PAGANINI: Clinical Study to Evaluate the Efficacy and Safety of Three Different Doses of BAY1817080 Compared to Placebo in Patients With Chronic Cough

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04562155
• Collaborator: (none)
• Enrollment: 310
• Locations: 99
• Arms: 4
• Actual Duration (Months): 9.7
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Refractory and/or Unexplained Chronic Cough	Drug: BAY1817080; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 310 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Oct 2, 2020
• Actual Primary Completion Date: Jun 22, 2021
• Actual Study Completion Date: Jul 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BAY1817080 dose A BID 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.	Drug: BAY1817080; Study drug BAY1817080 will be administered orally as tablet.
Experimental: BAY1817080 dose B BID 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.	Drug: BAY1817080; Study drug BAY1817080 will be administered orally as tablet.
Experimental: BAY1817080 dose C BID 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.	Drug: BAY1817080; Study drug BAY1817080 will be administered orally as tablet.
Placebo Comparator: Placebo 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.	Drug: Placebo; Matching Placebo for BAY1817080 will be administered orally as tablet.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 24-hour Cough Count After 12 Weeks of Intervention [From baseline up to 12 weeks]

   The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. For the ratio between the geometric means of 24-hour cough count, the geometric mean of 24-hour cough count after 12 weeks of intervention was divided by the geometric mean of 24-hour cough count at baseline. btw = between geo = geometric

Secondary Outcome Measures

1. Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Cough Count After 12 Weeks of Intervention [From baseline up to 12 weeks]

   The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. The change from baseline in 24-hour cough count was calculated by the geometric mean of 24-hour cough count after 12 weeks of intervention minus the geometric mean at baseline divided by the geometric mean at baseline. The percentage of participants with a reduction of ≥30% is shown

2. Change From Baseline in 24-hour Cough Count After 2, 4, and 8 Weeks of Intervention [From baseline up to 2 weeks, 4 weeks and 8 weeks]

   The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. For the ratio between the geometric means of 24-hour cough count, the geometric mean of 24-hour cough count after 2, 4, and 8 weeks of intervention was divided by the geometric mean of 24-hour cough count at baseline. btw = between geo = geometric

3. Change From Baseline in Awake Cough Frequency Per Hour After 2, 4, 8 and 12 Weeks of Intervention [From baseline up to 2 weeks, 4 weeks, 8 weeks and 12 weeks]

   Measured by cough recording digital wearable monitoring device btw = between geo = geometric

4. Change From Baseline in Cough Related Quality of Life After 12 Weeks of Intervention [From baseline up to 12 weeks]

   Measured by Leicester Cough Questionnaire (LCQ) total score. The LCQ was a 19-item instrument that asked 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, 11, 14, 15 built the physical domain. 7 items: 4, 5, 6, 12, 13, 16, 17 built the psychological domain. Further 4 items: 7, 8, 18 and 19 built the social domain. Study participants responded to the items using a 7-point Likert scale from 1 (all of the time) to 7 (none of the time) and entered their assessments on a tablet device. Completion of the LCQ took approximately five minutes. The LCQ total score was 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.

5. Change From Baseline in Cough Severity After 12 Weeks of Intervention [From baseline up to 12 weeks]

   Measured by Cough Severity Visual Analogue Scale (VAS). The Cough Severity VAS was a single item instrument, asking the study participant to assess the severity of his/her cough using a 0-100 VAS. This was a vertically oriented line ordered from 0-100, with 0 = "No Cough" and 100 = "Extremely Severe Cough".

6. Percentage of Participants With a ≥30 Scale Units Reduction From Baseline After 12 Weeks of Intervention [From baseline up to 12 weeks]

   Measured by cough Severity VAS

7. Percentage of Participants With a ≥1.3-point Increase From Baseline After 12 Weeks of Intervention [From baseline up to 12 weeks]

   Measured by LCQ total score. The LCQ was a 19-item instrument that asked 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, 11, 14, 15 built the physical domain. 7 items: 4, 5, 6, 12, 13, 16, 17 built the psychological domain. Further 4 items: 7, 8, 18 and 19 built the social domain. Study participants responded to the items using a 7-point Likert scale from 1 (all of the time) to 7 (none of the time) and entered their assessments on a tablet device. Completion of the LCQ took approximately five minutes. The LCQ total score was 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. The percentage of participants with a >= 1.3-point increase in LCQ total score is shown.

8. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Associated Severity [From the start of study intervention administration until 14 days after the last study medication intake, with an average of 80.0 + 14 days]

   Adverse event (AE) was defined as any untoward medical occurrence in a study participant, whether or not considered related to the study intervention, occurring from the time of signing the informed consent until the follow-up visit. TEAE was defined as any event occurring or worsening after the start of study intervention administration until 14 days after the last intake of study intervention.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults ≥ 18 years of age at the time of signing the informed consent.

• 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.

• Persistent cough for at least the last 8 weeks before screening.

• 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.

• Capable of giving signed informed consent.

Exclusion Criteria:

• 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.

• 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.

• Respiratory tract infection within 4 weeks before screening.

• History of chronic bronchitis.

• Systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening visit.

• Positive SARS-CoV-2 virus RNA and/or serology IgG tests at screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Allergy & Asthma Medical Group & Research Center	Los Angeles	California	United States	90025
2	Florida Pediatrics	Largo	Florida	United States	33778
3	Chesapeake Clinical Research, Inc.	White Marsh	Maryland	United States	21162
4	Minnesota Lung Center	Edina	Minnesota	United States	55435
5	Montana Medical Research, Inc	Missoula	Montana	United States	59808
6	Vanderbilt University Medical School	Nashville	Tennessee	United States	37212-1610
7	Pharmaceutical Research & Consulting, Inc.	Dallas	Texas	United States	75231
8	Bellingham Asthma, Allergy & Immunology Clinic	Bellingham	Washington	United States	98225
9	Instituto Ave Pulmo	Mar del Plata	Buenos Aires	Argentina
10	Centro Respiratorio Quilmes	Quilmes	Buenos Aires	Argentina
11	Centro Médico Dra. De Salvo - Clinical Research Center	Buenos Aires	Ciudad Auton. De Buenos Aires	Argentina	C1426ABP
12	Centro de Investigaciones Clínicas	Caba	Ciudad Auton. De Buenos Aires	Argentina	C1018DES
13	Fundación CIDEA	Caba	Ciudad Auton. De Buenos Aires	Argentina	C1121ABE
14	Investigación en Alergias y Enfermedades Respiratorias-INAER	Caba	Ciudad Auton. De Buenos Aires	Argentina	C1425
15	Investigaciones en Patologías Respiratorias	San Miguel de Tucumán	Tucuman	Argentina
16	Macquarie University Hospital	Macquarie University	New South Wales	Australia	2109
17	Maroubra Medical Centre	Maroubra	New South Wales	Australia	2035
18	Holdsworth House Medical Practice	Sydney	New South Wales	Australia	2010
19	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
20	Western Respiratory Trial Specialists	Spearwood	Western Australia	Australia	6163
21	Dr. MARTINOT Jean-Benoît	Erpent		Belgium	5101
22	UZ Gent	Gent		Belgium	9000
23	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
24	CHU de Liège	Liege		Belgium	4000
25	VZW Emmaus	Mechelen		Belgium	2800
26	Burlington Lung Clinic (BLC) Clinical Research	Burlington	Ontario	Canada	L7N 3V2
27	Clinique de pneumologie et du sommeil de Lanaudière (CPSL)	St-Charles-Borromée	Quebec	Canada	J6E 2B4
28	MUDr Otakar Hokynar - Plicni ambulance	Kralupy nad Vltavou		Czechia	278 01
29	Ordinace pro TBC a respiracni nemoci, s.r.o.	Olomouc		Czechia	772 00
30	Dawon s.r.o.	Praha 4		Czechia	14800
31	Plicní stredisko Teplice, s.r.o.	Teplice		Czechia	415 01
32	MUDr. Milan Sklenar	Varnsdorf		Czechia	407 47
33	Cochin - Paris	Paris		France	75674
34	CHU de Toulouse - Hôpital Larrey	TOULOUSE Cedex 9		France	31059
35	Klinikum Konstanz	Konstanz	Baden-Württemberg	Germany	78464
36	Zentrum f. ambulante pneumologische Forschung Marburg GbR	Marburg	Hessen	Germany	35037
37	Ballenberger, Freytag, Wenisch	Neu-Isenburg	Hessen	Germany	63263
38	Pneumologicum im Südstadt Forum	Hannover	Niedersachsen	Germany	30173
39	Medizinische Hochschule Hannover (MHH)	Hannover	Niedersachsen	Germany	30625
40	Priv.-Doz. Dr. med. Christian Gessner	Leipzig	Sachsen	Germany	04357
41	Praxis f. Lungen- und Bronchialheilkunde,	Berlin		Germany	10717
42	D.Kenessey A Hospital	Balassagyarmat		Hungary	2660
43	EKBC, Uj Szent Janos Korhaz es Szakrendelo	Budapest		Hungary	1122
44	Erzsebet Gondozohaz	Godollo		Hungary	2100
45	Da Vinci Maganklinika	Pecs		Hungary	7635
46	Farmakontroll Bt.	Szazhalombatta		Hungary	2440
47	ASST Lodi	Lodi	Lombardia	Italy	26845
48	A.O.U. Careggi	Firenze	Toscana	Italy	50134
49	IRCCS Ospedale Sacro Cuore Don Calabria	Verona	Veneto	Italy	37024
50	A.O.U.I. Verona	Verona	Veneto	Italy	37126
51	Nagoya City University Hospital	Nagoya	Aichi	Japan	467-8602
52	University of Fukui Hospital	Yoshida	Fukui	Japan	910-1193
53	University of Occupational and Environmental Health	Kitakyushu	Fukuoka	Japan	807-8556
54	Idaimae Minami Yojo	Sapporo	Hokkaido	Japan	064-0804
55	Japan community health care organization Kanazawa Hospital	Kanazawa	Ishikawa	Japan	920-8610
56	Komatsu Municipal Hospital	Komatsu	Ishikawa	Japan	923-8560
57	Yokohama City Minato Red Cross Hospital	Yokohama	Kanagawa	Japan	231-8682
58	Saiseikai Yokohamashi Nanbu Hospital	Yokohama	Kanagawa	Japan	234-8503
59	Matsusaka Municipal Hospital	Matsusaka	Mie	Japan	515-8544
60	Hamamatsu Rosai Hospital	Hamamatsu	Shizuoka	Japan	430-8525
61	Tokyo Shinagawa Hospital	Shinagawa-ku	Tokyo	Japan	140-8522
62	Fukushima Medical University Hospital	Fukushima		Japan	960-1295
63	Catharina Ziekenhuis	Eindhoven	Noord-Brabant	Netherlands	5623 EJ
64	Isala	Zwolle		Netherlands	8025 AB
65	Centrum Medycyny Oddechowej Mroz Spolka Jawna	Bialystok		Poland	15-044
66	KLIMED Marek Klimkiewicz	Bychawa		Poland	23-100
67	Centrum Alergologii Sp. z o.o.	Lublin		Poland	20-552
68	Ostrowieckie Centrum Medyczne Sp. Cyw. A.O-C. K.C.	Ostrowiec Swietokrzyski		Poland	27-400
69	Centrum Medyczne Lucyna Andrzej Dymek	Strzelce Opolskie		Poland	47-100
70	Region Clinical Emergency Hospital n.a. M.A.Podgorbunskogo	Kemerovo		Russian Federation	650000
71	City Clinical Hospital n.a. D.D. Pletnev	Moscow		Russian Federation	105077
72	LLC "Medical Center "SibNovoMed""	Novosibirsk		Russian Federation	630005
73	City Clinical Hospital #4 Samara	Samara		Russian Federation	453056
74	City Consultative and Diagnostic Center #1	St. Petersburg		Russian Federation	194354
75	LLC Astarta	St. Petersburg		Russian Federation	199226
76	Voronezh Regional Clinical Hospital #1	Voronezh		Russian Federation	394066
77	ALIAN s.r.o.	Bardejov		Slovakia	085 01
78	INSPIRO, s.r.o.	Humenne		Slovakia	066 01
79	AlergoImunocentrum, s.r.o.	Kezmarok		Slovakia	060 01
80	Plucna ambulancia s.r.o.	Poprad		Slovakia	058 01
81	Ambulancia klin. imunologie a alergologie, ANA JJ, s.r.o.	Topolcany		Slovakia	955 01
82	Hospital Clínico Universitario de Santiago de Compostela	Santiago de Compostela	A Coruña	Spain	15706
83	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
84	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	08036
85	Chang Gung Memorial Hospital Keelung	Keelung		Taiwan	20401
86	Far Eastern Memorial Hospital	New Taipei City		Taiwan	220
87	Taichung Veterans General Hospital	Taichung		Taiwan	40705
88	National Taiwan University Hospital	Taipei		Taiwan	100
89	Taipei Medical University Hospital	Taipei		Taiwan	110
90	Akdeniz Universitesi Tip Fakultesi Hastanesi	Antalya		Turkey	07058
91	Istanbul Universitesi Cerrahpasa-Cerrahpasa Tip Fakultesi	Istanbul		Turkey	34098
92	Ege Universitesi Tip Fakultesi	Izmir		Turkey	35100
93	Sureyyapasa Gogus Hasalikleri. ve Gogus Cerrahisi EAH	Maltepe		Turkey	34844
94	Mersin Universitesi Tip Fakultesi	Mersin		Turkey	33343
95	North Tyneside General Hospital	North Shields	Tyne And Wear	United Kingdom	NE29 8NH
96	West Walk Surgery	Bristol		United Kingdom	BS37 4AX
97	Castle Hill Hospital	Cottingham		United Kingdom	HU16 5JQ
98	King's College Hospital - NHS Foundation Trust	London		United Kingdom	SE5 9RS
99	University Hospital of South Manchester	Manchester		United Kingdom	M23 9LT

Sponsors and Collaborators

• Bayer

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 28, 2021
• Statistical Analysis Plan - Jul 8, 2021

More Information

Additional Information:

• Click here to find results for studies related to Bayer products
• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Publications

• Fletcher MC. Selectivity of the P2X3 receptor antagonist Eliapixant, and its potential use in the treatment of endometriosis. Purinergic Signal. 2022 Mar;18(1):1-3. doi: 10.1007/s11302-021-09831-5. Epub 2022 Jan 3.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT04562155
• Other Study ID Numbers: 20393; 2019-004169-42
• First Posted: Sep 24, 2020
• Last Update Posted: Aug 18, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: RUCC; Chronic cough; P2X3 receptor antagonist
• Additional relevant MeSH terms: Cough

Study Results

Participant Flow

Recruitment Details	The study was conducted at 99 centers in 19 countries/regions with first participant first visit on 02-Oct-2020 and last participant last visit on 23-Jul-2021.
Pre-assignment Detail	Overall, 399 participants were screened, 89 of whom were screening failures. The remaining 310 participatns were randomized to 4 treatment groups (75 to eliapixant 25 mg BID, 78 to eliapixant 75 mg BID, 80 to eliapixant 150 mg BID, and 77 to placebo).

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Period Title: Overall Study
STARTED	75	78	80	77
COMPLETED	64	69	67	71
NOT COMPLETED	11	9	13	6

Baseline Characteristics

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo	Total
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.	Total of all reporting groups
Overall Participants	75	78	80	77	310
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.81 (9.64)	58.62 (12.7)	58.98 (11.8)	56.91 (12.4)	59.06 (11.79)
Age, Customized (Number) [Number]
Adults (18-64 years)	45 60%	50 64.1%	49 61.3%	49 63.6%	193 62.3%
From 65-84 years	30 40%	28 35.9%	31 38.8%	28 36.4%	117 37.7%
Sex: Female, Male (Count of Participants)
Female	56 74.7%	63 80.8%	61 76.3%	61 79.2%	241 77.7%
Male	19 25.3%	15 19.2%	19 23.8%	16 20.8%	69 22.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.3%	4 5.1%	3 3.8%	2 2.6%	10 3.2%
Not Hispanic or Latino	74 98.7%	74 94.9%	77 96.3%	75 97.4%	300 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Baseline 24-hour coughs per hour (24-hour cough count per hour) [Geometric Mean (Standard Deviation) ]
Geometric Mean (Standard Deviation) [24-hour cough count per hour]	17.49 (2.94)	19.23 (2.94)	15.61 (2.34)	17.63 (3.07)	17.42 (2.81)
Baseline Leicester Cough Questionnaire (LCQ) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	12.00 (2.54)	11.76 (2.77)	11.15 (2.56)	11.53 (3.27)	11.60 (2.81)
Baseline awake cough count per hour (Cough count per hour) [Geometric Mean (Standard Deviation) ]
Geometric Mean (Standard Deviation) [Cough count per hour]	23.62 (3.02)	26.41 (2.97)	21.19 (2.39)	24.01 (3.18)	23.70 (2.88)
Baseline Cough Severity Visual Analogue Scale [VAS] Value (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	65.51 (14.64)	67.08 (14.89)	66.79 (15.86)	61.52 (18.51)	65.20 (16.16)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 24-hour Cough Count After 12 Weeks of Intervention
Description	The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. For the ratio between the geometric means of 24-hour cough count, the geometric mean of 24-hour cough count after 12 weeks of intervention was divided by the geometric mean of 24-hour cough count at baseline. btw = between geo = geometric
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

All participants in PPS with valid 24-hour cough count values in Week 12 or Termination visit.

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	64	68	72	73
Geometric Mean (Standard Deviation) [Ratio btw geoMeans of 24h cough count]	0.56 (0.9191)	0.47 (0.9019)	0.52 (0.8608)	0.64 (0.7855)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eliapixant 25 mg BID, Eliapixant 75 mg BID, Eliapixant 150 mg BID, Placebo
	Comments	Detection of dose-response: Emax model (ED50=30) Dose response relationship was assessed using the MCP-Mod method combining multiple comparison procedures (MCP) principles with modeling techniques. A generalized MCP approach (with adjustment for baseline cough count and geographic region) was applied to calculate the adjusted one-sided p-values of the contrast test. Pre-specified overall Type one error at alpha level of 0.1 (one-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0345
	Comments	Adjusted p-value
	Method	MCP-Mod method
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eliapixant 25 mg BID, Eliapixant 75 mg BID, Eliapixant 150 mg BID, Placebo
	Comments	Detection of dose-response: Emax model (ED50=50) Dose response relationship was assessed using the MCP-Mod method combining multiple comparison procedures (MCP) principles with modeling techniques. A generalized MCP approach (with adjustment for baseline cough count and geographic region) was applied to calculate the adjusted one-sided p-values of the contrast test. Pre-specified overall Type one error at alpha level of 0.1 (one-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0376
	Comments	Adjusted p-value
	Method	MCP-Mod method
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eliapixant 25 mg BID, Eliapixant 75 mg BID, Eliapixant 150 mg BID, Placebo
	Comments	Detection of dose-response: sigm. Emax model (ED50=30, h=3) sigm = sigmoidal h = hill parameter Dose response relationship was assessed using the MCP-Mod method combining multiple comparison procedures (MCP) principles with modeling techniques. A generalized MCP approach (with adjustment for baseline cough count and geographic region) was applied to calculate the adjusted one-sided p-values of the contrast test. Pre-specified overall Type one error at alpha level of 0.1 (one-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0319
	Comments	Adjusted p-value
	Method	MCP-Mod method
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eliapixant 25 mg BID, Eliapixant 75 mg BID, Eliapixant 150 mg BID, Placebo
	Comments	Detection of dose-response: sigm. Emax model (ED50=60, h=5) sigm = sigmoidal h = hill parameter Dose response relationship was assessed using the MCP-Mod method combining multiple comparison procedures (MCP) principles with modeling techniques. A generalized MCP approach (with adjustment for baseline cough count and geographic region) was applied to calculate the adjusted one-sided p-values of the contrast test. Pre-specified overall Type one error at alpha level of 0.1 (one-sided).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0603
	Comments	Adjusted p-value
	Method	MCP-Mod method
	Comments

2. Secondary Outcome

Title	Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Cough Count After 12 Weeks of Intervention
Description	The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. The change from baseline in 24-hour cough count was calculated by the geometric mean of 24-hour cough count after 12 weeks of intervention minus the geometric mean at baseline divided by the geometric mean at baseline. The percentage of participants with a reduction of ≥30% is shown
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

PPS

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	73	74
Number (95% Confidence Interval) [Percentage of participants]	52.24 (39.67) 69.7%	63.77 (51.31) 81.8%	53.42 (41.37) 66.8%	45.95 (34.29) 59.7%

3. Secondary Outcome

Title	Change From Baseline in 24-hour Cough Count After 2, 4, and 8 Weeks of Intervention
Description	The raw 24-hour cough count measured by cough recording digital wearable monitoring device was standardized to an average hourly count. For the ratio between the geometric means of 24-hour cough count, the geometric mean of 24-hour cough count after 2, 4, and 8 weeks of intervention was divided by the geometric mean of 24-hour cough count at baseline. btw = between geo = geometric
Time Frame	From baseline up to 2 weeks, 4 weeks and 8 weeks

Outcome Measure Data

Analysis Population Description

PPS

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	73	74
Week 2	0.75 (0.6134)	0.58 (0.8209)	0.61 (0.6636)	0.75 (0.4762)
Week 4	0.64 (0.7237)	0.51 (0.8192)	0.58 (0.8589)	0.69 (0.6657)
Week 8	0.55 (0.8737)	0.46 (0.9484)	0.51 (0.8827)	0.70 (0.6451)

4. Secondary Outcome

Title	Change From Baseline in Awake Cough Frequency Per Hour After 2, 4, 8 and 12 Weeks of Intervention
Description	Measured by cough recording digital wearable monitoring device btw = between geo = geometric
Time Frame	From baseline up to 2 weeks, 4 weeks, 8 weeks and 12 weeks

Outcome Measure Data

Analysis Population Description

PPS

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	73	74
Week 2	0.78 (0.6324)	0.60 (0.8295)	0.60 (0.6695)	0.77 (0.4660)
Week 4	0.67 (0.7390)	0.53 (0.8128)	0.57 (0.8983)	0.72 (0.6637)
Week 8	0.55 (0.9274)	0.47 (0.9576)	0.50 (0.9154)	0.72 (0.6698)
Week 12	0.56 (0.9582)	0.47 (0.9051)	0.47 (1.1338)	0.65 (0.7926)

5. Secondary Outcome

Title	Change From Baseline in Cough Related Quality of Life After 12 Weeks of Intervention
Description	Measured by Leicester Cough Questionnaire (LCQ) total score. The LCQ was a 19-item instrument that asked 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, 11, 14, 15 built the physical domain. 7 items: 4, 5, 6, 12, 13, 16, 17 built the psychological domain. Further 4 items: 7, 8, 18 and 19 built the social domain. Study participants responded to the items using a 7-point Likert scale from 1 (all of the time) to 7 (none of the time) and entered their assessments on a tablet device. Completion of the LCQ took approximately five minutes. The LCQ total score was 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.
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

All participants in PPS with valid Leicester Cough Questionnaire scores in Week 12 or Termination visit were included.

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	72	74
Mean (Standard Deviation) [Scores on a scale]	2.18 (3.44)	2.50 (3.29)	2.73 (3.53)	2.16 (3.12)

6. Secondary Outcome

Title	Change From Baseline in Cough Severity After 12 Weeks of Intervention
Description	Measured by Cough Severity Visual Analogue Scale (VAS). The Cough Severity VAS was a single item instrument, asking the study participant to assess the severity of his/her cough using a 0-100 VAS. This was a vertically oriented line ordered from 0-100, with 0 = "No Cough" and 100 = "Extremely Severe Cough".
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

All participants in PPS with valid VAS scores in Week 12 or Termination visit.

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	61	68	67	68
Mean (Standard Deviation) [Scores on a scale]	-17.69 (23.87)	-22.66 (22.98)	-22.87 (24.54)	-17.02 (21.88)

7. Secondary Outcome

Title	Percentage of Participants With a ≥30 Scale Units Reduction From Baseline After 12 Weeks of Intervention
Description	Measured by cough Severity VAS
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

PPS

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	73	74
Number (95% Confidence Interval) [Percentage of participants]	26.87 (16.76) 35.8%	36.23 (24.99) 46.4%	27.40 (17.61) 34.3%	20.27 (11.81) 26.3%

8. Secondary Outcome

Title	Percentage of Participants With a ≥1.3-point Increase From Baseline After 12 Weeks of Intervention
Description	Measured by LCQ total score. The LCQ was a 19-item instrument that asked 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, 11, 14, 15 built the physical domain. 7 items: 4, 5, 6, 12, 13, 16, 17 built the psychological domain. Further 4 items: 7, 8, 18 and 19 built the social domain. Study participants responded to the items using a 7-point Likert scale from 1 (all of the time) to 7 (none of the time) and entered their assessments on a tablet device. Completion of the LCQ took approximately five minutes. The LCQ total score was 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. The percentage of participants with a >= 1.3-point increase in LCQ total score is shown.
Time Frame	From baseline up to 12 weeks

Outcome Measure Data

Analysis Population Description

PPS

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	67	69	73	74
Number (95% Confidence Interval) [Percentage of participants]	47.76 (35.40) 63.7%	60.87 (48.37) 78%	64.38 (52.31) 80.5%	51.35 (39.44) 66.7%

9. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Associated Severity
Description	Adverse event (AE) was defined as any untoward medical occurrence in a study participant, whether or not considered related to the study intervention, occurring from the time of signing the informed consent until the follow-up visit. TEAE was defined as any event occurring or worsening after the start of study intervention administration until 14 days after the last intake of study intervention.
Time Frame	From the start of study intervention administration until 14 days after the last study medication intake, with an average of 80.0 + 14 days

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF): All participants randomly assigned to study intervention and who took at least one tablet of study intervention. Participants were analyzed according to the intervention they actually received.

Arm/Group Title	Eliapixant 25 mg BID	Eliapixant 75 mg BID	Eliapixant 150 mg BID	Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.	Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
Measure Participants	75	78	80	77
Any TEAE	43 57.3%	51 65.4%	51 63.8%	39 50.6%
Maximum intensity for any TEAE - mild	21 28%	32 41%	23 28.8%	18 23.4%
Maximum intensity for any TEAE - moderate	22 29.3%	16 20.5%	25 31.3%	20 26%
Maximum intensity for any TEAE - severe	0 0%	3 3.8%	3 3.8%	1 1.3%
Any serious TEAE	0 0%	1 1.3%	2 2.5%	1 1.3%

Adverse Events

Time Frame	From the start of study intervention administration until 14 days after the last study medication intake, with an average of 80.0 + 14 days. Adverse event reporting for the all-cause mortality considers all deaths that occurred at any time during the study before the last contact, with an average of 80.0 + 30 ± 5 days.
Arm/Group Title	Eliapixant 25 mg BID		Eliapixant 75 mg BID		Eliapixant 150 mg BID		Placebo
Arm/Group Description	Participants were randomized to receive 25 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.		Participants were randomized to receive 75 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.		Participants were randomized to receive 150 mg oral doses of eliapixant, administered twice daily over the course of 12 weeks.		Participants were randomized to receive placebo for eliapixant, administered twice daily over the course of 12 weeks.
All Cause Mortality
	Eliapixant 25 mg BID		Eliapixant 75 mg BID		Eliapixant 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/78 (0%)		0/80 (0%)		0/77 (0%)
Serious Adverse Events
	Eliapixant 25 mg BID		Eliapixant 75 mg BID		Eliapixant 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		1/78 (1.3%)		2/80 (2.5%)		1/77 (1.3%)
Cardiac disorders
Angina unstable	0/75 (0%)	0	0/78 (0%)	0	0/80 (0%)	0	1/77 (1.3%)	1
Infections and infestations
Pneumonia	0/75 (0%)	0	1/78 (1.3%)	1	0/80 (0%)	0	0/77 (0%)	0
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/75 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/77 (0%)	0
Investigations
Liver function test abnormal	0/75 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/77 (0%)	0
Other (Not Including Serious) Adverse Events
	Eliapixant 25 mg BID		Eliapixant 75 mg BID		Eliapixant 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/75 (42.7%)		37/78 (47.4%)		45/80 (56.3%)		25/77 (32.5%)
Gastrointestinal disorders
Abdominal discomfort	0/75 (0%)	0	0/78 (0%)	0	2/80 (2.5%)	2	1/77 (1.3%)	1
Abdominal pain upper	3/75 (4%)	3	3/78 (3.8%)	3	2/80 (2.5%)	2	1/77 (1.3%)	1
Diarrhoea	3/75 (4%)	3	2/78 (2.6%)	2	1/80 (1.3%)	1	1/77 (1.3%)	1
Dry mouth	1/75 (1.3%)	1	3/78 (3.8%)	3	2/80 (2.5%)	2	4/77 (5.2%)	5
Flatulence	2/75 (2.7%)	2	1/78 (1.3%)	1	0/80 (0%)	0	0/77 (0%)	0
Gastrooesophageal reflux disease	1/75 (1.3%)	1	2/78 (2.6%)	2	2/80 (2.5%)	2	0/77 (0%)	0
Nausea	2/75 (2.7%)	2	2/78 (2.6%)	3	5/80 (6.3%)	5	1/77 (1.3%)	2
Vomiting	0/75 (0%)	0	0/78 (0%)	0	3/80 (3.8%)	3	0/77 (0%)	0
General disorders
Chest discomfort	2/75 (2.7%)	2	1/78 (1.3%)	1	0/80 (0%)	0	0/77 (0%)	0
Fatigue	2/75 (2.7%)	2	6/78 (7.7%)	6	5/80 (6.3%)	6	2/77 (2.6%)	2
Oedema peripheral	0/75 (0%)	0	2/78 (2.6%)	2	1/80 (1.3%)	1	0/77 (0%)	0
Pyrexia	3/75 (4%)	3	0/78 (0%)	0	0/80 (0%)	0	1/77 (1.3%)	1
Swelling face	2/75 (2.7%)	2	0/78 (0%)	0	0/80 (0%)	0	0/77 (0%)	0
Infections and infestations
Gastroenteritis	2/75 (2.7%)	3	0/78 (0%)	0	0/80 (0%)	0	0/77 (0%)	0
Nasopharyngitis	2/75 (2.7%)	2	3/78 (3.8%)	3	2/80 (2.5%)	3	1/77 (1.3%)	1
Sinusitis	1/75 (1.3%)	1	0/78 (0%)	0	2/80 (2.5%)	2	1/77 (1.3%)	1
Urinary tract infection	1/75 (1.3%)	1	2/78 (2.6%)	2	3/80 (3.8%)	3	0/77 (0%)	0
COVID-19	2/75 (2.7%)	2	2/78 (2.6%)	2	0/80 (0%)	0	3/77 (3.9%)	3
Injury, poisoning and procedural complications
Ligament sprain	0/75 (0%)	0	2/78 (2.6%)	2	0/80 (0%)	0	1/77 (1.3%)	1
Investigations
Alanine aminotransferase increased	0/75 (0%)	0	1/78 (1.3%)	1	2/80 (2.5%)	2	0/77 (0%)	0
Aspartate aminotransferase increased	0/75 (0%)	0	0/78 (0%)	0	2/80 (2.5%)	2	0/77 (0%)	0
Blood fibrinogen increased	1/75 (1.3%)	1	1/78 (1.3%)	1	2/80 (2.5%)	2	0/77 (0%)	0
Weight increased	1/75 (1.3%)	1	1/78 (1.3%)	1	2/80 (2.5%)	2	0/77 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/75 (1.3%)	2	2/78 (2.6%)	2	2/80 (2.5%)	2	1/77 (1.3%)	1
Back pain	0/75 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	2/77 (2.6%)	2
Myalgia	2/75 (2.7%)	2	0/78 (0%)	0	0/80 (0%)	0	1/77 (1.3%)	1
Pain in extremity	2/75 (2.7%)	2	0/78 (0%)	0	2/80 (2.5%)	2	2/77 (2.6%)	2
Nervous system disorders
Ageusia	0/75 (0%)	0	0/78 (0%)	0	2/80 (2.5%)	2	1/77 (1.3%)	1
Dizziness	2/75 (2.7%)	2	2/78 (2.6%)	2	1/80 (1.3%)	1	5/77 (6.5%)	5
Dysgeusia	1/75 (1.3%)	1	9/78 (11.5%)	9	13/80 (16.3%)	14	1/77 (1.3%)	1
Headache	6/75 (8%)	6	5/78 (6.4%)	10	6/80 (7.5%)	7	4/77 (5.2%)	4
Hypogeusia	2/75 (2.7%)	2	1/78 (1.3%)	1	4/80 (5%)	4	2/77 (2.6%)	2
Balance disorder	0/75 (0%)	0	1/78 (1.3%)	1	2/80 (2.5%)	2	0/77 (0%)	0
Taste disorder	0/75 (0%)	0	2/78 (2.6%)	2	1/80 (1.3%)	1	1/77 (1.3%)	1
Psychiatric disorders
Anxiety	1/75 (1.3%)	1	2/78 (2.6%)	2	0/80 (0%)	0	0/77 (0%)	0
Insomnia	4/75 (5.3%)	4	0/78 (0%)	0	1/80 (1.3%)	1	0/77 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	4/75 (5.3%)	4	7/78 (9%)	7	7/80 (8.8%)	7	3/77 (3.9%)	3
Nasal dryness	0/75 (0%)	0	0/78 (0%)	0	0/80 (0%)	0	2/77 (2.6%)	3
Throat irritation	0/75 (0%)	0	1/78 (1.3%)	1	2/80 (2.5%)	2	0/77 (0%)	0
Oropharyngeal pain	2/75 (2.7%)	2	0/78 (0%)	0	1/80 (1.3%)	1	0/77 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	3/75 (4%)	3	0/78 (0%)	0	1/80 (1.3%)	1	2/77 (2.6%)	2
Rash	2/75 (2.7%)	2	0/78 (0%)	0	2/80 (2.5%)	4	0/77 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.