Clinical Trials Register

Summary
EudraCT Number:	2019-004169-42
Sponsor's Protocol Code Number:	20393
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-25
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-004169-42

A.3

Full title of the trial

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)

Studio di fase 2b randomizzato, in doppio cieco, a gruppi paralleli riguardante la determinazione della dose, l’efficacia e la sicurezza della somministrazione per via orale di BAY 1817080 due volte al giorno per 12 settimane, rispetto al placebo, nel trattamento della tosse cronica refrattaria e/o idiopatica (refractory and/or unexplained chronic cough, RUCC)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical study to evaluate the efficacy and safety of three different doses of BAY 1817080 compared to placebo in patients with chronic cough

Studio riguardante la determinazione di dose, efficacia e sicurezza di BAY 1817080 nel trattamento della tosse cronica refrattaria e/o idiopatica

A.3.2

Name or abbreviated title of the trial where available

PAGANINI

A.4.1

Sponsor's protocol code number

20393

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bayer AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bayer AG
B.5.2	Functional name of contact point	Clinical Trial Contacts
B.5.3	Address:
B.5.3.1	Street Address	CTP Team / Ref: "EU CTR" /Bayer Pharma AG
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.6	E-mail	clinical-trials-contact@bayer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bay 1817080 25mg tablets
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.2	Current sponsor code	BAY 1817080
D.3.9.3	Other descriptive name	BAY 1817080
D.3.9.4	EV Substance Code	SUB181864
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bay 1817080 100mg tablets
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.2	Current sponsor code	BAY 1817080
D.3.9.3	Other descriptive name	BAY 1817080
D.3.9.4	EV Substance Code	SUB181864
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Refractory and/or unexplained chronic cough (RUCC)

tosse cronica refrattaria

E.1.1.1

Medical condition in easily understood language

Refractory chronic cough

tosse cronica

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10080782
E.1.2	Term	Refractory chronic cough
E.1.2	System Organ Class	100000004855

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10080781
E.1.2	Term	Unexplained chronic cough
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Assess the efficacy of P2X3 receptor antagonist BAY1817080 as
compared with placebo in terms of change in 24-hour cough count from
baseline to week 12

valutare l’efficacia dell’antagonista del recettore P2X3, BAY 1817080, rispetto al placebo in termini di variazione del conteggio dei colpi di tosse nell’arco di 24 ore (misurata da dispositivo portatile per il monitoraggio digitale della tosse mediante registrazione) dal basale alla settimana 12

E.2.2

Secondary objectives of the trial

Further assess the efficacy, safety and tolerability profile of
BAY1817080 in patients with RCC

L’obiettivo secondario valutare l’efficacia di BAY 1817080 e caratterizzarne ulteriormente il profilo di sicurezza e tollerabilità.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 with persistently
bothersome refractory (unresponsive to treatment options) or idiopathic
(unexplained) chronic cough that has lasted for at least 8 weeks before
screening.
3. 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.
4. Capable of giving signed informed consent.

1. Adulti di età ≥ 18 anni alla data della firma del consenso informato.
2. Tosse cronica, della durata di almeno 12 mesi, costantemente fastidiosa e refrattaria (non rispondente alle opzioni terapeutiche) o idiopatica (inspiegabile), che persiste da almeno 8 settimane prima dello screening.
3. Gravità della tosse allo screening, misurata con la scala VAS, pari ad almeno 40 unità.
4. Le donne in età potenzialmente fertile devono acconsentire ad utilizzare metodi contraccettivi accettabili efficaci o altamente efficaci durante lo studio e per almeno 30 giorni dall’ultima dose. Per ulteriori dettagli relativi alla contraccezione (e ai metodi contraccettivi altamente efficaci), consultare la sezione 10.4.
5. Capacità di fornire il consenso informato firmato, che include la conformità ai requisiti e alle restrizioni elencati nel consenso informato stesso (ICF) e in questo protocollo.

E.4

Principal exclusion criteria

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. Respiratory tract infection within 4 weeks before screening.
4. History of chronic bronchitis.
5. Uncontrolled hypertension despite optimal treatment with
antihypertensive(s), indicated by a sitting systolic blood pressure ≥ 180
mmHg and/or diastolic blood pressure ≥ 110 mmHg.

E.4 Criteri di esclusione principali(elencare i più importanti):
Condizioni mediche correlate alla RUCC
1. Storia di tabagismo negli ultimi 12 mesi precedenti lo screening (tutte le forme di tabagismo, tra cui sigarette elettroniche, cannabis e altro) e tutti gli ex fumatori con indice tabagico di oltre 20 pack-year.
2. Esposizione in corso o pregressa a fumi tossici da inalazione (ad es. ammoniaca, cloro, biossido d’azoto, fosgene e anidride solforosa) negli ultimi 12 mesi precedenti lo screening.
3. Radiografia toracica o TC negli ultimi 24 mesi precedenti lo screening e successiva all’insorgenza di tosse cronica, con presenza di qualsiasi evidente malattia polmonare che potrebbe essere responsabile o concorrere alla comparsa della tosse (ad es. bronchiectasia, lesioni cavitarie, fibrosi polmonare interstiziale, pneumotorace, malattia pleurica, frattura costale instabile, tubercolosi).
4. Rapporto Volume Espiratorio Forzato in 1 secondo (FEV1)/Capacità Vitale Forzata (FVC) <60% o frequenti esacerbazioni di bronco-pneumopatia cronica ostruttiva (BPCO) in anamnesi.
5. Infezione delle vie aeree nelle 4 settimane precedenti lo screening.
6. Pregressa bronchite cronica.
7. Stato attivo di emottisi o emorragia polmonare massiva, tra cui eventi gestiti tramite embolizzazione dell’arteria bronchiale o qualsiasi pregressa embolizzazione dell’arteria bronchiale, oppure emottisi massiva nei 3 mesi precedenti lo screening.
Criteri correlati a fattori epatici
8. Insufficienza epatica da moderata a grave di classe B o C secondo la classificazione Child-Pugh.
9. ALT >2 x ULN* o AST >2 x ULN, oppure bilirubina totale superiore a ULN, o fosfatasi alcalina (FA) >2 x ULN, oppure INR superiore a ULN (se non correlato a trattamento con anticoagulanti). *(ULN, Upper Limit of Normal, limite superiore della norma)
Criteri correlati a fattori renali
10. Velocità di filtrazione glomerulare stimata (eGFR) < 30 mL/min/1,73 m2, calcolata con la formula MDRD (Modification of Diet in Renal Disease, modifica della dieta nella malattia renale).
Condizioni mediche generali
11. Ipertensione non controllata nonostante trattamento ottimale con antipertensivi, indicata da pressione arteriosa sistolica in posizione seduta ≥ 180 mmHg e/o pressione arteriosa diastolica ≥ 110 mmHg.
12. Qualsiasi altra patologia o condizione che, secondo lo sperimentatore, possa compromettere le funzioni dell’organismo e possa tradursi in eccessivo accumulo o assorbimento, metabolismo o eliminazione alterati dell’intervento in studio (ad es. malattia intestinale cronica, morbo di Crohn e colite ulcerosa).
13. Acalasia esofagea.
14. Qualsiasi patologia o condizione seria o instabile, ivi inclusi disturbi psichiatrici, che potrebbero interferire con la conduzione dello studio o l’interpretazione dei risultati.
15. Neoplasia maligna concomitante o cancro in anamnesi (eccetto carcinoma squamoso o basocellulare della pelle) negli ultimi 5 anni precedenti lo screening.
Terapia precedente/concomitante
16. Intenzione di avviare un nuovo trattamento della RUCC durante lo studio.
17. Assunzione di terapia vietata precedente o concomitante, come specificato nella sezione 6.5.
Altre esclusioni
18. Indice di massa corporea (IMC) > 40 kg/m2.
19. Ipersensibilità a uno qualsiasi degli ingredienti dell’intervento in studio (vedere l’ultima versione disponibile del Dossier per lo Sperimentatore).
20. Desiderio di gravidanza durante lo studio, gravidanza in corso o allattamento al seno.
21. Importante intervento chirurgico programmato durante il periodo di studio.
22. Incapacità a collaborare nelle procedure dello studio per qualsiasi ragione, tra cui ad esempio: comprensione della lingua, incapacità di raggiungere il centro di sperimentazione.
23. Abuso di alcol o medicinali, oppure consumo di droghe leggere/illegali, previa valutazione dello sperimentatore.
24. Precedente assegnazione al trattamento (ad es. randomizzazione) durante il presente studio.
25. Contemporanea partecipazione ad un’altra sperimentazione clinica con il/i medicinali
sperimentali.
26. Partecipazione ad un’altra sperimentazione con P2X3 nei 3 mesi precedenti lo screening.
27. Stretta relazione con il centro di sperimentazione, ad es. stretto legame di parentela con lo sperimentatore, rapporto di dipendenza (ad es. dipendente o studente del centro di sperimentazione, oppure personale del promotore).
28. Pazienti diversamente vulnerabili. Pazienti sotto custodia per ordine di un’autorità o un tribunale.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in 24-hour cough count (measured by cough
recording digital wearable monitoring device) after 12 weeks of
intervention

Variazione rispetto al basale del conteggio dei colpi di tosse nell’arco di 24 ore (misurata con dispositivo portatile per il monitoraggio digitale della tosse mediante registrazione) dopo 12 settimane di intervento

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline up to 12 weeks

da basale fino a 12 settimane

E.5.2

Secondary end point(s)

1. Frequency of adverse events (AEs), serious and/or drug related AEs
and dose-dependency of taste-related AEs
2. Severity of adverse events
3. The incidence of AEs during safety follow-up
4. 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)
5. Change from baseline in 24-hour cough count after 2, 4, and 8 weeks
of intervention (measured by cough recording digital wearable
monitoring device)
6. 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)
7. Change from baseline in cough related quality of life (measured by
Leicester Cough Questionnaire [LCQ]) after 12 weeks of intervention
8. Change from baseline in cough severity after 12 weeks of intervention
(measured by Cough Severity Visual Analogue Scale [VAS])
9. Percentage of participants with a ≥30 scale units reduction from
baseline after 12 weeks of intervention (measured by cough Severity
VAS)
10. Percentage of participants with a ≥1.3-point increase from baseline
after 12 weeks of intervention (measured with LCQ Total Score)

1. Frequenza degli Eventi Avversi (AE), AE gravi e/o correlate al farmaco e dose-dipendenza di eventi avversi legati all’alterazione del gusto
2. Gravità degli AE
3. Incidenza di AE durante safety follow-up
4. Percentuale di partecipanti con riduzione ≥30% rispetto al basale del conteggio dei colpi di tosse nell’arco di 24 ore dopo 12 settimane di intervento (misurata con dispositivo portatile per il monitoraggio digitale della tosse mediante registrazione)
5. Variazione rispetto al basale del conteggio dei colpi di tosse nell’arco di 24 ore dopo 2, 4 e 8 settimane di intervento (misurata con dispositivo portatile per il monitoraggio digitale della tosse mediante registrazione).
6. Variazione rispetto al basale della frequenza oraria della tosse in fase di veglia dopo 2, 4, 8 e 12 settimane di intervento (misurata con dispositivo portatile per il monitoraggio digitale della tosse mediante registrazione)
7. Variazione rispetto al basale della quality of life legata alla tosse (misurata secondo Leicester Cough Questionnaire [LCQ]) dopo 12 settimane di intervento
8. Variazione rispetto al basale della gravità della tosse dopo 12 settimane di intervento (misurata secondo Cough Severity Visual Analogue Scale [VAS])
9. Percentuale di partecipanti con riduzione ≥30 unità da basale dopo 12 settimane di intervento (misurata secondo cough Severity VAS)
10. Percentuale di partecipanti con aumento di punti ≥1.3 da basale dopo 12 settimane di intervento (misurata secondo LCQ Total Score)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 - 2: From the start of study intervention until the safety follow-up visit
(up to 16 weeks)
3: During safety follow-up (approximately 4 weeks)
4: From baseline up to 12 weeks
5: From baseline up to 2 weeks, 4 weeks, and 8 weeks
6: From baseline up to 2 weeks, 4 weeks, 8 weeks, and 12 weeks
7 - 10: From baseline up to 12 weeks

1 - 2: Da inizio intervento studio fino a visita di safety follow-up

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Canada

Czech Republic

France

Germany

Hungary

Italy

Japan

Netherlands

Poland

Russian Federation

Slovakia

Spain

Taiwan

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last Patient Last Visit (last Safety follow-up Visit)

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

136

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception