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Clinical Trial Results:
A DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF THREE DOSES OF ORVEPITANT IN SUBJECTS WITH CHRONIC REFRACTORY COUGH

Summary
EudraCT number	2016-004979-49
Trial protocol	GB
Global end of trial date	05 Feb 2019

Results information
Results version number	v1(current)
This version publication date	06 Feb 2022
First version publication date	06 Feb 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

VOLCANO-2

ISRCTN number

US NCT number

NCT02993822

WHO universal trial number (UTN)

Sponsor organisation name

NeRRe Therapeutics Ltd

Sponsor organisation address

Gunnels Wood Road, Stevenage, United Kingdom, SG1 2FX

Public contact

Elizabeth Ballantyne, NeRRe Therapeutics Ltd., +44 (0) 1438906960, Elizabeth.Ballantyne@nerretherapeutics.com

Scientific contact

Stephen Pawsey MBBS FFPM, NeRRe Therapeutics Ltd., +44 (0) 7827 460726, steve.pawsey@nerretherapeutics.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Jan 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

24 Jan 2019

Global end of trial reached?

Yes

Global end of trial date

05 Feb 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of once daily doses of 10 mg, 20 mg, and 30 mg orvepitant versus placebo in reducing awake objective cough frequency

Protection of trial subjects

No specific measures required.

Background therapy

None

Evidence for comparator

Placebo was used as the reference agent in the study to allow comparisons of the effects of orvepitant on both safety and efficacy, and was considered justifiable in relation to the duration of the study and the nature of the disorder being evaluated. Placebo has been used commonly as the reference agent in similar trials.

Actual start date of recruitment

02 May 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 113

Country: Number of subjects enrolled

United States: 199

Country: Number of subjects enrolled

Canada: 3

Worldwide total number of subjects

315

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

183

From 65 to 84 years

129

85 years and over

Subject disposition

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Recruitment details

USA recruitment from 31-May-2017 to 28-Sep-2018 UK recruitment from 26-Sep-2017 to 28-Sep-2018 Canada recruitment from 29-Jun-2018 to 28-Sep-2018

Screening details

488 subjects were screened, of whom 315 (64.5%) completed screening and were randomised. Screening failures occurred due to not meeting inclusion criteria (74 subjects [15.2%]) or exclusion criteria (79 subjects [16.2%]), withdrawal of consent (nine [1.8%] subjects) and AEs (2 [0.4%] subjects). All other reasons reported in individual subjects.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Data analyst, Subject, Assessor

Blinding implementation details

The study was conducted in a double blind manner, with the subjects, Investigators and Sponsor all blinded to the treatment allocated. Both orvepitant and placebo were presented as white tablets, identical in size, colour and shape.

Are arms mutually exclusive

Yes

Orvepitant 10mg

Arm description

Subjects receive orvepitant 10 mg

Arm type

Experimental

Investigational medicinal product name

Orvepitant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orvepitant 10mg tablet administered orally once daily for 12 weeks

Orvepitant 20mg

Arm description

Subjects receive orvepitant 20mg

Arm type

Experimental

Investigational medicinal product name

Orvepitant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orvepitant 20mg tablet administered orally once daily for 12 weeks

Orvepitant 30mg

Arm description

Subjects receive orvepitant 30mg

Arm type

Experimental

Investigational medicinal product name

Orvepitant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orvepitant 30mg tablet administered orally once daily for 12 weeks

Reference

Arm description

Subjects receive placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablet administered orally once daily for 12 weeks

Number of subjects in period 1	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Started	79	78	79	79
Completed	69	74	69	75
Not completed	10	4	10	4
Consent withdrawn by subject	4	2	2	3
Adverse event, non-fatal	3	1	7	-
Unable to attend follow-up due to illness	-	-	-	1
Lost to follow-up	1	-	1	-
Protocol deviation	1	-	-	-
Lack of efficacy	1	-	-	-
Lack of efficacy	-	1	-	-

Baseline characteristics

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Reporting group title

Orvepitant 10mg

Reporting group description

Subjects receive orvepitant 10 mg

Reporting group title

Orvepitant 20mg

Reporting group description

Subjects receive orvepitant 20mg

Reporting group title

Orvepitant 30mg

Reporting group description

Subjects receive orvepitant 30mg

Reporting group title

Reference

Reporting group description

Subjects receive placebo

Reporting group values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference	Total
Number of subjects	79	78	79	79	315
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	46	44	56	37	183
From 65-84 years	32	33	22	42	129
85 years and over	1	1	1	0	3
Age continuous
Units: years
arithmetic mean (standard deviation)	62.29 ( 9.850 )	59.86 ( 13.173 )	59.47 ( 10.020 )	62.24 ( 11.815 )	-
Gender categorical
Units: Subjects
Female	65	69	60	59	253
Male	14	9	19	20	62

End points

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Reporting group title

Orvepitant 10mg

Reporting group description

Subjects receive orvepitant 10 mg

Reporting group title

Orvepitant 20mg

Reporting group description

Subjects receive orvepitant 20mg

Reporting group title

Orvepitant 30mg

Reporting group description

Subjects receive orvepitant 30mg

Reporting group title

Reference

Reporting group description

Subjects receive placebo

Primary: Change from baseline to Week 12 in awake objective cough frequency

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End point title

Change from baseline to Week 12 in awake objective cough frequency

End point description

The change from Baseline to Week 12 in awake objective cough frequency measured with an automated cough monitor (ACM) and analysed after taking logs (to base 10).

End point type

Primary

End point timeframe

Change from baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	72	67	70
Units: coughs/hour (log transformed)
arithmetic mean (standard deviation)	-0.185 ( 0.3258 )	-0.912 ( 0.3405 )	-0.271 ( 0.4055 )	-0.243 ( 0.3225 )

Primary variable (10 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 12 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Reference v Orvepitant 10mg

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.324

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.49

Variability estimate

Standard deviation

Notes
[1] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 12 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Primary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.332

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.48

Variability estimate

Standard deviation

Notes
[2] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 12 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Primary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.531

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.2

Variability estimate

Standard deviation

Notes
[3] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 12 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary: Change in awake objective cough frequency at Week 2 compared to baseline

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End point title

Change in awake objective cough frequency at Week 2 compared to baseline

End point description

The change from Baseline to Week 2 in awake objective cough frequency measured with an automated cough monitor (ACM) and analysed after taking logs (to base 10).

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	73	74	75	73
Units: coughs/hour (log transformed)
arithmetic mean (standard deviation)	-0.180 ( 0.2791 )	-0.181 ( 0.3142 )	-0.215 ( 0.2515 )	-0.139 ( 0.2892 )

Secondary variable (10 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 2 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.482

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.15

Variability estimate

Standard deviation

Notes
[4] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 2 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary variable (20 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 2 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.46

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.14

Variability estimate

Standard deviation

Notes
[5] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 2 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary variable (30 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 2 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.144

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.06

Variability estimate

Standard deviation

Notes
[6] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 2 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary: Change in awake objective cough frequency at Week 4 compared to baseline

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End point title

Change in awake objective cough frequency at Week 4 compared to baseline

End point description

The change from Baseline to Week 4 in awake objective cough frequency measured with an automated cough monitor (ACM) and analyzed after taking logs (to base 10).

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	68	77	75	72
Units: coughs/hour (log transformed)
arithmetic mean (standard deviation)	-0.188 ( 0.3292 )	-0.231 ( 0.3665 )	-0.211 ( 0.2994 )	-0.169 ( 0.2699 )

Secondary variable (10 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 4 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.992

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.27

Variability estimate

Standard deviation

Notes
[7] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 4 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary variable (20 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 4 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.387

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.14

Variability estimate

Standard deviation

Notes
[8] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 4 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary variable (30 mg)

Statistical analysis description

Change from baseline to each visit (Week 2, Week 4 and Week 12) in log transformed awake objective cough frequency was analysed using a mixed model for repeated measures (MMRM) with restricted maximum likelihood (REML) estimation. The treatment effect at Week 4 was estimated using the ratio of geometric means (i.e. the difference between the treatments least squares means [adjusted means] on the log scale, back transformed to the original scale).

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.6

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.19

Variability estimate

Standard deviation

Notes
[9] - This study was designed to test for superiority. The null hypothesis for the treatment comparison was that there is no difference between orvepitant treatment group and placebo in mean change in log transformed (to base 10) awake objective cough frequency at Week 4 compared to Baseline. The alternative hypothesis was that there is a difference. Two-sided tests with alpha=0.05 were used to test this hypothesis.

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 2 compared to baseline

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End point title

Change in the Leicester Cough Questionnaire (LCQ) at Week 2 compared to baseline

End point description

The LCQ is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 2 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12.

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	72	77	75	75
Units: Total score
arithmetic mean (standard deviation)	2.41 ( 3.309 )	2.37 ( 3.252 )	2.93 ( 3.010 )	1.24 ( 2.714 )

Secondary variable (10 mg)

Statistical analysis description

The change from baseline in LCQ total score and the three domain scores was summarised by treatment group and visit (Weeks 2, 4, 8 and 12) in terms of absolute values and changes from baseline. The effect of treatment in terms of the change from baseline to each scheduled visit (Week 2, Week 4, Week 8 and Week 12) in LCQ total score and the three domain scores was analysed using a MMRM with REML estimation.

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.042

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Notes
[10] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.026

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

Variability estimate

Standard deviation

Notes
[11] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.003

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

2.4

Variability estimate

Standard deviation

Notes
[12] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 4 compared to baseline

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End point title

Change in the Leicester Cough Questionnaire (LCQ) at Week 4 compared to baseline

End point description

The LCQ is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 4 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	68	77	74	76
Units: Total score
arithmetic mean (standard deviation)	2.50 ( 3.416 )	2.15 ( 3.490 )	2.98 ( 3.163 )	1.61 ( 3.132 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.25

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Variability estimate

Standard deviation

Notes
[13] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.325

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.5

Variability estimate

Standard deviation

Notes
[14] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.029

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

2.2

Variability estimate

Standard deviation

Notes
[15] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 8 compared to baseline

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End point title

Change in the Leicester Cough Questionnaire (LCQ) at Week 8 compared to baseline

End point description

The LCQ is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 8 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	76	70	75
Units: Total score
arithmetic mean (standard deviation)	2.78 ( 3.535 )	2.19 ( 3.602 )	2.82 ( 3.960 )	1.34 ( 3.222 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.038

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

2.3

Variability estimate

Standard deviation

Notes
[16] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.118

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

Variability estimate

Standard deviation

Notes
[17] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.025

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

2.4

Variability estimate

Standard deviation

Notes
[18] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 12 compared to baseline

Top of page

End point title

Change in the Leicester Cough Questionnaire (LCQ) at Week 12 compared to baseline

End point description

The LCQ is a 19 item questionnaire that assessed cough related quality of life. It has three domains (physical, psychological and social) and subjects were asked to complete it based on their experience in a recall period of 12 weeks. The total score range is 3 to 21 and domain scores each range from 1 to 7; a higher score indicated a better quality of life. Subjects completed the LCQ whilst in the clinic at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	74	67	74
Units: Total score
arithmetic mean (standard deviation)	2.38 ( 3.609 )	2.09 ( 3.736 )	3.23 ( 4.007 )	1.50 ( 3.586 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.258

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.9

Variability estimate

Standard deviation

Notes
[19] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.243

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.8

Variability estimate

Standard deviation

Notes
[20] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.009

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

2.8

Variability estimate

Standard deviation

Notes
[21] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups are presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Day-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Day-time

End point description

The cough VAS is a 100 mm scale on which subjects indicated their severity of cough over the previous 24 hours, both during the day-time and during night time separately. The VAS ranged from “no cough” (0 mm) on the left to “worst cough” (100 mm) on the right. Subjects completed the cough severity VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12.

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	71	77	75	75
Units: Score
arithmetic mean (standard deviation)	-17.7 ( 26.06 )	-10.5 ( 27.78 )	-13.5 ( 22.93 )	-6.3 ( 19.24 )

Secondary variable (10 mg)

Statistical analysis description

Change in the Cough Severity VAS was summarised by treatment group and visit (Weeks 2, 4, 8 and 12) in terms of absolute values and changes from baseline. The effect of treatment in terms of the change from baseline to each scheduled visit (Week 2, Week 4, Week 8 and Week 12) in Cough Severity VAS was analysed using a MMRM with REML estimation.

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.008

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-9.6

Confidence interval

level

95%

sides

2-sided

lower limit

-16.6

upper limit

-2.5

Variability estimate

Standard deviation

Notes
[22] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.198

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11.4

upper limit

2.4

Variability estimate

Standard deviation

Notes
[23] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.055

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-13.7

upper limit

0.1

Variability estimate

Standard deviation

Notes
[24] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Day-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Day-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	68	77	75	76
Units: Score
arithmetic mean (standard deviation)	-17.9 ( 27.11 )	-9.4 ( 26.76 )	-15.9 ( 25.02 )	-7.8 ( 22.36 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.026

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-8.7

Confidence interval

level

95%

sides

2-sided

lower limit

-16.3

upper limit

-1.1

Variability estimate

Standard deviation

Notes
[25] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.571

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-9.6

upper limit

5.3

Variability estimate

Standard deviation

Notes
[26] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.043

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-7.7

Confidence interval

level

95%

sides

2-sided

lower limit

-15.2

upper limit

-0.3

Variability estimate

Standard deviation

Notes
[27] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Day-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Day-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	76	72	75
Units: Score
arithmetic mean (standard deviation)	-21.0 ( 30.37 )	-9.9 ( 29.57 )	-18.6 ( 27.24 )	-8.2 ( 23.58 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.006

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-11.5

Confidence interval

level

95%

sides

2-sided

lower limit

-19.7

upper limit

-3.3

Variability estimate

Standard deviation

Notes
[28] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.435

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-11.1

upper limit

4.8

Variability estimate

Standard deviation

Notes
[29] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.022

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-9.4

Confidence interval

level

95%

sides

2-sided

lower limit

-17.4

upper limit

-1.4

Variability estimate

Standard deviation

Notes
[30] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Day-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Day-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	74	68	73
Units: Score
arithmetic mean (standard deviation)	-18.8 ( 31.27 )	-11.6 ( 27.33 )	-20.1 ( 29.33 )	-10.6 ( 24.46 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.103

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-7

Confidence interval

level

95%

sides

2-sided

lower limit

-15.3

upper limit

1.4

Variability estimate

Standard deviation

Notes
[31] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.546

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

5.6

Variability estimate

Standard deviation

Notes
[32] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.034

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-17.2

upper limit

-0.7

Variability estimate

Standard deviation

Notes
[33] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Night-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Night-time

End point description

End point type

Secondary

End point timeframe

Change from baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	71	77	75	75
Units: Score
arithmetic mean (standard deviation)	-12.8 ( 28.96 )	-7.8 ( 26.76 )	-6.2 ( 24.97 )	-3.9 ( 27.62 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.004

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-11.2

Confidence interval

level

95%

sides

2-sided

lower limit

-18.8

upper limit

-3.6

Variability estimate

Standard deviation

Notes
[34] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.282

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

3.4

Variability estimate

Standard deviation

Notes
[35] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.398

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-10.7

upper limit

4.3

Variability estimate

Standard deviation

Notes
[36] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Night-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Night-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	68	77	75	76
Units: Score
arithmetic mean (standard deviation)	-10.1 ( 32.87 )	-7.9 ( 27.52 )	-5.8 ( 27.96 )	-2.7 ( 27.99 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

= 0.019

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-18.3

upper limit

-1.7

Variability estimate

Standard deviation

Notes
[37] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.17

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-5.6

Confidence interval

level

95%

sides

2-sided

lower limit

-13.7

upper limit

2.4

Variability estimate

Standard deviation

Notes
[38] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.384

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.7

upper limit

4.5

Variability estimate

Standard deviation

Notes
[39] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Night-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Night-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	76	72	75
Units: Score
arithmetic mean (standard deviation)	-11.5 ( 32.65 )	-6.8 ( 29.07 )	-9.8 ( 28.73 )	-2.2 ( 28.95 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.006

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-11.7

Confidence interval

level

95%

sides

2-sided

lower limit

-20

upper limit

-3.3

Variability estimate

Standard deviation

Notes
[40] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.222

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-13

upper limit

Variability estimate

Standard deviation

Notes
[41] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.058

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-7.9

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

0.3

Variability estimate

Standard deviation

Notes
[42] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Night-time

Top of page

End point title

Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Night-time

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	74	68	73
Units: Score
arithmetic mean (standard deviation)	-8.9 ( 35.99 )	-7.1 ( 26.88 )	-9.6 ( 30.24 )	-1.5 ( 33.74 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

= 0.027

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-10

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

-1.2

Variability estimate

Standard deviation

Notes
[43] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.147

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-6.4

Confidence interval

level

95%

sides

2-sided

lower limit

-14.9

upper limit

2.2

Variability estimate

Standard deviation

Notes
[44] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

= 0.046

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

-0.1

Variability estimate

Standard deviation

Notes
[45] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 2 compared to baseline

Top of page

End point title

Change in the urge-to-cough visual analogue scale (VAS) at Week 2 compared to baseline

End point description

The urge-to-cough VAS was a 100 mm scale on which subjects indicated their urge to cough over the previous 24 hours (day/awake time and night time combined). The VAS ranged from “no urge to cough” (0 mm) on the left to “severe urge to cough” (100 mm) on the right. Subjects completed the urge to cough VAS at baseline/Day 1 (pre dose) and at Weeks 2, 4, 8, and 12.

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	72	77	75	74
Units: Score
arithmetic mean (standard deviation)	-20.8 ( 24.59 )	-12.0 ( 25.09 )	-13.8 ( 22.03 )	-7.0 ( 20.35 )

Secondary variable (10 mg)

Statistical analysis description

Change in the urge-to-cough VAS was summarised by treatment group and visit (Weeks 2, 4, 8 and 12) in terms of absolute values and changes from baseline. The effect of treatment in terms of the change from baseline to each scheduled visit (Week 2, Week 4, Week 8 and Week 12) in urge-to cough VAS was analysed using a MMRM with REML estimation.

Comparison groups

Reference v Orvepitant 10mg

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

< 0.001

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-12.5

Confidence interval

level

95%

sides

2-sided

lower limit

-19.5

upper limit

-5.5

Variability estimate

Standard deviation

Notes
[46] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.114

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-5.5

Confidence interval

level

95%

sides

2-sided

lower limit

-12.4

upper limit

1.3

Variability estimate

Standard deviation

Notes
[47] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

P-value

= 0.056

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-13.7

upper limit

0.2

Variability estimate

Standard deviation

Notes
[48] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 4 compared to baseline

Top of page

End point title

Change in the urge-to-cough visual analogue scale (VAS) at Week 4 compared to baseline

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	68	77	75	76
Units: Score
arithmetic mean (standard deviation)	-19.0 ( 26.93 )	-12.0 ( 26.67 )	-17.3 ( 24.73 )	-8.8 ( 24.26 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.027

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-16.8

upper limit

-1

Variability estimate

Standard deviation

Notes
[49] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority ^[50]

P-value

= 0.357

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.3

upper limit

4.1

Variability estimate

Standard deviation

Notes
[50] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.031

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-8.5

Confidence interval

level

95%

sides

2-sided

lower limit

-16.2

upper limit

-0.8

Variability estimate

Standard deviation

Notes
[51] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 8 compared to baseline

Top of page

End point title

Change in the urge-to-cough visual analogue scale (VAS) at Week 8 compared to baseline

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	65	76	72	75
Units: Score
arithmetic mean (standard deviation)	-23.8 ( 28.00 )	-14.5 ( 27.55 )	-19.7 ( 26.80 )	-11.0 ( 24.78 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.008

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-11.1

Confidence interval

level

95%

sides

2-sided

lower limit

-19.2

upper limit

-2.9

Variability estimate

Standard deviation

Notes
[52] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.321

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-11.8

upper limit

3.9

Variability estimate

Standard deviation

Notes
[53] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.047

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-8.1

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

-0.1

Variability estimate

Standard deviation

Notes
[54] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 12 compared to baseline

Top of page

End point title

Change in the urge-to-cough visual analogue scale (VAS) at Week 12 compared to baseline

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	66	74	68	74
Units: Score
arithmetic mean (standard deviation)	-23.7 ( 27.30 )	-12.6 ( 28.57 )	-22.9 ( 28.43 )	-11.8 ( 26.50 )

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.018

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-10.1

Confidence interval

level

95%

sides

2-sided

lower limit

-18.4

upper limit

-1.8

Variability estimate

Standard deviation

Notes
[55] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.682

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-9.8

upper limit

6.4

Variability estimate

Standard deviation

Notes
[56] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

P-value

= 0.005

Method

Mixed model repeated measures

Parameter type

Mean difference (final values)

Point estimate

-11.8

Confidence interval

level

95%

sides

2-sided

lower limit

-20

upper limit

-3.6

Variability estimate

Standard deviation

Notes
[57] - The treatment effect was estimated using the difference between the treatments least squares means (adjusted means). The 95% confidence interval for the difference between the treatments least squares means and the p-value from the hypothesis test of no difference between the treatment groups was presented.

Secondary: • Global Rating of Change in cough frequency at Week 2

Top of page

End point title

• Global Rating of Change in cough frequency at Week 2

End point description

In the Global Rating of Change scale, subjects indicated if there had been a change in their symptoms (cough frequency and, separately, cough severity) since starting the IMP. Subjects responded with “worse”, “about the same” or “better”. If subjects indicated a change (either “worse” or “better”) they then indicated on a 7 point scale the degree of change ranging from 1 (almost the same, hardly any change) to 7 (a very great deal changed). Subjects documented their Global Rating of Change in cough frequency and cough severity at Weeks 2, 4, 8, and 12.

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	73	77	76	74
Units: Number of patients
Worse	4	10	5	11
About the same	35	37	34	44
Better	34	30	37	19

Secondary variable (10 mg)

Statistical analysis description

The Global Rating of Change responses were summarised by treatment group and visit (Weeks 2, 4, 8 and 12) as categorical endpoints (“worse”, “about the same” and “better”). Pairwise comparisons were performed using the Cochran Mantel Haenszel test stratified by region using modified ridit scores (row mean scores differ).

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.134

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough frequency at Week 4

Top of page

End point title

Global Rating of Change in cough frequency at Week 4

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	69	76	74	76
Units: Number of patients
Worse	9	8	6	12
About the same	32	36	37	39
Better	28	32	31	25

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.401

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.175

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.126

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough frequency at Week 8

Top of page

End point title

Global Rating of Change in cough frequency at Week 8

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	67	75	72	75
Units: Number of patients
Worse	11	17	10	20
About the same	22	31	37	38
Better	34	27	25	17

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 10mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.144

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough frequency at Week 12

Top of page

End point title

Global Rating of Change in cough frequency at Week 12

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	67	74	67	74
Units: Number of patients
Worse	7	13	7	13
About the same	32	33	31	37
Better	28	28	29	24

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.158

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Orvepitant 20mg v Reference

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.597

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.124

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough severity at Week 2

Top of page

End point title

Global Rating of Change in cough severity at Week 2

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 2

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	73	77	76	74
Units: Number of patients
Worse	7	8	4	12
About the same	33	39	35	44
Better	33	30	37	18

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough severity at Week 4

Top of page

End point title

Global Rating of Change in cough severity at Week 4

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 4

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	69	76	74	76
Units: Number of patients
Worse	9	7	7	14
About the same	32	43	31	37
Better	28	26	36	25

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.309

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.387

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough severity at Week 8

Top of page

End point title

Global Rating of Change in cough severity at Week 8

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 8

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	67	75	72	75
Units: Number of patients
Worse	8	12	6	15
About the same	26	36	35	42
Better	33	27	31	18

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.152

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Global Rating of Change in cough severity at Week 12

Top of page

End point title

Global Rating of Change in cough severity at Week 12

End point description

End point type

Secondary

End point timeframe

Change from Baseline to Week 12

End point values	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Reference
Number of subjects analysed	67	74	67	74
Units: Number of patients
Worse	5	15	8	16
About the same	38	33	30	36
Better	24	26	29	22

Secondary variable (10 mg)

Statistical analysis description

Comparison groups

Orvepitant 10mg v Reference

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (20 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 20mg

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.557

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Secondary variable (30 mg)

Statistical analysis description

Comparison groups

Reference v Orvepitant 30mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.054

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

22 May 2017 (first subject screening) to 24 January 2019 (last subject last visit)

Adverse event reporting additional description

Adverse events that occurred from the time of consent up to the final study visit (Week 14) were recorded. Adverse events could be volunteered spontaneously by the subject, or were discovered as a result of general, non leading questioning. Note: The adverse events posted in EudraCT results are treatment-emergent adverse events.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Orvepitant 10mg

Reporting group description

Subjects receive orvepitant 10 mg

Reporting group title

Orvepitant 20mg

Reporting group description

Subjects receive orvepitant 20mg

Reporting group title

Orvepitant 30mg

Reporting group description

Subjects receive orvepitant 30mg

Reporting group title

Placebo

Reporting group description

Subjects receive placebo

Serious adverse events	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 79 (1.27%)	1 / 78 (1.28%)	3 / 79 (3.80%)	1 / 79 (1.27%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 79 (1.27%)	0 / 78 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Intestinal anastomosis complication
subjects affected / exposed	0 / 79 (0.00%)	0 / 78 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 79 (1.27%)	0 / 78 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 79 (1.27%)	0 / 78 (0.00%)	0 / 79 (0.00%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 79 (0.00%)	0 / 78 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 79 (0.00%)	0 / 78 (0.00%)	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 79 (0.00%)	1 / 78 (1.28%)	0 / 79 (0.00%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Orvepitant 10mg	Orvepitant 20mg	Orvepitant 30mg	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	63 / 79 (79.75%)	48 / 78 (61.54%)	53 / 79 (67.09%)	40 / 79 (50.63%)
Nervous system disorders
Headache
subjects affected / exposed	7 / 79 (8.86%)	10 / 78 (12.82%)	7 / 79 (8.86%)	4 / 79 (5.06%)
occurrences all number	7	19	9	6
Dizziness
subjects affected / exposed	5 / 79 (6.33%)	4 / 78 (5.13%)	5 / 79 (6.33%)	1 / 79 (1.27%)
occurrences all number	5	4	6	1
Somnolence
subjects affected / exposed	2 / 79 (2.53%)	4 / 78 (5.13%)	5 / 79 (6.33%)	0 / 79 (0.00%)
occurrences all number	2	4	5	0
Paraesthesia
subjects affected / exposed	4 / 79 (5.06%)	0 / 78 (0.00%)	0 / 79 (0.00%)	1 / 79 (1.27%)
occurrences all number	4	0	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	13 / 79 (16.46%)	13 / 78 (16.67%)	11 / 79 (13.92%)	4 / 79 (5.06%)
occurrences all number	14	14	11	4
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 79 (2.53%)	1 / 78 (1.28%)	4 / 79 (5.06%)	3 / 79 (3.80%)
occurrences all number	2	1	4	4
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	5 / 79 (6.33%)	1 / 78 (1.28%)	4 / 79 (5.06%)	3 / 79 (3.80%)
occurrences all number	6	2	5	3
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 79 (5.06%)	1 / 78 (1.28%)	6 / 79 (7.59%)	0 / 79 (0.00%)
occurrences all number	4	1	6	0
Arthralgia
subjects affected / exposed	4 / 79 (5.06%)	1 / 78 (1.28%)	1 / 79 (1.27%)	1 / 79 (1.27%)
occurrences all number	4	1	1	1
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	8 / 79 (10.13%)	7 / 78 (8.97%)	4 / 79 (5.06%)	10 / 79 (12.66%)
occurrences all number	9	10	4	11
Upper respiratory tract infection
subjects affected / exposed	5 / 79 (6.33%)	4 / 78 (5.13%)	3 / 79 (3.80%)	9 / 79 (11.39%)
occurrences all number	6	5	3	9
Urinary tract infection
subjects affected / exposed	4 / 79 (5.06%)	2 / 78 (2.56%)	3 / 79 (3.80%)	4 / 79 (5.06%)
occurrences all number	4	2	4	4

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Were there any global substantial amendments to the protocol? Yes

11 May 2017

In addition to minor typographical, formatting and administrative alterations, the following changes were made: • Removal of all reference to sampling and analysis for Substance P. • Rationalisation of prohibited concomitant cough medications. • Deletion of exclusion based on smoking pack history. • An alternative method of assessing for obstructive lung disease at screening was added. • Addition of pregnancy as a specific withdrawal criterion in Section 7.4 (Withdrawal criteria) of the protocol and modification of text in Section 10.3.9.3 (Pregnancy) of the protocol. • Correction of visit windows. • Removal of the requirement for subjects to fast for 1 hour before dosing on visit days. • Removal of references to pre dose for the Week 14 visits. • Addition of specific guidance for pregnancy reporting windows (30 days for exposed females and 90 days for partners of exposed males). • Removal of requirement to collect a PK sample in the event of an SAE. • Amendment of the criteria for inclusion in the per protocol analysis set from major deviations to relevant deviations.

08 Aug 2017

The following changes were made: • Number of tablets in each bottle of IMP was amended to 36. • Sentence added stating that randomisation would be stratified by region (North America and Europe).

25 Sep 2017

The following change was made: • Exclusion criterion #6 was amended to state that subjects were excluded if both FEV1 <80% predicted and FEV1/FVC ratio <0.7.

21 Feb 2018

The following changes were made: • Planned sample size was increased to 292 subjects and second sample size re estimate added. • Exclusion criterion #8 was amended to provide additional guidance for evidence of uncontrolled hypertension. • Exclusion criterion #16 was amended to remove specific examples of clinically significant abnormal laboratory tests. • Exclusion criterion #17f was amended to add two additional prohibited concomitant medications. • Clarification that for the primary efficacy analysis a mixed model for repeated measures was to be used. This also applied to analysis of selected secondary endpoints. • Clarification that AE summary by severity was for all treatment emergent adverse events.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF THREE DOSES OF ORVEPITANT IN SUBJECTS WITH CHRONIC REFRACTORY COUGH

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to Week 12 in awake objective cough frequency

Primary: Change from baseline to Week 12 in awake objective cough frequency

Secondary: Change in awake objective cough frequency at Week 2 compared to baseline

Secondary: Change in awake objective cough frequency at Week 2 compared to baseline

Secondary: Change in awake objective cough frequency at Week 4 compared to baseline

Secondary: Change in awake objective cough frequency at Week 4 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 2 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 2 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 4 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 4 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 8 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 8 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 12 compared to baseline

Secondary: Change in the Leicester Cough Questionnaire (LCQ) at Week 12 compared to baseline

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Day-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 2 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 4 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 8 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Night-time

Secondary: Change in the cough severity visual analogue scale (VAS) at Week 12 compared to baseline - Night-time

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 2 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 2 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 4 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 4 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 8 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 8 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 12 compared to baseline

Secondary: Change in the urge-to-cough visual analogue scale (VAS) at Week 12 compared to baseline

Secondary: • Global Rating of Change in cough frequency at Week 2

Secondary: • Global Rating of Change in cough frequency at Week 2

Secondary: Global Rating of Change in cough frequency at Week 4

Secondary: Global Rating of Change in cough frequency at Week 4

Secondary: Global Rating of Change in cough frequency at Week 8

Secondary: Global Rating of Change in cough frequency at Week 8

Secondary: Global Rating of Change in cough frequency at Week 12

Secondary: Global Rating of Change in cough frequency at Week 12

Secondary: Global Rating of Change in cough severity at Week 2

Secondary: Global Rating of Change in cough severity at Week 2

Secondary: Global Rating of Change in cough severity at Week 4

Secondary: Global Rating of Change in cough severity at Week 4

Secondary: Global Rating of Change in cough severity at Week 8

Secondary: Global Rating of Change in cough severity at Week 8

Secondary: Global Rating of Change in cough severity at Week 12

Secondary: Global Rating of Change in cough severity at Week 12

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A DOUBLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF THREE DOSES OF ORVEPITANT IN SUBJECTS WITH CHRONIC REFRACTORY COUGH