 
Bayer study drug 
BAY 1817080  
Study purpose: 
Investigation of safety and tolerability; dose-finding  
Clinical study 
phase: 
IIb 
Date: 
08 JUL 2021 
Study No.: 
 
20393 
Version: 
2.0 
Author: 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended 
solely for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, 
the appearance of product names without these symbols does not imply that these names are not 
protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
 
PPD


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 2 of 32
 
 
 
Table of Contents 
Title page ............................................................................................................................... 1 
Abbreviations ........................................................................................................................ 3 
1. 
Introduction ................................................................................................................... 4 
2. 
Study Objectives ............................................................................................................ 5 
3. 
Study Design .................................................................................................................. 5 
4. 
General Statistical Considerations .............................................................................. 6 
4.1 
General Principles ........................................................................................................ 6 
4.2 
Handling of Dropouts .................................................................................................. 6 
4.3 
Handling of Missing Data ............................................................................................ 6 
4.3.1 
General rules ............................................................................................................. 6 
4.3.2 
COVID-19 pandemic-related missing data .............................................................. 7 
4.4 
Interim Analyses and Data Monitoring ....................................................................... 7 
4.5 
Data Rules .................................................................................................................... 7 
4.5.1 
Definition of Baseline ............................................................................................... 7 
4.5.2 
Handling of Repeated Measurements ....................................................................... 8 
4.5.3 
Data Rules in case of COVID-19 infection .............................................................. 8 
4.5.4 
Twenty-four-hour cough recording .......................................................................... 9 
4.5.5 
Cough Severity VAS and SCCD .............................................................................. 9 
4.5.6 
Unscheduled Visits and Safety Follow-up (SFU) .................................................... 9 
4.5.7 
Definition of Region ................................................................................................. 9 
4.5.8 
Definition of Treatment-emergence ......................................................................... 9 
4.5.9 
Data Rules for laboratory measurements................................................................ 10 
4.6 
Blind Review ............................................................................................................. 10 
5. 
Analysis Sets ................................................................................................................ 10 
5.1 
Assignment of analysis sets ....................................................................................... 10 
6. 
Statistical Methodology .............................................................................................. 11 
6.1 
Population characteristics .......................................................................................... 11 
6.1.1 
Demographics and Baseline Characteristics........................................................... 11 
6.1.2 
Subject Validity and Disposition ............................................................................ 12 
6.1.3 
Medical History ...................................................................................................... 12 
6.1.4 
Prior and Concomitant Medications ....................................................................... 12 
6.2 
Efficacy ...................................................................................................................... 14 
6.2.1 
Primary Efficacy Endpoint ..................................................................................... 14 
6.2.2 
Secondary Efficacy Endpoints................................................................................ 20 
6.2.3 
Exploratory Endpoints ............................................................................................ 23 
6.2.4 
Subgroup Analyses ................................................................................................. 25 
6.3 
Pharmacokinetics/pharmacodynamics (PK/ PD) ....................................................... 26 
6.4 
Safety ......................................................................................................................... 26 
6.4.1 
Adverse Events (AEs) ............................................................................................ 26 
6.4.2 
Study Treatment Duration and Exposure ............................................................... 28 
6.4.3 
Liver Function Laboratory Parameters ................................................................... 30 
6.4.4 
Other Safety Assessments ...................................................................................... 31 
7. 
Document history and changes in the planned statistical analysis ......................... 31 


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 3 of 32
 
 
 
8. 
References .................................................................................................................... 32 
 
Abbreviations 
 
ADT 
ACIR 
AE 
AIC 
BID 
BRR 
Adenosine triphosphate  
Assessment Criteria and Identification Requirement  
Adverse event 
Akaike information criterion 
Bis in die (twice a day) 
Blind Review Report 
CI 
CS 
CSH 
CSP 
Confidence interval 
Compound symmetry 
Heterogenous compound symmetry 
Clinical Study Protocol  
CSR 
EQ-5D-5L 
Clinical Study Report 
European Quality of Life 5 Dimension 5 Level Scale 
FAS 
FEV1 
FVC 
HrQoL 
ICE 
ICF 
Full Analysis Set 
Forced expiratory volume in 1 second 
Forced vital capacity 
Health-related Quality of Life 
Intercurrent event 
Informed consent form 
LOS  
LCQ 
MCP 
MCP-Mod 
Listing only set 
Leicester Cough Questionnaire 
Multiple comparison procedure 
Multiple comparison procedure modelling 
MedDRA 
MAR 
MED 
MMRM 
Medical Dictionary for Regulatory Activities 
Missing at random 
Minimal Effective Dose 
Mixed Model Repeated Measurement 
N/A 
P2X3 
PGI-C 
PGI-S 
PK 
popPK 
Not applicable 
Purinergic receptor P2X  
Patient Global Impression of Change 
Patient Global Impression of Severity 
Pharmacokinetic(s) 
Population pharmacokinetic(s) 
PPS 
PRO 
RUCC 
Per protocol set 
Patient report outcome 
Refractory and/or unexplained chronic cough 
SAE 
SAF 
Serious adverse event 
Safety analysis set 
SAP 
SARS-CoV-2 
SAS 
SFU 
SCCD 
VAS 
WHO-DD 
Statistical Analysis Plan 
Severe Acute Respiratory Syndrome Coronavirus 2 
Statistical Analysis System 
Safety Follow-Up 
Severity of Chronic Cough Diary 
Visual Analogue Scale 
WHO Drug Dictionary 
 
 
 


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 4 of 32
 
 
 
 
1. 
Introduction 
Cough is one of the symptoms for which patients most frequently seek medical attention.  In 
most patients, cough manifests itself as an acute cough, e.g. due to an upper respiratory 
infection, and lasts a few days to weeks and is usually self-limiting.  In general cough is 
classified, on the basis of its duration, into acute cough (<3 weeks), sub-acute cough (3–8 
weeks) and chronic cough (>8 weeks).  The prevalence of chronic cough, i.e. a cough that is 
not self-limiting, is estimated to be around 10% in the adult population.  In several patients an 
underlying etiology may contribute to the cough (such as gastroesophageal reflux disease, 
asthma, rhinosinusitis) and the cough in those patients is adequately addressed by treating the 
underlying etiology. However, in a proportion of those their cough is not well controlled, 
even with optimum treatment for all such potential underlying etiologies. These patients are 
termed as having a refractory chronic cough.  In other patients with chronic cough no 
potential underlying etiology is found – those are patients with a so-called idiopathic (or 
unexplained) chronic cough. Despite the aforementioned distinction, publications in the 
public domain often summarize both refractory and idiopathic chronic cough simply as 
refractory chronic cough. In this study, both will be jointly referred to as refractory and/or 
unexplained chronic cough (RUCC). 
Inflammatory response with the activation of cytokines, and other processes such as 
mechanical stretching, may lead to local release of adenosine triphosphate (ATP). 
P2X3 is a non-selective cation channel that is activated by ATP and has been described as a 
prominent mediator of pain. The expression of P2X3 is up-regulated during inflammation, 
and it may sensitize peripheral nerves to play a role in central sensitization. 
Beside their prominent role in nociception and in pain-related diseases involving both chronic 
and acute pain, P2X3 receptors have been shown to be involved in genitourinary, 
gastrointestinal and respiratory conditions and disorders, including overactive bladder and 
chronic cough.  In chronic cough, ATP might be released from epithelial cells, glial cell etc. 
which in turn activates P2X3 on sensory vagal afferent fibers in the airway leading to cough.  
The concept of treating refractory chronic cough has been already clinically validated. 
 Eliapixantis a potent and selective P2X3 ion channel antagonist and provides a new approach 
for the treatment of chronic cough, and also of several other indications, including 
endometriosis, diabetic neuropathic pain, bladder disorders such as interstitial cystitis or 
overactive bladder. 
Therefore, Eliapixant presents a potential target for e.g. chronic-cough therapy. 
This Statistical Analysis Plan (SAP) is based on the Integrated Clinical Study Protocol (CSP) 
BAY 1817080 / 20393,  
• Version 1.0, dated 19 DEC 2019 
• Version 2.0, Amendment 1, dated 17 JUL 2020 
• Version 3.0, Amendment 2, dated 28 APR 2021 
 
 


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 5 of 32
 
 
 
2. 
Study Objectives 
The objective of this study is to identify the optimal dose of P2X3 receptor antagonist 
Eliapixant in patients with RUCC and further assess efficacy and characterize safety and 
tolerability profile ofEliapixant .  
The primary study objective is to  
• assess the efficacy of P2X3 receptor antagonist Eliapixant as compared with placebo 
in terms of change in 24-hour cough count from baseline to week 12 
The secondary study objectives are to  
• further assess efficacy of Eliapixant  
• further characterize safety and tolerability profile of Eliapixant  
 
Other objectives are to 
• further describe the efficacy profile of BAY 1817080 through the impact of 
intervention as patient reported outcomes 
• to further evaluate the impact of the disease and associated comorbidities 
A table that lists all primary, secondary and exploratory objectives with the corresponding 
endpoints can be found in section 3 of the CSP. Additional other objectives listed in the CSP 
refer to analyses that are outside the scope of this SAP, and thus are not described in this 
document. 
3. 
Study Design 
This is a randomized, placebo-controlled, double-blind, parallel group, multi-center phase 2b 
dose-finding, efficacy and safety study. 
The study population consists of participants with a cough that has lasted for at least 12 
months (unresponsive to treatment options) with a diagnosis of refractory chronic cough 
and/or idiopathic (unexplained) chronic cough and with persistent cough for at least the last 8 
weeks before screening. 
Approximately 337 participants will be screened to achieve 236 randomly assigned to study 
intervention and 200 evaluable participants for an estimated total of 50 evaluable participants 
per intervention group. The number of participants to be randomized might be 
increased if more participants than expected become unevaluable due to COVID-19 related 
circumstances, to maintain the goal of 50 evaluable participants per intervention group. 
Following screening, eligible participants will be randomized to one of four parallel 
intervention groups in a 1:1:1:1 ratio. 
After randomization, each participant will receive one of three doses of Eliapixant (25 mg, 75 
mg or 150 mg) or placebo administered orally with or without food, twice daily (BID) over 
the course of 12 weeks. 
After last intake of study intervention, participants will enter an observational safety follow-
up period of 30±5 days. During this period, AEs will continue to be collected.  
The study will be analyzed once all participants have completed treatment. The last end of 
treatment/premature discontinuation visit will be the cut-off date for the primary completion 
analysis. With that, the full efficacy data will be available, and a full analysis will be provided for 


Statistical Analysis Plan 
BAY 1817080/20393 
Page: 6 of 32
 
 
 
all available data. The study will continue with the safety follow-up for the remaining participants 
and the final analysis for the study will occur at the conclusion of the study. All measures to 
restrict access to unblinding data until the final database closure are described in the study 
blinding plan, that is approved and signed prior to the first unblinding of the database. 
 
For details regarding the Pre-intervention, Intervention and Post-Intervention Period see CSP 
section 4.1. 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software SAS (release 9.4 or higher; 
SAS Institute Inc., Cary, NC, USA) and ValidR (version 3.5.2 or higher; Mango Solutions 
Ltd., UK). 
All variables will be analyzed by descriptive statistical methods. The number of data available 
and missing data, arithmetic mean, standard deviation, minimum, quartiles, median, and 
maximum will be calculated for metric data. For cough count data, in addition, the geometric 
mean and the geometric SD will also be reported. Frequency tables will be generated for 
categorical data. 
In general, confidence intervals (CIs) will be two-sided with a coverage probability of 95%. 
For the primary analysis of the primary efficacy variable, 80% CIs will be reported in addition 
for consistency with the one-sided α-level of 10%. 
 
4.2 
Handling of Dropouts 
A participant who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the participant has already been randomized to study intervention. Dropouts will 
not be replaced. 
4.3 
Handling of Missing Data 
Subjects with missing baseline assessments will be excluded from all analyses that require the 
respective baseline assessment. 
4.3.1 
General rules 
When appropriate, the following rules will be implemented so as not to exclude subjects from 
statistical analyses due to missing or incomplete data: 
4.3.1.1 
Efficacy Variables 
See Section 6 Statistical Methodology, for details of imputation for missing data regarding 
efficacy variables. 
4.3.1.2 
Safety Variables 
Missing AE information 
When only partial dates are available, the following rules will be used for the derivation: 
For incomplete start date of adverse events a worst case assumption is made for the treatment-
emergent flag. For example, if study medication starts on 15 JUL 2020 and the adverse event 


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start date is recorded as JUL 2020, then this is considered treatment-emergent, as it is possible 
the adverse event started while the patient is on study medication. 
Missing intensity, relationship, outcome, serious flag for AEs will be set to missing.  
Missing prior/ concomitant medication information 
For partially/completely missing start or end dates of prior/ concomitant medication, a worst 
case assumption is made, i.e. if there is the possibility that the medication was taken during 
the intervention period, it will be classified as “concomitant”. 
All missing or partial data will be presented in the patient data listings as they are recorded on 
the Case Report Form.  
Additional descriptive analyses in the presence of missing data 
The number of participants who prematurely discontinue the study and study intervention for 
any reason, as well as the reasons for premature discontinuation of study and study 
intervention will be reported.  
All dropouts will be carefully evaluated with respect to baseline characteristics. If necessary, 
additional sensitivity analyses may be performed. 
4.3.2 
COVID-19 pandemic-related missing data 
4.3.2.1 
Efficacy Variables 
Data collected during an active COVID-19 infection (confirmed by a positive SARS-CoV-2 
test by PCR or a positive serology IgG test or an AE confirming COVID-19 infection) will be 
discarded from the analysis as they are expected to be biased (see Section 4.5.3). 
Treatment interruptions and additional pandemic-related reasons for treatment interruption 
will be collected and the time of the interruption will be subtracted from the exposure 
duration (for details see Section 6.4.2). 
The number of participants who prematurely discontinue the study and study intervention for 
any pandemic-related reason, as well as the reasons for premature discontinuation of study 
and study intervention will be reported.  
The number of subjects with missed visits and the number of subjects with missed cough 
count key assessments due to COVID-19 pandemic will be displayed as well as the reason 
why the visit/ assessment was not performed. 
4.3.2.2 
Safety Data 
All available safety data will be reported without any imputations besides the ones described 
in Section 4.3.1.2. 
4.4 
Interim Analyses and Data Monitoring 
Not applicable. 
4.5 
Data Rules 
4.5.1 
Definition of Baseline 
Baseline values for descriptive statistics and model-based analyses will be determined as the 
last non-missing values before the start of treatment. 


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4.5.2 
Handling of Repeated Measurements 
If more than one measurement is available at screening (e.g. for laboratory), the last 
observation of those will be used for descriptive statistics tables as well as for frequency 
tables. In case of repeated measurements at planned time points after intake of study 
medication, the earliest measured value will be used for descriptive statistics tables as well as 
for frequency tables. 
4.5.3 
Data Rules in case of COVID-19 infection  
Efficacy data collected from the start of an active COVID-19 infection until the end of the 
study will be discarded for the primary analysis. The start of an active COVID-19 infection is 
defined as the date of the first positive SARS-CoV-2 test or the first positive serology IgG test 
or the start date of the AE confirming the COVID-19 infection, whichever is earliest.  
The relevant MedDRA preferred terms are:  
• PT: COVID-19 
• PT: COVID-19 pneumonia 
• PT: Coronavirus infection 
• PT: Asymptomatic COVID-19 
• PT: Coronavirus test positive 
• PT: Exposure to SARS-CoV-2 
• PT: Occupational exposure to SARS-CoV-2 
• PT: Middle East respiratory syndrome 
• PT: Severe acute respiratory syndrome 
• PT: Suspected COVID-19 
• PT: COVID-19 treatment 
• PT: SARS-CoV-2 test false negative 
• PT: SARS-CoV-2 test positive 
• PT: SARS-CoV-2 test false positive 
• PT: SARS-CoV-2 antibody test positive 
• PT: SARS-CoV-2 carrier 
• PT: SARS-CoV-2 sepsis 
• PT: SARS-CoV-2 viraemia 
see Appendix 3 [2].  
Sensitivity analyses with inclusion of all available data will be performed for the primary and 
secondary efficacy endpoint (for details see Sections 6.2.1.3.2 and 6.2.2 ).  
The distinguishment of P2X3 related taste AEs from COVID-19 related smell/taste symptoms 
will be done by medical review based on the details of smell/taste disturbance assessments, 
the SARS-CoV-2 test results, the AEs confirming COVID-19 and the timing information.  
 


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4.5.4 
Twenty-four-hour cough recording 
24h-cough recordings with less than 20 hours of valid cough recording will be excluded from 
the primary analysis. A sensitivity analysis including all available cough count data will be 
performed. 
 
4.5.5 
Cough Severity VAS and SCCD 
VAS and SCCD are collected on a daily basis from Visit 1 until the Safety Follow-up Visit.  
The baseline value is calculated as the average of the 14 days up to and including Visit 2, i.e. 
the average of day -13 up to day 0.  
The value at a post-baseline visit is calculated analogously as the average of the 14 days up to 
and including the respective visit.  
If there are less then 14 days between consecutive visits, the average will only be taken over 
the days between the visits and including the respective visit. 
If there are less than 8 out of 14 days available, the value will be set to missing [3]. The VAS 
reported for the day of Visit 1 will not be considered at all for statistical analyses, as it has a 
different recall period. 
For the SCCD item-levelscore calculation rules see Psychometric SAP v3.0. [4]. Missing data 
will not be imputed. 
4.5.6 
Unscheduled Visits and Safety Follow-up (SFU) 
Data from unscheduled visits will generally not be considered for descriptive tables with the 
exception of laboratory parameters see section 6.4.3 and 6.4.4. For the compliance calculation 
data from unscheduled visits will be used see section 6.4.2. The data from unscheduled visits 
will be displayed in the listings in Appendix 16 of CSR. 
For cough severity VAS, PGI-S/C, EQ-5D-5L and LCQ, an extra line showing Safety follow-
up (SFU) data will be added to the respective descriptive tables of the intervention period.   
4.5.7 
Definition of Region 
Subjects will be stratified for randomization according to geographic region  
• Japan,  
• Europe (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, 
Poland, Slovakia, Spain, United Kingdom),  
• ROW (Argentina, Australia, Canada, Russian Federation, Taiwan, Turkey, United 
States). 
 
4.5.8 
Definition of Treatment-emergence 
A treatment-emergent AE is defined as any event arising or worsening after the start of study 
drug administration until 14 days after the last study medication intake.  
 


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4.5.9 
Data Rules for laboratory measurements 
For lab values reported as “<x”, “<x.x”,“ <x.xx” or etc. the value for analysis used will be 
derived by “x/2”, “x.x/2”,“ x.xx/2” etc . For lab values reported as “>x”, “>x.x”,“ >x.xx” or 
etc. the value for analysis used will be derived by increasing the last digit by 1. 
 
4.6 
Blind Review 
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP. 
The number of positive SARS-CoV-2 tests and positive serology IgG tests and the outcomes 
of AEs confirming COVID-19 infections will be monitored throughout the study.  
 
5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
Final decisions regarding the assignment of participants to analysis sets will be made during 
the review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis set(s) (see Section 4.6). 
Enrolled 
                         
All participants who sign the Informed consent form (ICF). 
Full analysis set (FAS) 
 
All participants randomly assigned to study intervention. Participants will be analyzed 
according to the intervention they were randomized to. 
Safety analysis set (SAF) 
 
All participants randomly assigned to study intervention and who take at least 1tablet of study 
intervention. Participants will be analyzed according to the intervention they actually 
received. If participants received different interventions throughout the course of the study, it 
will be decided in the assessment meeting on a case-by-case decision which group they will 
be assigned to for the final analysis.  


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Per protocol set (PPS) 
 
All participants randomly assigned to study intervention, who have no validity findings 
affecting efficacy.  
A list of potential validity findings will be provided in a separate important deviations and 
validity specifications document (Assessment Criteria and Identification Requirement 
(ACIR)) which will be finalized before database lock. The assignment of patients to this 
analysis set will be based on the assessment meetings.  
The patients with invalid/missing baseline cough count measurements or only invalid/missing 
post-baseline cough count measurements will be excluded from the PPS.  
Cough count measurements will be considered invalid if the duration of valid recording is less 
than 20 hours. If the treatment compliance between the previous visit and the visit of the 
cough count measurement is <80% or >120%, the measurement will also be considered 
invalid for the primary analysis. 
Due to the repeated measurements design of the study a patient dropping out of the study may 
still be evaluable for efficacy and will therefore not be excluded from PPS. The minimum 
required treatment duration is up to including Visit 3 to allow for a valid post-baseline cough 
count measurement.  
Participants will be analyzed according to the intervention they actually received. If 
participants received different interventions throughout the course of the study, they will be 
excluded from the PPS. 
Listing Only Set (LOS) 
 
This set contains all screening failures. It will be used for listing purposes only. 
 
The efficacy endpoints will be analyzed using the PPS, with analyses on the FAS serving as 
sensitivity analyses. The safety endpoints will be analyzed using the SAF. All other endpoints 
will be analyzed on the FAS, unless specified otherwise.  
 
6. 
Statistical Methodology 
6.1 
Population characteristics 
6.1.1 
Demographics and Baseline Characteristics 
The following demographic data and baseline characteristics will be summarized: 
• Age at baseline (years); 
• Age category (<60 vs ≥60 years; <65 vs ≥65 years); 
• Sex (male vs. female) 
• Race and ethnicity; 
• Height (cm); 
• Weight (kg) at baseline; 
• BMI (kg/m²); 
• Tobacco smoking history  


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o Pack-years: (<10 vs ≥10 pack-years) 
o Smoking status:  
▪ Never 
▪ Stopped smoking  ≥ 10 years ago  
▪ Stopped smoking 3 to < 10 years ago  
▪ Stopped smoking < 3 years ago  
• Alcohol consumption history 
Demographic variables and baseline characteristics will be summarized using descriptive 
statistics and will be reported for the FAS and PPS. 
Any table displaying demographics and baseline characteristics will be repeated for the 
following COVID-19 pandemic related subgroups: 
• all randomized subjects affected by COVID-19 pandemic related study disruption  
• all randomized subjects with COVID-19 adverse event and/or positive SARS-CoV-2 
PCR test and/or positive serology IgG test after start of treatment 
 
6.1.2 
Subject Validity and Disposition 
Disposition will be summarized by frequency tables. The number of subjects in SAF, FAS, 
PPS, the number of screening failures, patients randomized but not treated, and patients who 
completed study will be summarized.  
Screening failures are patients who were screened, but not randomized. The reason for failed 
screening will be included in the summary.  
A patient completed study if he/she completed all phases of the study including the last visit. 
In addition, a disposition summary by study period (epoch), i.e. screening, treatment, and 
follow-up, will show the number of subjects completing the respective epoch and the number 
of subjects discontinuing it prematurely including information of the reasons for 
discontinuation. The table will include COVID-19 pandemic associated reasons for 
discontinuation, i.e. the information whether decision for discontinuation was made by the 
patient, the physician or was due to logistical reasons.   
 
6.1.3 
Medical History 
Medical history findings will be summarized using Medical Dictionary for Regulatory 
Activities (MedDRA) terms.  
Medical history of chronic cough will be analyzed using descriptive statistics based on the 
FAS and PPS. 
 
6.1.4 
Prior and Concomitant Medications 
The number of participants that used prior and concomitant medication will be analyzed using 
frequency tables based on classified data. The classification will be done according to the 
WHO-DD.  All prior and concomitant medications will be listed separately. The tables will 
display the following three categories: prior, prior/concomitant and post-treatment. 


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Regarding medication data collected during the study course, the following rules will be 
implemented:  
• If the stop time of medication is before the time of the first study drug administration 
then medication is considered to be prior medication. 
• If the start time of medication is before or at the time of the first study drug 
administration and the stop time of medication is after or at the time of the first study 
drug administration then the medication is considered to be concomitant medication. 
• If the start time of medication is at or after the time of the first study drug 
administration and earlier than 14 days after or at the time of the last study drug 
administration then the medication is considered to be concomitant medication. 
• If the start time of medication is later than 14 days after the time of the last study drug 
administration then the medication is considered to be post-treatment medication. 
If time information is missing but only date information is given then classification of 
medication as prior or concomitant will be done by date information only. In such case, if the 
start day of medication is the same date as the first study drug administration, then the 
medication will be classified as concomitant medication. 
6.1.4.1 
Bayer/Standardized Drug Grouping specification 
In addition, the prior/concomitant medication will be displayed using the following 
Bayer/Standardized Drug Groupings:  
• Analgesia producing opioids  
• Benzodiazepines  
• Corticosteroids  
• Non-biologic DMARDs  
• Adjuvant pain medication 
PT: Allergic cough  
PT: Antitussive therapy  
PT: Atopic cough  
PT: Cough  
PT: Cough variant Asthma  
PT: Habit cough  
PT: Upper-airway cough syndrome  
• Interferons  
• Antihistamines and antiallergics 
PT: Allergic cough  
PT: Antitussive therapy  
PT: Atopic cough  
PT: Cough  


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PT: Cough variant Asthma  
PT: Habit cough  
PT: Upper-airway cough syndrome 
• Cardiac glycosides  
• Angiotensin converting enzyme (ACE) inhibitors  
• Macrolides  
• Direct factor Xa inhibitors  
• Direct thrombin inhibitors  
• Other medications for obstructive airways disorders  
• Corticosteroids for obstructive airway disease  
• Leukotriene receptor antagonists for obstructive airway diseases  
• Monoclonal antibodies for obstructive airway diseases 
• Other anti-inflammatory drugs for obstructive airway diseases  
• Long acting beta agonists (LABA)  
• Other bronchodilators  
• Short acting beta agonist (SABA)  
• Strong CYP3A inducers  
• Strong CYP3A inhibitors  
• Proton pump inhibitors  
• Clinical BCRP substrates  
• Clinical OATP1B1 substrates  
• Clinical OATP1B3 substrates  
• Clinical P-gp substrates  
 
6.2 
Efficacy 
6.2.1 
Primary Efficacy Endpoint 
The primary efficacy variable is the change from baseline in 24h cough count after 12 weeks 
of intervention. Baseline is defined as the measurement at Visit 2. The raw 24h cough count 
will be standardized to an average hourly count, and then log-transformed for the analysis due 
to the expected range and distribution of the data. After applying a log-transformation, the 
data are expected to be normally distributed. 
The data will be log-transformed first, before calculating any group means or changes from 
baseline, i.e. the observation of participant i at visit j, 𝑥𝑖𝑗 will be transformed into 𝑦𝑖𝑗=
log⁡(𝑥𝑖𝑗)⁡ with log(.) being the natural logarithm. All inferential statistics and modelling will 


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be based on the log-transformed observations 𝑦𝑖𝑗. However, for easier interpretation of the 
magnitude of effects, the display of the results will focus on values on the original scale. 
This results in display of geometric means for observations obtained at specific visits as  
exp(𝑦̅𝑗
𝑎𝑟𝑖𝑡ℎ) = exp (1
𝑛∑𝑦𝑖𝑗
𝑛
𝑖=1
) 
=⁡exp (1
𝑛∑log(𝑥𝑖𝑗)
𝑛
𝑖=1
) = exp (1
𝑛log ∏𝑥𝑖𝑗
𝑛
𝑖=1
) = exp (log √∏𝑥𝑖𝑗
𝑛
𝑖=1
𝑛
)⁡=⁡𝑥̅𝑗
𝑔𝑒𝑜 
where 𝑦̅𝑗
𝑎𝑟𝑖𝑡ℎ and 𝑥̅𝑗
𝑔𝑒𝑜 denote arithmetic and geometric means, respectively. 
Similarly, for the change from baseline, the arithmetic mean of the difference on the log scale 
translates into the ratio of geometric means on the original scale: 
exp(𝑦̅𝑐ℎ𝑔
𝑎𝑟𝑖𝑡ℎ) = exp (1
𝑛∑(𝑦𝑖𝑗−⁡𝑦𝑖,𝐵𝐿)
𝑛
𝑖=1
) =⁡exp(𝑦̅𝑗
𝑎𝑟𝑖𝑡ℎ−𝑦̅𝐵𝐿
𝑎𝑟𝑖𝑡ℎ) ⁡ 
= exp (log(𝑥̅𝑗
𝑔𝑒𝑜) −log(𝑥̅𝐵𝐿
𝑔𝑒𝑜)) = exp (log (
𝑥̅𝑗
𝑔𝑒𝑜
𝑥̅𝐵𝐿
𝑔𝑒𝑜)) =⁡
𝑥̅𝑗
𝑔𝑒𝑜
𝑥̅𝐵𝐿
𝑔𝑒𝑜 
For ease of interpretation, in addition to the ratio of geometric means, the relative change (of 
geometric means) in % will be displayed as  
𝑥̅𝑟𝑒𝑙⁡𝑐ℎ𝑔= (
𝑥̅𝑗
𝑔𝑒𝑜
𝑥̅𝐵𝐿
𝑔𝑒𝑜−1) ∗100% =⁡
𝑥̅𝑗
𝑔𝑒𝑜−⁡𝑥̅𝐵𝐿
𝑔𝑒𝑜
𝑥̅𝐵𝐿
𝑔𝑒𝑜
∗100%.  
For cough counts per hour, any value smaller than 0.1 will be included into the analysis as 
0.05 (in order to avoid taking the log of 0 if a response of 0 is recorded). 
The treatments the primary analysis investigates are Eliapixant (25 mg, 75 mg, 150 mg 
BID), and placebo. The minimum required treatment duration is up to including Visit 3 for 
inclusion in the PPS.  
Intercurrent events: 
a) Early discontinuation of study or study intervention for any reason: use data until 
discontinuation (while on treatment strategy). For handling the intercurrent event 
(ICE) of early discontinuation of the study and of the study intervention the while on 
treatment strategy will be applied. This strategy considers measurements of the 
endpoint up until the time of the intercurrent event. The last observation of the 
endpoint prior to the event will be used in the analysis. LOCF for all missing data due 
to early discontinuation will be applied. 
 
b) Non-compliance with study intervention: use data during compliant periods (while on 
treatment strategy) on a visit-by-visit approach: 
compliance will be calculated for the period between two consecutive visits. If the 
compliance is too low (i.e. below 80%), or too high (i.e. >120%, which is highly 
unlikely) the data collected during this period and the subsequent visit will not be 
used. Instead, the mean value of the observations between the adjacent compliant 


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visits (i.e. end point of the preceding compliant period and end point of the following 
compliant period) is taken. If there is no following period that can be used, LOCF will 
be applied. If there is no preceding compliant period, the mean value of the baseline 
value and the observation of the end of the first compliant period will be used. 
c) COVID-19 infection: use data prior to an active COVID-19 infection which is defined 
as the date of the first positive SARS-CoV-2 test or the date of the first positive 
serology IgG testor the start date of the AE confirming a COVID-19 infection (while 
on treatment), whichever is earliest.  Symptoms of an acute COVID-19 infection are 
expected to have a major impact on the primary endpoint. Since long term effect of 
such an infection is unknown, only the data prior to the intercurrent event of an active 
COVID-19 infection will be used. LOCF imputation will be used in this case. 
The population the primary estimand bases on is the population as described by the 
inclusion/exclusion criteria given in section 5 of the CSP and further by the PPS analysis 
population in section 5.1.  
The population-level summary is the estimated geometric mean ratio (relative to baseline) of 
the primary efficacy variable by intervention group. 
6.2.1.1 
Primary Analysis  
For the primary efficacy variable, it is planned to perform a test for a dose-response signal in 
the study population, under the assumption of a monotone dose-response relationship in the 
dose range considered. The MCP-Mod method [5] combining multiple comparison 
procedures principles with modeling techniques (MCP-Mod) will be used for the primary 
analysis of the primary efficacy variable. This method allows the flexibility of modeling for 
dose estimation, while preserving the robustness to model misspecification associated with 
MCP procedures. More specifically, it is planned to use a generalization of the original MCP-
Mod method which allows to perform dose-response testing and modeling in conjunction with 
the response variable being described by a parametric model [6].The key idea of this 
generalization is to decouple the dose-response model from the expected response so that the 
dose response can be characterized using a suitable parameter in the probability distribution 
of the response. 
Assumptions 
It is assumed that the primary efficacy variable, denoted as⁡𝑌, is observed at the patient level 
for the 4 parallel groups corresponding to doses levels:  
(placebo =) 𝑑1 < 𝑑2 < … < 𝑑K, where K = 4. 
Furthermore, assume that the probability model for the patient responses 𝑌 includes 
parameters 𝜇𝑑1, . . . , 𝜇𝑑𝐾 for the changes from baseline in log (average hourly cough count) 
after 12 weeks of intervention capturing the dose-response effect for the doses 𝑑1, 𝑑2 , … , 𝑑K. 
This probability model may depend on other (nuisance) parameters and covariates.  
Subsequently, it is assumed that the dose-response parameters 𝜇𝑑𝑘,  𝑘= 1, … , 𝐾 are related 
through a dose-response model 𝜇𝑑= 𝑓(d, 𝜽) where 𝑓(. ) is parameterized by a vector of 
parameters 𝛉.  Let 𝝁̂ denote the vector of estimated dose-response parameters obtained from 
an appropriate estimation method for the assumed parametric model. The key assumption for 
the generalized MCP-Mod method is that 𝝁̂ has an approximate distribution 𝑁(𝝁, 𝑺), where 𝑺 
denotes the variance-covariance of 𝝁̂. The estimates for 𝝁̂ and 𝑺̂ are obtained first, while the 
estimation of 𝜽 is done in a separate second stage based on 𝝁̂ and 𝑺̂.  


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The candidate set of models for 𝑓(. ) consists of four models, two Emax models with 
parameter 𝐸𝐷50= 30 and 𝐸𝐷50= 50 and two sigmoidal models with the parameters 𝐸𝐷50 = 30 
and 𝐻𝑖𝑙𝑙= 3, and  𝐸𝐷50 = 60 and 𝐻𝑖𝑙𝑙= 5. All these candidate models assume a 
monotonically decreasing dose-response for the changes from baseline on the log scale. The 
parameters of the models are based on Phase 2a data and literature review. The dose-response 
candidate models are shown in Figure 6–1 and Table 6–1.  
 
Figure 6–1: Candidate Set of Dose Response Curves 
 
 
 
Analysis 
In a first step the mean parameter estimates from an ANCOVA model and the corresponding 
covariance matrix are obtained. After this step, these two parameters will then be used during 
the rest of the MCP-Mod procedure. 
For the estimation of 𝝁̂ and 𝑺̂ in the initial stage SAS will be used. All MCP-Mod steps will 
be performed using the R “DoseFinding” package (version 0.9-17 or higher) [7].    
 
Table 6–1: Dose-Response Candidate Models 
Model 
Response as function of dose d 
Emax1 
-0.19 - 0.42 * d / (30 + d) 
Emax2 
-0.19 - 0.47 * d / (50 + d) 
sigmoidal Emax1 
-0.19 - 0.35 * d^3/(30^3 + d^3) 
sigmoidal Emax2 
-0.19 - 0.35 * d^5/(60^5 + d^5) 


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Step 1: Estimation of 𝝁 and 𝑺⁡from ANCOVA model with covariate adjustment 
An ANCOVA model, following adjustment for baseline cough count and region via the 
inclusion of covariates z, will be used to estimate the expected dose response 𝜇𝑑𝑘 in each dose 
group k.  
For participant i the response is then defined by: 
𝑌𝑘𝑖= 𝛽0 + 𝑧1𝑘𝑖𝛽1 + 𝑧2𝑘𝑖𝛽2 + 𝜇𝑑𝑘+ 𝜀𝑘𝑖 
 
where 𝜀𝑘𝑖~𝒩(0, 𝜎2), 𝑘= 1, … , 𝐾 and  𝑖= 1, … , 𝑛𝑘. 
Let 𝝁̂ denote the vector of estimated dose-response and let⁡𝑺 denote the variance-covariance 
of 𝝁̂ .The estimate of the covariance matrix S will be denoted by 𝑺̂. 
Step 2: Detection of dose-response signal 
For detecting an overall trend, or a dose-response signal, each of the M=4 dose-response 
shapes in the candidate set will be tested, using a single contrast test. 
For each model m in the candidate set  
the null hypothesis 
 𝐻0𝑚: (𝒄𝑚)′𝝁= 0   
will be tested against  
the respective 1-sided alternative hypothesis, 
𝐻1𝑚: (𝒄𝑚)′𝝁> 0   
where 𝑐𝑚= (𝑐𝑚1, … , 𝑐𝑚𝐾)′ is the optimal contrast vector representing model m. The contrast 
coefficients for the m-th model are chosen such that they maximize the power for a single 
candidate model shape  
 𝜇𝑚
0 = (𝜇𝑚1
0 , … , 𝜇𝑚𝐾
0 )′ = (𝑓𝑚
0(𝑑1, 𝛉𝑚
0 ), … , 𝑓𝑚
0(𝑑K, 𝛉𝑚
0 ))′, 
where 𝑓0⁡is the standardized version of the dose-response model 
𝑓(𝑑, 𝛉) =⁡𝜃0 + 𝜃1𝑓0(𝑑, 𝛉0). 
In this parameterization, 𝜃0 is a location parameter and 𝜃1 is a scale parameter such that only 
𝛉0⁡determines the shape of the model function. The optimal contrast coefficients 𝒄𝑚depend 
only on the parameters in the standardized model function 𝜽0 . 
The optimum contrast coefficients and critical values for the four contrast tests on the dose-
response shapes will be derived based on the guestimates for parameters 𝛉0 of standardized 
versions of the models in the candidate set specified at the design stage, the actual sample size 
for each treatment group after study completion, and the covariance matrix 𝑺̂ estimated from 
actual data [6]. 
Each dose-response model m will be tested using a single contrast test:  
𝑇𝑚⁡ = (𝒄𝑚)′⁡𝝁̂/[(𝒄𝑚)′𝑺̂𝒄𝑚]𝒎,𝒎
𝟏/𝟐 
where [𝑨]𝒎,𝒎 denotes the mth diagonal element of the matrix 𝑨. 
The final detection of a dose-response signal is based on the maximum contrast test statistic 
𝑇𝑚𝑎𝑥=⁡max(𝑇1 , … , 𝑇4) and can be concluded if 𝑇𝑚𝑎𝑥> 𝑞1−𝛼, where 𝑞1−𝛼 is the multiplicity 
adjusted critical value at level 𝛼= 0.1. The MCP-Mod method takes multiplicity into 
account, and no further multiplicity adjustments are needed.  


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The selection of the best dose-estimation model will first be based on an assessment of the p 
value of the contrast tests. If no candidate model is statistically significant, the procedure 
stops indicating that a dose-response relationship cannot be established from the observed 
data. If there is one or more models with a significant adjusted p value, they will be retained 
and fitted as described in the next step.  
Step 3: Modeling and estimation of target doses 
The selected dose-response models (with a significant dose-response trend detected at the 
previous step) will be fitted to 𝝁̂ and 𝑺̂ to estimate the model parameters 𝛉 using a generalized 
least squares (GLS) estimation criterion [6]. 
The evaluation of these models will be based on Akaike’s Information Criterion (AIC), p 
value and numerical stablility.  
In case more than one appropriate model has been identified, model averaging based on the 
individual model fits will be applied. The following weights for model m proposed by 
Buckland et. al. [8] will be used: 
𝑤𝑚=
exp⁡(−𝐴𝐼𝐶𝑚/2)
∑
exp⁡(−𝐴𝐼𝐶𝑙2
⁄ )
𝐿
𝑙=1
 
To estimate the target dose(s) of interest the minimal effective dose (MED) will be 
determined:  
𝑀𝐸𝐷=⁡𝑎𝑟𝑔𝑚𝑖𝑛(𝑑1,𝑑4]{f(𝑑, 𝜃) > f(𝑑1, 𝜃) +⁡∆} 
where ∆⁡ is a clinically relevant effect. The MED will be provided for the following change 
relative to placebo: 
• -15%, ∆ = log(0.85) = – 0.163 
• -20%, ∆⁡= log(0.8)   = – 0.223 
• -25%, ∆ = log(0.75) = – 0.288 
• -30%, ∆⁡= log(0.7)   = – 0.357 
• -35%, ∆ = log(0.65) = – 0.431 
The final choice of the target dose will be based on the analyses of the primary, secondary and 
other efficacy variables, as well as safety considerations. 
 
6.2.1.2 
Secondary Analysis  
As a secondary analysis pairwise comparisons of the active dose groups with the placebo 
group will be performed without controlling the family-wise error rate, by calculating the 
80% and 95% confidence intervals for the difference in primary efficacy variable between 
each active dose and placebo.  
 
6.2.1.3 
Sensitivity Analysis  
6.2.1.3.1 Treatment effect in FAS 
The primary analysis of the primary endpoint will be repeated on the FAS population defined 
in section 5.1.  
 


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6.2.1.3.2 COVID-19 related sensitivity analyses 
1. The primary analysis will be repeated on the subpopulations of patients in PPS with 
and without an active COVID-19 infection (positive SARS-CoV-2 test by PCR / 
positive serology IgG test / an AE confirming COVID-19). 
2. The same estimand as the primary efficacy estimand will be used with the 
modification that COVID-19 affected efficacy measurements will not be excluded, i.e. 
all available cough count data will be used for analysis. (The ICEs a) and b) will be 
handled as described in Section 6.2.1.)  
3. The analysis specified in 2. will be repeated on the FAS population. 
6.2.1.3.3 Accounting for taste-related events  
In order to account for confounding by taste disturbances, the primary analysis will be 
repeated on the subpopulations of patients in PPS with and without at least one treatment-
emergent taste-related adverse event which cannot be attributed to a SARS-CoV-2 infection. 
6.2.1.3.4 Accounting for respiratory tract infections  
To account for the possible impact of respiratory tract infections on cough count, the primary 
analysis will be repeated on the subpopulations of patients in the PPS with and without a 
treatment-emergent AE belonging to the MedDRA HLGT “Respiratory tract infection”, to the 
HLT”Upper respiratory tract infections” or to the HLT”Lower respiratory tract and lung 
infections”.  
 
6.2.1.3.5 Accounting for different lengths of measurements 
Since average numbers of cough counts per hour will be used, different lengths of 
measurement will not be a problem. However, time of sleep / awake times may be a source of 
bias for the overall cough rate. Therefore, a sensitivity analysis will be performed with a 
weighted average of awake and asleep cough counts, i.e. weighting awake cough counts as if 
always coming from 16 hours and sleep cough times as if always coming from 8 hours. The 
following formula will be used: 
𝑐𝑜𝑢𝑔ℎ⁡𝑐𝑜𝑢𝑛𝑡𝑐𝑜𝑟𝑟= 2 3
⁄ 𝑐𝑜𝑢𝑔ℎ⁡𝑐𝑜𝑢𝑛𝑡𝑎𝑤𝑎𝑘𝑒+ 1 3
⁄ 𝑐𝑜𝑢𝑔ℎ⁡𝑐𝑜𝑢𝑛𝑡𝑠𝑙𝑒𝑒𝑝 
Here, ‘cough count’ means the average cough count per hour (on the original scale), as in the 
above analyses. The analysis will follow the outline given above. 
Further sensitivity analyses may be performed if the missing data patterns suggest further 
exploration.  
 
6.2.2 
Secondary Efficacy Endpoints  
For each secondary endpoint the following three analyses will be provided: 
1. The same estimand as the primary efficacy estimand will be used, in particular the 
analysis will be on PPS and COVID-19 affected efficacy measurements will be 
excluded. (The ICEs a), b) and c) will be handled as described in Section 6.2.1.) 
2. The analysis specified in 1. will be repeated on FAS.  
3. The analysis specified in 1. will be repeated on PPS including also all data during and 
after potential COVID-19 infection (treatment policy strategy for ICE COVID-19 
infection in c) and the ICEs a) and b) will be handled as described in Section 6.2.1.)). 


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6.2.2.1 
Secondary Efficacy Based on Cough Counts 
• Percentage of participants with a ≥30% reduction from baseline in 24-hour cough 
count after 12 weeks of intervention  
The proportion of participants meeting the responder threshold by intervention group 
will be compared across intervention groups using a Chi-square test. 
Estimates and two-sided 80% and 95% confidence intervals will be provided for each 
treatment group and the treatment differences. Clopper Pearson confidence intervals 
will be calculated for each treatment group, while for treatment differences, due to the 
computational burden of exact unconditional confidence limits, Wald asymptotic 
confidence limits will be calculated. 
 
The following two secondary efficacy endpoints will be analyzed with the same model as the 
primary efficacy endpoint. 
• Change from baseline in 24-hour cough count after 2, 4, and 8 weeks of intervention.  
• Change from baseline in awake cough frequency per hour after 2, 4, 8 and 12 weeks of 
intervention 
 
6.2.2.2 
HRQoL and PRO Associated Secondary Endpoints 
• Change from baseline in cough related quality of life (measured by Leicester Cough 
Questionnaire (LCQ)) after 12 weeks of intervention. 
The scoring algorithm described in the LCQ manual [9] will be used.  
The analysis will be the change in LCQ (each domain as well as the total score) from 
baseline to week 12 using mixed model repeated measures (MMRM). This method 
will assume that any missing data is Missing at Random (MAR). 
The model statement is:  
∆𝑌𝑗𝑡𝑘𝑙= 𝑌𝑗0 + 𝜇0 + 𝑡𝑟𝑡𝑘+ 𝑣𝑖𝑠𝑖𝑡𝑡+ (𝑡𝑟𝑡∗𝑣𝑖𝑠𝑖𝑡)𝑘𝑡+ 𝑟𝑒𝑔𝑖𝑜𝑛𝑙+ 𝑃𝑗+ 𝜀𝑗𝑡𝑘𝑙, 


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where ∆𝑌𝑗𝑡𝑘𝑙is the change from baseline to visit t for subject j within treatment group k 
and region l. 
𝜇0              is the intercept 
Yj0              is the baseline covariate effect 
trtk                     is the fixed effect of treatment group k 
visitt                 is the fixed effect visit t  
(trt∗visit)kt   is the interaction fixed effect of treatment k by visit t 
Regionl        is the fixed effect of stratification factor 
Pj                        is the patient specific random effect. 
P and 𝜀𝑡𝑘𝑙 will be assumed as normally distributed random variables. 
Correlations among measurements taken on the same patient will be modelled with an 
unstructured covariance assumption.  The degrees of freedom will be computed 
according to the method detailed by Kenward and Roger. 
 
For each active dose 𝑑𝑘 the null hypothesis: 
𝐻0𝑘:⁡⁡⁡⁡⁡⁡⁡⁡⁡𝜇1 = 𝜇𝑘 
will be tested against the alternative hypothesis  
𝐻1𝑘:⁡⁡⁡⁡⁡⁡⁡⁡⁡𝜇1 ≠𝜇𝑘 
within this model. 
Least square mean estimates, estimates of treatment differences and corresponding 
confidence intervals (CIs) will be computed. The least square mean estimates of 
treatment difference at week 12 are the main estimates of interest; however, 
differences at all other visits and overall treatment differences (averaged across all 
visits) will also be estimated as exploratory endpoints. 
 
The core SAS-code to be used is the following (variable and dataset names are for 
illustration only and may be subject to change):  
 
proc mixed data=adqslcq;  
class subject treat visit region;  
model change = base treat visit region treat*visit /ddfm=KR;  
repeated visit / subject=subject type=un group=treat;  
lsmeans treat*visit /cl diff;  
ODS OUTPUT TESTS3=TYPE3 LSMeans=LSMEAN ESTIMATES=ESTIM;  
run; 
If the model does not converge or the SAS log contains additional notes (e.g. that the 
Hessian matrix is non-positive definite), it will be tried to fit a simplified model assuming 
following covariance structure: without same covariate parameters within treatment 
groups (by deleting the group option) first, then heterogenous compound symmetry 
(CSH, without group option), then compound symmetry (CS, without group option). 
 
• Change from baseline in cough severity after 12 weeks of intervention (measured by 
Cough Severity Visual Analogue Scale (VAS)) 


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The change will be analyzed using MMRM as described above. 
 
6.2.2.3 
Further secondary efficacy endpoints 
• Percentage of participants with a ≥30 scale units reduction from baseline after 12 
weeks of intervention (measured by Cough Severity VAS) 
• Percentage of participants with a ≥1.3- point increase from baseline after 12 weeks of 
intervention (measured with LCQ Total Score) [10]  
The proportion of participants meeting Cough Severity VAS and LCQ Total Score responder 
thresholds by intervention group will be compared across intervention groups using a Chi-
square test. 
Point estimates and CIs for the probability of being a responder will be displayed by 
intervention group.   
 
6.2.3 
Exploratory Endpoints 
For each exploratory endpoint the following three analyses will be provided: 
1. The same estimand as the primary efficacy estimand will be used, in particular the 
analysis will be on PPS and COVID-19 affected efficacy measurements will be 
excluded. (The ICEs a), b) and c) will be handled as described in Section 6.2.1.) 
2. The analysis specified in 1. will be repeated on FAS.  
3. The analysis specified in 1. will be repeated on PPS including also all available data 
during and after potential COVID-19 infection (treatment policy strategy for ICE 
COVID-19 infection in c) and the ICEs a) and b) will be handled as described in 
Section 6.2.1.)). 
 
6.2.3.1 
Exploratory Efficacy Based on Cough Counts 
• Change from baseline in night cough frequency per hour after 2, 4, 8, and 12 weeks of 
intervention (measured by cough recording digital wearable monitoring device) 
The exploratory efficacy endpoints of night cough count at different time points will 
be analyzed similar to the secondary efficacy endpoint of awake cough count at 
different time points. 
• Percentage of participants with a ≥50% and ≥70% reduction from baseline in 24-hour 
cough count after 12 weeks of intervention 
The proportion of participants meeting the responder threshold will be compared 
across intervention groups using a Chi-square test. 
Point estimates and CIs for the probability of being a responder will be displayed by 
intervention group. 
 
6.2.3.2 
HRQoL and PRO Associated Exploratory Endpoints 
• Change from baseline in cough severity after 2, 4, and 8 weeks of intervention 
(measured by Cough Severity VAS) 


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• Change from baseline in cough related quality of life after 2, 4, and 8 weeks of 
intervention (measured by LCQ) [each domain as well as the total score]) 
Summary statistics (arithmetic mean, SD, minimum, median, quartiles and maximum) and 
difference to baseline will be provided for the LCQ and VAS by treatment.  
As exploratory endpoint the change in Cough Severity VAS and LCQ from baseline to Week 
2, Week 4 and Week 8 will be analyzed with the same repeated measurement model as the 
secondary efficacy endpoint. 
 
• Change from baseline in daily cough severity after 2, 4, 8, and 12 weeks of 
intervention (measured by the individual items of the Severity of Chronic Cough 
Diary [SCCD]) 
• Patient Global Impression of Change (PGI-C) and change from baseline in Patient 
Global Impression of Severity (PGI-S), after 2, 4, 8 and 12 weeks of intervention. 
 
SCCD (individual items), PGI-C and PGI-S will be summarized by minimum, median, 
quartiles and maximum.  
Frequency tables providing the number and percentages of the different response options to 
individual questions will be displayed for PGI-S and PGI-C.  
In addition, changes from baseline for the single questions will be displayed. 
These summary statistics and difference to baseline will be presented by treatment. 
 
• Change from baseline in Health-related quality of Life (HrQoL) after 2, 4, 8 and 12 
weeks of intervention (as measured by EQ-5D-5L) 
Descriptive assessment will be done on the basis of the VAS and on dimension level 
assessment basis.  
Frequency tables providing the number and percentages of the different response 
options to individual questions will be displayed. In addition, changes from baseline 
for the single questions will be displayed by treatment. 
The EQ visual analogue scale (VAS) values of the EQ-5D-5L and their changes to 
baseline will be summarized by treatment as continuous variable; arithmetic mean, 
SD, minimum, quartiles, median and maximum will be displayed by treatment. 
The scoring algorithm described in the EQ-5D-5L manual [11] will be used. 
6.2.3.3 
Further exploratory efficacy endpoints 
 
• Sleep disturbance (prevalence and impact) associated with cough in patients with 
RUCC 
For the endpoint of sleep disturbance question 12 and 13 of SCCD will be assessed. 
The following scores for the verbal rating answers will be used: 
0 = “No cough”,  
0 = “Not at all”,  
1 = “A little”,  


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2 = “Some”,  
3 = “A lot”,  
4 = “Could not sleep” 
The total score will be the average of the individual scores of question 12 and 13.  
A flag variable will be added so that it is possible to go back and distinguish which 0- 
responses were originally ‘No cough’ and which ’Not at all’. 
 
• Frequency of urinary incontinence associated with cough in patients with RUCC.          
This endpoint will be based on question 14 of SCCD.  
6.2.4 
Subgroup Analyses  
The primary analysis of the primary and secondary endpoints will be repeated for the 
following subgroups: 
• 
Duration of cough (since the start of Chronic Cough in years) (<10 years, ≥ 10 years)  
• Baseline 24-hour coughs per hour  
o <10 coughs/hr, ≥10 coughs/hr 
o <20 coughs/hr, ≥20 coughs/hr 
o <30 coughs/hr, ≥30 coughs/hr 
• Baseline awake coughs per hour (<20 coughs/hr, ≥20 coughs/hr) 
• Baseline Cough Severity VAS (<60 mm, ≥60 mm) 
• FEV1/FVC ratio (60 to <70, ≥70) 
• Primary diagnosis: Unexplained Chronic Cough vs Refractory Chronic Cough 
o Patients with MHTERM = “Unexplained Chronic Cough” and MHOCCURN 
= “NO” will be |assigned to the subgroup “Refractory Chronic Cough”. 
o Patients with MHTERM = “Unexplained Chronic Cough” and MHOCCURN 
= “YES” will be |assigned to the subgroup “Unexplained Chronic Cough”.  
• Standard Subgroups 
o Age (<60 years vs. ≥60 years; <65 years vs. ≥65 years) 
o Sex (male vs. female)  
o Race (white, black, Asian, other) 
o BMI (< 30 kg/m², ≥ 30 kg/m²)  
o Weight (<60, 60 to <90, ≥90 kg) 
o Region:  
▪ 
Asia - Japan and Taiwan 
▪ Europe -  Belgium, Czech Republic, France, Germany, Hungary, Italy, 
Netherlands, Poland, Slovakia, Spain, United Kingdom 
▪ Pacific - Australia 
▪ North America - United States and Canada 
▪ ROW -  Argentina, Russian Federation, Turkey 
• eGFR category at baseline (eGFR < 60 and ≥ 60 mL/min/1.73m2) 
• Smoking status: 
▪ Never 


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▪ Stopped smoking  ≥ 10 years ago  
▪ Stopped smoking 3 to < 10 years ago  
▪ Stopped smoking < 3 years ago 
 
• Background medication (medications taken at least once during the study):  
o azithromycin/erythromycinuse the following ATC codes at the same time:  
▪ D06AX, D10AF, J01FA, S01AA (azithromycin) 
▪ D10AF, J01FA, S01AA (erythromycin) 
o gabapentin/pregabalin: use the following ATC codes at the same time  
▪ N02BG, N03AX, N07XX (gabapentin) 
▪ N02BG, N03AX, N05BX (pregabalin) 
o antihistamines with chronic cough indication: use the SDG "Antihistamines 
and antiallergics" and the indication        
o tricyclic antidepressants use all ATC codes for amitriptyline and amitriptyline 
hydrochloride at the same time (other tricyclic antidepressants are not 
relevant): G04BD, N02BG, N02CX, N05BX, N06AA  
o asthma medications: use the SDG "Drugs for obstructive airway diseases"   
o proton-pump inhibitors: use the SDG "Proton-pump inhibitors"        
• Previous treatment with a P2X3 receptor antagonist in the last three months (no vs. 
yes) 
• Time of randomization (“Patients randomized up to and including the day the first 236 
patients were randomized” vs. “Patients randomized after the day the first 236 patients 
were randomized”) 
The primary analysis of the primary efficacy will only be conducted for subgroups consisting 
of at least 5 participiants. The MMRM for the HRQoL and PRO associated secondary 
endpoints will only be applied for subgroups consisting of at least 5 participiants. 
6.3 
Pharmacokinetics/pharmacodynamics (PK/ PD) 
Plasma concentration of Eliapixant for all subjects will be listed in the clinical study report by 
dose and by planned sampling time window.  
Under a separate cover a Population PK / PD analysis will be performed. 
6.4 
Safety 
6.4.1 
Adverse Events (AEs) 
 
All AEs will be collected from signing the informed consent until the SFU visit. 
All safety analyses will be performed on the Safety Analysis set (SAF). 
The incidence of TEAEs will be assessed as secondary safety endpoint. The incidence of AEs 
and TEAEs will be analyzed by descriptive statistics, such as frequency tables.  
An overall summary of the number and percentage of patients with AEs and TEAE will be 
presented. In addition, all AEs and TEAEs will be tabulated according to the affected system 
organ class and preferred term, as coded by the Medical Dictionary for Regulatory Affairs 
(MedDRA).  


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The frequency of the AEs related to potential and identified risks of Eliapixant will be 
displayed. Regarding the identification specifications for these AEs, the following SMQs and 
PTs will be applied: 
• SMQ “Taste and smell disorders” 
• SMQ “Haemorrhages” 
• MLG Hypotension 
o PT: Blood pressure ambulatory decreased; 
o PT: Blood pressure decreased; 
o PT: Blood pressure diastolic decreased 
o PT: Blood pressure systolic decreased; 
o PT: Diastolic hypotension 
o PT: Hypotension;  
o PT: Mean arterial pressure decreased 
• + other PTs of interest 
o PT: Heart rate decreased 
o PT: Bradyarrhythmia 
o PT: Bradycardia 
o PT: Sinus bradycardia 
o PT: Dizziness 
o PT: Dizziness postural 
o PT: Dizziness exertional 
o PT: Syncope 
o PT: Presyncope 
o PT: Loss of consciousness 
o PT: Blood pressure orthostatic decreased; 
o PT: Orthostatic hypotension; 
• SMQ “Drug related hepatic disorders - comprehensive search” 
Further tables will be provided for serious and/or drug related TEAEs. Tables for non-serious 
TEAEs will also be provided. 
In addition, a separate table summarizing TEAEs that occurred in more than 5% of the 
subjects in any treatment group will be provided.   
The incidence of all AEs during pre-treatment and during post-treatment (that is, AEs 
occurring more than 14 days after end of treatment with study drug) will be tabulated 
separately. 
The summaries will be tabulated by intervention group and overall. 
Serious adverse events, deaths and adverse events leading to discontinuation will be listed. 
The date, relative day (to study intervention) and treatment-emergent flag will be included. 
Further summaries of adverse events by intensity and worst outcome, may be provided, 
consistent with Bayer Global Medical Standards. 


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6.4.1.1 
Taste-related and smell-related AEs 
Impairment or loss of smell and/or taste is a common symptom of COVID-19. Taste-related/ 
smell-related AEs as well as the responses to the questions of the taste/smell disturbance 
assessments will be analyzed using descriptive statistics. 
To distinguish P2X3 related taste AEs from COVID-19 related smell/taste AEs the details of 
smell/taste disturbance assessments will be evaluated together with the SARS-CoV-2 test 
results, the AEs confirming COVID-19 and the timing information by medical review.  
The following list of MedDRA PTs defines the SMQ “Taste and smell disorders”.  
In addition, the following preferred terms will be combined into the PBMQ  “Taste AE”:  
• PT: Ageusia 
• PT: Dysgeusia 
• PT: Gustometry abnormal 
• PT: Hallucination, gustatory 
• PT: Hypergeusia 
• PT: Hypogeusia 
• PT: Taste disorder 
The following preferred terms will  be included in the “Smell-related AEs” category:  
• PT: Anosmia 
• PT: Congenital anosmia 
• PT: Hallucination, olfactory 
• PT: Hyposmia 
• PT: Olfactory nerve disorder 
• PT: Olfactory test abnormal 
• PT: Parosmia 
 
Taste- and smell-related AEs, along with responses about frequency and bothersomeness, will 
be analyzed using descriptive statistics. 
In addition, the dose-dependency of taste-related AEs will be assessed using a logistic 
regression model with treatment as factor. The odds ratio and its 80% and 95% confidence 
intervals, and the p-value for treatment comparisons from the logistic regression model will 
be provided. Only taste-related AEs that cannot be attributed to a SARS-CoV-2 infection will 
be considered for the model. 
6.4.2 
Study Treatment Duration and Exposure 
Study treatment duration and the average daily dose will be summarized overall for SAF.  
The average daily dose will be summarized descriptively by treatment group and overall. In 
addition, it will be categorized into the following groups: 
 


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<    20mg 
>=  20mg   to <=    30mg    (80%-120% of 25mg) 
>    30mg   to <      60mg 
>=  60mg   to <=    90mg    (80%-120% of 75mg) 
>     90mg  to <     120mg 
>= 120mg  to <=  180mg    (80%-120% of 150mg) 
>    180mg 
and summarized by treatment group and overall. 
The duration of study treatment (in days) is derived by the following formula:   
last dose date – first dose date + 1- number of days treatment was interrupted due to COVID-
19 pandemic-related reasons. 
Descriptive statistics of treatment duration will be presented. 
The number of tablets taken will be summarized descriptively by treatment group and overall.  
Using the drug accountability data, the average daily dose for overall study is calculated for 
subjects on active treatment based on the following formulas depending on the treatment arm: 
For the 25mg treatment arm 
25mg ·
1
3 · Total⁡Number⁡of⁡25mg⁡tablets⁡taken
min(last⁡tablets⁡returned⁡date, last⁡treatment⁡intake⁡date)⁡−⁡first⁡tablets⁡dispensed⁡date 
 
For the 75mg treatment arm 
25mg ·
Total⁡Number⁡of⁡25mg⁡tablets⁡taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date 
 
For the 150mg treatment arm 
25mg ·
2
3 · Total⁡Number⁡of⁡25mg⁡tablets⁡taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date 
+100mg ·
Total⁡Number⁡of⁡100mg⁡tablets⁡taken
min(last tablets returned date,   last treatment intake date) − first tablets dispensed date 
 
Overall Compliance will be calculated as 
Total⁡Number⁡of⁡25mg⁡tablets⁡taken⁡ + ⁡4 · Total⁡Number⁡of⁡100mg⁡tablets⁡taken
14⁡ · (min(last tablets returned date,   last treatment intake date) − first tablets dispensed date)⁡. 
 
Compliance between visits will be calculated as 
 
Number of 25mg tablets taken between visits +  4 · Number of 100mg tablets taken between visits.
14 · (min(tablets returned date; last treatment intake) at Visit x − tablets dispensed date at Visit (x −1)) 


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If compliance between two consecutive visits cannot be determined (e.g., if a patient does not 
return medication at the scheduled time), then compliance will be averaged across the periods 
that are affected. 
For between-visit compliance, periods from unscheduled visits are assigned to nearest 
scheduled between visit periods. 
The compliance will be summarized descriptively by treatment group and overall. In addition, 
compliance will be categorized into three groups (<80%, 80-120%, >120%) and summarized 
by treatment group and overall. 
6.4.3 
Liver Function Laboratory Parameters 
The number of subjects with laboratory abnormalities will be provided for SAF for the following 
liver function laboratory parameters. The table will be provided for both baseline and post-
baseline measurements. The measurements from both scheduled / unscheduled visits  will be used. 
The ratio to the upper limits of normal (ULN) will be used for these parameters. 
• Alanine aminotransferase (ALT): > 2xULN – ≤3xULN, > 3xULN – ≤ 5xULN, > 
5xULN – ≤ 8xULN, > 8xULN 
• Aspartate aminotransferase (AST): > 2xULN – ≤3xULN, > 3xULN – ≤ 5xULN, > 
5xULN – ≤ 8xULN, > 8xULN 
• Total bilirubin (TBL): > 2xULN 
• alkaline phosphatase (AP): ≥ 2xULN 
• γ-GT (gamma GT): ≥ 2xULN 
• International normalized ratio (INR): > 1.5xULN 
In addition, frequency tables based on categories above and box plot for measurements over 
time by visit will be provided. 
Subject listings will be provide for subjects who had > 3xULN of ALT or > 3xULN AST.  
  
The number of subjects with postbaseline elevated liver values according to the following 
criteria will be provided: 
• > 3xULN of ALT or AST accompanied (using the values taken from the same serum 
sample) by > 2xULN of TBL, or  
• > 3xULN of ALT or AST accompanied by > 1.5xULN of INR (using the values taken 
from the same date), or  
• Subjects who reported unspecific symptom (fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever, rash and/or eosinophilia) with the CRF 
pages: Clinical Signs and Symptoms with elevated liver enzymes / Clinical Signs and 
Symptoms with elevated liver enzymes (Follow-up)  
o For subjects with eosinophilia, only the case if their measurement of laboratory 
parameter of Eosinophils/Leukocytes > 5% will be included into the analysis. 
A subject listing will be provided for those subjects.  
The eDISH plot (maximum of ALT postbaseline value × maximum of TBL postbaseline 
value) will be provided. A line plot of AP, ALT, AST and TBL over time will be provided for 
subjects fulfilling Hy’s Law.  


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BAY 1817080/20393 
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6.4.3.1 
INR normal ranges 
The following normal ranges for INR will be used: 
• For patients who have been taking medication belonging to   
CMATC01=” BLOOD AND BLOOD FORMING ORGANS; VITAMIN K 
ANTAGONISTS" on the day of the measurement the range 2.0 - 3.0 will be used.  
• For all other patients the range 0.8 - 1.2 will be applied.  
 
6.4.4 
Other Safety Assessments  
Quantitative data (e.g. vital signs, 12-lead ECG, spirometry, blood laboratory data) will be 
described by the following summary statistics: arithmetic mean, standard deviation, quartiles, 
median, minimum and maximum. Safety parameters with categorical data will be summarized 
by reporting number and percent of subjects under such categories. 
These summary statistics and the difference to baseline (i.e. pre-dose measurements, 
performed before the first administration of the study medication) will be presented by 
intervention.   
Subjects with abnormal laboratory values (values out of the reference range) will be 
summarized using shift tables comparing the baseline to post-baseline meadurements by 
timepoint and also for the worst post-baseline measurement. The worst post baseline 
measurement includes all post baseline values including laboratory values from unscheduled 
visits. 
Frequency tables will be provided for qualitative data. Laboratory data outside the reference 
range will be listed and flagged with ‘L’ for low and ‘H’ for high. The results of the 
pregnancy blood test will be reported by frequency. The following categories will be used: 
• B-hCG values < 5.0 mlU/ml will be considered negative. 
• B-hCG values >= 25.0 mlU/ml will be considered positive.  
• B-hCG values > 5.0 mlU/ml and < 25.0 mlU/ml will be considered indecidable.  
 
The results of the SARS-CoV-2 tests will be displayed descriptively. 
7. 
Document history and changes in the planned statistical analysis 
 
• SAP final version 1.0, dated 20 JAN 2021 
SAP final version 2.0, dated 02 JUL 2021. SAP was updated to correct categories for liver 
function laboratory parameters and add analyses of close liver obervations. In addition the list of 
preferred MedDRA terms relevant to COVID-19 has been updated. The BAY number was 
replaced by the INN Eliapixant. Description of interim analyses (section 4.4) was deleted and “not 
applicable” was included. The descritipn of the primary outcome analysis was clarified and a 
reference to the Study Blinding Plan was added to section 3. Data rules in case of COVID-19 
infection (section 4.5.3) have been updated, since current evidence suggests that vaccination 
against COVID-19 does not cause a positivity in IgG serology test. Data rules for intercurrent 
events have been clarified.The description of the MMRM model was extended by SAS code. 


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INR normal range derivation was added to section 6.4 as well as the pregnancy categorization 
based on the B-hCG values. In addition the SMQs and PTs regarding the identification 
specifications for the AEs related to potential and identified risks of Eliapixant have been added. 
The compliance calculation has been adapted to cover specific cases. In addition the compliance 
definition for overall compliance and between-visit compliance was updated to be aligned on 
compound level. Three subgroup analyses and one sensitivity analysis have been added to 
section 6.2.4 and section 6.2.1.3 respectively. A clarification has been added regarding the 
minimum number of patients required to perform a subgroup analysis. The subgroup analysis 
concerning relevant comorbidities has been deleted. 
 
 
8. 
References 
 
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for Statistical Computing, Vienna, Austria, 2020.  
[2]  „RD-M-0001: COVID_CAT_05_SPA related tasks to COVID19-pandemic v4.0,“ 2020. 
[3]  Thomas N, Harel O, Little RJ, „Analyzing clinical trial outcomes based on incomplete 
daily diary reports,“ Stat Med., pp. 2894-906, 2016.  
[4]  Adelphi Values, „Statistical Analysis Plan for the Regulatory support and psychometric 
validation of the Severity of Chronic Cough Diary (SCCD),“ 2020. 
[5]  Bretz F, Pinheiro JC, Branson M, „Combining multiple comparisons and modeling 
techniques in dose-response studies,“ Biometrics, Bd. 61(3), pp. 738-48, 2005.  
[6]  Pinheiro JC, Bornkamp B, Glimm E, Bretz F, „Model-based dose finding under model 
uncertainty using general parametric models,“ Statistics in Medicine, Bd. 33, p. 1646–
1661, 2014.  
[7]  Bornkamp B, „DoseFinding: Planning and Analyzing Dose Finding Experiments,“ R 
package version 0.9-17, 2019.  
[8]  Buckland ST, Burnham KP, Augustin NH, „Model Selection an Integral Part of 
Inference,“ Biometrics, Bd. 53(2), pp. 603-618, 1997.  
[9]  Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MDL, Pavord ID, „Development of a 
symptom specific health status measure for patients with chronic cough: Leicester 
Cough Questionnaire (LCQ),“ Thorax, Bd. 58, pp. 339-343, 2003.  
[10] Raj AA, Pavord DI, Birring SS., „Clinical cough IV: what is the minimal important 
difference for the Leicester Cough Questionnaire?,“ Handb Exp Pharmacol., Bd. 187, 
pp. 311-20, 2009.  
[11] Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X, 
„Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-
5L).,“ Qual Life Res., Bd. 20(10), pp. 1727-36, 2011.