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Clinical Trial Results:
Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants With Chronic Obstructive Pulmonary Disease (COPD)

Summary
EudraCT number	2016-003675-21
Trial protocol	ES DE NL PL RO
Global end of trial date	05 Oct 2018

Results information
Results version number	v2(current)
This version publication date	27 Nov 2019
First version publication date	13 Oct 2019
Other versions	v1
Version creation reason

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

205724

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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

21 Mar 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Oct 2018

Was the trial ended prematurely?

Main objective of the trial

To characterize the dose response of danirixin compared with placebo, on the incidence and severity of respiratory symptoms in participant with COPD and the annual rate of moderate/severe COPD exacerbations in participants with COPD.

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Apr 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 37

Country: Number of subjects enrolled

Canada: 48

Country: Number of subjects enrolled

Germany: 103

Country: Number of subjects enrolled

Korea, Republic of: 79

Country: Number of subjects enrolled

Netherlands: 38

Country: Number of subjects enrolled

Poland: 82

Country: Number of subjects enrolled

Romania: 106

Country: Number of subjects enrolled

Spain: 62

Country: Number of subjects enrolled

United States: 59

Worldwide total number of subjects

614

EEA total number of subjects

391

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)

259

From 65 to 84 years

355

85 years and over

Subject disposition

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Recruitment details

This study investigated the dose response and safety of danirixin compared with placebo in COPD participants with respiratory symptoms including cough, increased sputum production and dyspnoea.

Screening details

A total of 614 participants were randomized in this study across 9 countries.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received placebo white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Danirixin 5 mg

Arm description

Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Danirixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received danirixin 5 mg white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Danirixin 10 mg

Arm description

Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Danirixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received danirixin 10 mg white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Danirixin 25 mg

Arm description

Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Danirixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received danirixin 25 mg white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Danirixin 35 mg

Arm description

Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Danirixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received danirixin 35 mg white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Danirixin 50 mg

Arm description

Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Danirixin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received danirixin 50 mg white film coated tablets either round or oval in shape, orally twice daily with food and standard care of treatment for 24 weeks.

Number of subjects in period 1	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Started	102	102	103	103	102	102
Completed	88	97	90	92	88	87
Not completed	14	5	13	11	14	15
Consent withdrawn by subject	9	2	6	6	9	2
Physician decision	1	-	1	1	1	-
Adverse Event, Serious Fatal	-	1	1	2	1	1
Adverse Event, non-fatal	3	1	2	-	2	8
Liver function test abnormality	-	-	1	-	-	-
Lost to follow-up	-	-	-	1	-	2
Protocol deviation	1	-	-	-	-	2
Lack of efficacy	-	1	2	1	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 5 mg

Reporting group description

Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 10 mg

Reporting group description

Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 25 mg

Reporting group description

Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 35 mg

Reporting group description

Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 50 mg

Reporting group description

Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg	Total
Number of subjects	102	102	103	103	102	102	614
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	43	38	45	40	46	47	259
From 65-84 years	59	64	58	63	56	55	355
85 years and over	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.2 ± 7.31	66.3 ± 6.79	65.7 ± 7.48	66.3 ± 7.28	65.1 ± 7.58	65.7 ± 6.98	-
Sex: Female, Male
Units: Subjects
Female	29	36	32	38	35	32	202
Male	73	66	71	65	67	70	412
Race/Ethnicity, Customized
Units: Subjects
Asian - East Asian Heritage	10	6	18	17	10	17	78
Asian - South East Asian Heritage	1	0	0	0	0	0	1
Black or African American	2	2	1	0	0	1	6
Native Hawaiian or other Pacific Islander	1	0	0	0	0	0	1
White - Arabic/North African Heritage	1	1	0	0	0	0	2
White - White/Caucasian/European Heritage	87	93	84	86	92	84	526

End points

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Reporting group title

Placebo

Reporting group description

Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 5 mg

Reporting group description

Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 10 mg

Reporting group description

Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 25 mg

Reporting group description

Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 35 mg

Reporting group description

Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 50 mg

Reporting group description

Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Primary: Change from Baseline in respiratory symptoms measured by evaluating respiratory symptoms (E-RS) in COPD. E-RS: COPD Total Score

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End point title

Change from Baseline in respiratory symptoms measured by evaluating respiratory symptoms (E-RS) in COPD. E-RS: COPD Total Score

End point description

E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Per protocol population included all participants from the mITT population who did not have a protocol deviation considered to impact efficacy. Posterior mean change and standard deviation has been presented. Only those participants with data available at the specified data points was analyzed.

End point type

Primary

End point timeframe

Baseline and Month 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	86 ^[1]	95 ^[2]	87 ^[3]	91 ^[4]	85 ^[5]	86 ^[6]
Units: Scores on a scale
arithmetic mean (standard deviation)	-2.11 ± 0.345	-1.93 ± 0.289	-1.47 ± 0.349	-0.87 ± 0.286	-0.76 ± 0.259	-0.71 ± 0.281

Notes
[1] - Per Protocol Population.
[2] - Per Protocol Population.
[3] - Per Protocol Population.
[4] - Per Protocol Population.
[5] - Per Protocol Population.
[6] - Per Protocol Population.

Statistical Analysis of Placebo Vs Danirixin 5mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Median Posterior Difference

Point estimate

0.08

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

0.66

Notes
[7] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

4-parameter Emax model

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

Parameter type

Median Posterior Difference

Point estimate

0.61

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

1.52

Notes
[8] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

Median Posterior Difference

Point estimate

1.25

Confidence interval

level

90%

sides

2-sided

lower limit

0.43

upper limit

1.97

Notes
[9] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

Median Posterior Difference

Point estimate

1.34

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

2.03

Notes
[10] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Median Posterior Difference

Point estimate

1.38

Confidence interval

level

90%

sides

2-sided

lower limit

0.79

upper limit

2.07

Notes
[11] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Breathlessness Score)

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End point title

Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Breathlessness Score)

End point description

E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented. Only those participants with available data at the specified time points were analyzed.

End point type

Primary

End point timeframe

Baseline and Month 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	86 ^[12]	95 ^[13]	87 ^[14]	91 ^[15]	85 ^[16]	86 ^[17]
Units: Scores on a scale
arithmetic mean (standard deviation)	-0.82 ± 0.202	-0.69 ± 0.162	-0.41 ± 0.183	-0.15 ± 0.148	-0.10 ± 0.141	-0.09 ± 0.158

Notes
[12] - Per protocol population.
[13] - Per protocol population.
[14] - Per protocol population.
[15] - Per protocol population.
[16] - Per protocol population.
[17] - Per protocol population.

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other ^[18]

Method

Parameter type

Median Posterior Difference

Point estimate

0.09

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

0.42

Notes
[18] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

4-parameter Emax model

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

other ^[19]

Method

Parameter type

Median Posterior Difference

Point estimate

0.43

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

0.87

Notes
[19] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other ^[20]

Method

Parameter type

Median Posterior Difference

Point estimate

0.68

Confidence interval

level

90%

sides

2-sided

lower limit

0.23

upper limit

1.08

Notes
[20] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other ^[21]

Method

Parameter type

Median Posterior Difference

Point estimate

0.72

Confidence interval

level

90%

sides

2-sided

lower limit

0.37

upper limit

1.1

Notes
[21] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[22]

Method

Parameter type

Median Posterior Difference

Point estimate

0.73

Confidence interval

level

90%

sides

2-sided

lower limit

0.4

upper limit

1.12

Notes
[22] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)

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End point title

Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)

End point description

End point type

Primary

End point timeframe

Baseline and Month 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	86 ^[23]	95 ^[24]	87 ^[25]	91 ^[26]	85 ^[27]	86 ^[28]
Units: Scores on a scale
arithmetic mean (standard deviation)	-0.83 ± 0.107	-0.79 ± 0.090	-0.67 ± 0.109	-0.46 ± 0.104	-0.40 ± 0.088	-0.37 ± 0.098

Notes
[23] - Per protocol population.
[24] - Per protocol population.
[25] - Per protocol population.
[26] - Per protocol population.
[27] - Per protocol population.
[28] - Per protocol population.

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other ^[29]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

0.16

Notes
[29] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

4-parameter Emax model

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

other ^[30]

Method

Parameter type

Median Posterior Difference

Point estimate

0.12

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

0.43

Notes
[30] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

^[31]

Method

Parameter type

Median Posterior Difference

Point estimate

0.38

Confidence interval

level

90%

sides

2-sided

lower limit

0.04

upper limit

0.61

Notes
[31] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other ^[32]

Method

Parameter type

Median Posterior Difference

Point estimate

0.42

Confidence interval

level

90%

sides

2-sided

lower limit

0.21

upper limit

0.64

Notes
[32] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

4-parameter Emax model selected.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[33]

Method

Parameter type

Median Posterior Difference

Point estimate

0.45

Confidence interval

level

90%

sides

2-sided

lower limit

0.26

upper limit

0.66

Notes
[33] - Emax. Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)

Top of page

End point title

Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)

End point description

End point type

Primary

End point timeframe

Baseline and Month 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	86	95	87	91	85	86
Units: Scores on a scale
arithmetic mean (standard deviation)	-0.36 ± 0.148	-0.35 ± 0.061	-0.34 ± 0.062	-0.34 ± 0.069	-0.34 ± 0.073	-0.34 ± 0.078

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Log-linear model.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other ^[34]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.21

upper limit

0.23

Notes
[34] - Log-linear. Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Log-linear model

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

other ^[35]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.23

upper limit

0.25

Notes
[35] - Log-linear. Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Log-linear model

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other ^[36]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.27

upper limit

0.29

Notes
[36] - Log-linear. Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Log-linear model

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other ^[37]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.28

upper limit

0.3

Notes
[37] - Log-linear. Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Log-linear model

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[38]

Method

Parameter type

Median Posterior Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.29

upper limit

0.31

Notes
[38] - Log-linear. Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Primary: Number of participants with adverse events (AE) and serious adverse events (SAE)

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End point title

Number of participants with adverse events (AE) and serious adverse events (SAE) ^[39]

End point description

AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE. Modified Intent-to-Treat (mITT) population. mIIT population comprised of all randomized participants who were randomized apart from those randomized in error, received a treatment randomization number, modified and data for this population were based on actual treatment received.

End point type

Primary

End point timeframe

Up to Day 196

Notes
[39] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[40]	102 ^[41]	103 ^[42]	103 ^[43]	102 ^[44]	102 ^[45]
Units: Participants
Any AE	63	63	69	68	63	71
Any SAE	8	7	13	10	7	11

Notes
[40] - mIIT population.
[41] - mIIT population.
[42] - mIIT population.
[43] - mIIT population.
[44] - mIIT population.
[45] - mIIT population.

No statistical analyses for this end point

Primary: Number of participants with worst case hematology parameter results by potential clinical importance (PCI)

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End point title

Number of participants with worst case hematology parameter results by potential clinical importance (PCI) ^[46]

End point description

Blood samples were collected from participants for analysis of following hematology parameters with PCI low and high values: Basophils %(High5.00x),Eosinophils %(High 2.00x),Mean corpuscular hemoglobin concentration(MCHC)gram per deciliter(g/dL)(Low0.85x,high1.10x),Mean corpuscular hemoglobin(MCH)picograms(pg)(Low0.85x,high1.20x),Mean corpuscular volume(MCV)femtoliter(fL) (low0.25x,high2.00x),Erythrocytes(Ery.)(10^12cells/L)(Low0.93x,high1.07x),Hematocrit(Ratio of1) (Low0.50x,high0.50x),Hemoglobin g/liter (L)(Low0.85x,high1.20x),Leukocytes(x10^9/L) (Low0.70x,high1.60x),Lymphocytes%(Low0.80x,high1.20x),Monocytes%(Low0.80x,high1.60x), Neutrophils%(Low0.65x,high1.50x),Platelets(x10^9cells/L)(Low0.90x,high 1.10x).Multipliers are identified by“x”,otherwise actual comparison values are provided with units.Values above and below this range were considered of PCI.Only those participants with available data at the specified time points were analyzed(represented by n=X in the category titles).

End point type

Primary

End point timeframe

Up to Day 196

Notes
[46] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[47]	102 ^[48]	103 ^[49]	103 ^[50]	102 ^[51]	102 ^[52]
Units: Participants
Basophils, No change, n=97, 102, 101, 101, 101, 99	97	102	101	101	101	99
Basophils, High, n=97, 102, 101, 101, 101, 99	0	0	0	0	0	0
Eosinophils,No change,n=97,102,101,101,101,99	97	101	101	98	100	98
Eosinophils, High, n=97, 102, 101, 101, 101, 99	0	1	0	3	1	1
Ery. MCHC, Low, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Ery. MCHC,No change,n=97,102,101,101,102,99	97	102	101	101	102	99
Ery. MCHC, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Ery. MCH, Low, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	1
Ery. MCH, No Change, n=97, 102, 101, 101, 102, 99	97	102	101	101	102	98
Ery. MCH, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Ery. MCV, Low, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Ery. MCV, No Change, n=97, 102, 101, 101, 102, 99	97	102	101	101	102	99
Ery. MCV, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Erythrocytes, Low, n=97, 102, 101, 101, 102, 99	2	1	3	3	2	2
Erythrocytes, No change,n=97,102,101,101,102,99	93	99	97	97	99	97
Erythrocytes. High, n=97, 102, 101, 101, 102, 99	2	2	1	1	1	0
Hematocrit, Low, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Hematocrit, No Change, n=97,102,101,101,102,99	97	102	101	101	102	99
Hematocrit, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Hemoglobin, Low, n=97, 102, 101, 101, 102, 99	1	1	2	0	2	0
Hemoglobin, No change, n=97,102,101,101,102,99	96	101	99	101	100	99
Hemoglobin, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Leukocytes, Low, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	1
Leukocytes, No change, n=97,102,101,101,102,99	97	102	101	101	102	98
Leukocytes, High, n=97, 102, 101, 101, 102, 99	0	0	0	0	0	0
Lymphocytes, Low, n=97, 102, 101, 101, 101, 99	3	7	5	8	7	4
Lymphocytes, No change, n=97,102,101,101,101,99	94	95	96	92	93	94
Lymphocytes, High, n=97, 102, 101, 101, 101, 99	0	0	0	1	1	1
Monocytes, No change, n=97, 102, 101, 101, 101, 99	97	101	99	101	100	98
Monocytes, High, n=97, 102, 101, 101, 101, 99	0	1	2	0	1	1
Neutrophils, Low, n=97, 102, 101, 101, 101, 99	0	0	0	1	3	1
Neutrophils, No change, n=97,102,101,101,101,99	97	102	101	100	98	98
Neutrophils, High, n=97, 102, 101, 101, 101, 99	0	0	0	0	0	0
Platelets, Low, n=97, 102, 101, 101, 101, 99	0	1	0	0	0	0
Platelets, No change, n=97, 102, 101, 101, 101, 99	97	99	100	101	99	99
Platelets, High, n=97, 102, 101, 101, 101, 99	0	2	1	0	2	0

Notes
[47] - mITT population.
[48] - mITT population.
[49] - mITT population.
[50] - mITT population.
[51] - mITT population.
[52] - mITT population.

No statistical analyses for this end point

Primary: Number of participants with worst case clinical chemistry parameter results by PCI

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End point title

Number of participants with worst case clinical chemistry parameter results by PCI ^[53]

End point description

Blood samples were collected from participants for analysis of following chemistry parameters with PCI low and high values: Alanine aminotransferase (ALT) International units per liter (IU/L) (High => 3x ULN), Alkaline phosphatase (ALP) (IU/L) (High ≥ 2x ULN); Aspartate aminotransferase (AST) (IU/L) (High=> 3x ULN); Bilirubin micromole per liter (umol/L) (High ≥ 2x ULN); Calcium millimole per liter (mmol/L) (Low 0.85x, high 1.08x), Chloride (mmol/L) (Low 0.90x, high 1.10x), Creatinine (umol/L) (High 1.30x), Direct bilirubin (umol/L) (High ≥ 2x ULN), Glucose (mmol/L) (Low <0.6x, high >4x), Potassium (mmol/L) (Low 0.75x, high 1.30x); Protein (g/L) (High 1.25x), Sodium (mmol/L) (Low 0.80x, high 1.15x), Multipliers are identified by “x”, otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI. Only those participants with available data at the specified time points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Up to Day 196

Notes
[53] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[54]	102 ^[55]	103 ^[56]	103 ^[57]	102 ^[58]	102 ^[59]
Units: Participants
ALT, No change,n=99,102,102,102,101,100	99	102	101	102	101	100
ALT, High, n=99,102,102,102,101,100	0	0	1	0	0	0
ALP, No change,n=99,102,102,102,101,100	99	102	102	102	101	100
ALP, High, n=99,102,102,102,101,100	0	0	0	0	0	0
AST, No change,n=99,102,102,102,101,100	99	102	101	102	101	100
AST, High, n=99,102,102,102,101,100	0	0	1	0	0	0
Bilirubin, No change, n=99,102,102,102,101,100	99	101	102	102	101	100
Bilirubin, High, n=99, 102,102,102,101,100	0	1	0	0	0	0
Calcium, Low, n=96,102,101,101,101,99	0	0	0	0	0	0
Calcium, No change, n=96,102,101,101,101,99	96	102	101	101	101	99
Calcium, High, n=96,102,101,101,101,99	0	0	0	0	0	0
CO2, Low, n=96,102,101,101,101,99	1	0	2	1	0	1
CO2, No change, n=96,102,101,101,101,99	94	102	99	99	101	98
CO2, High, n=96,102,101,101,101,99	1	0	0	1	0	0
Chloride, Low, n=96,102,101,101,101,99	0	0	0	0	0	0
Chloride, No change, n=96,102,101,101,101,99	96	102	101	101	101	99
Chloride, High, n=96,102,101,101,101,99	0	0	0	0	0	0
Creatinine, No change, n=96,102,101,101,101,99	94	100	99	99	99	99
Creatinine, High, n=96, 102, 101, 101, 101, 99	2	2	2	2	2	0
Direct bilirubin,NoChange,n=99,102,102,102,101,100	98	102	102	102	101	100
Direct bilirubin,High,n=99,102,102,102,101,100	1	0	0	0	0	0
Glucose, Low, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Glucose, No change, n=96, 102, 101, 101, 101, 99	96	102	101	101	101	99
Glucose, High, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Potassium, Low, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Potassium, No change, n=96, 102, 101, 101, 101, 99	96	102	101	101	101	99
Potassium, High, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Protein, No change, n=99, 102, 102, 102, 101, 100	99	102	102	102	101	100
Protein, High, n=99, 102, 102, 102, 101, 100	0	0	0	0	0	0
Sodium, Low, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Sodium, No change, n=96, 102, 101, 101, 101, 99	96	102	101	101	101	99
Sodium, High, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Urea, Low, n=96, 102, 101, 101, 101, 99	0	0	0	0	0	0
Urea, No change, n=96, 102, 101, 101, 101, 99	96	101	101	100	101	98
Urea, High, n=96, 102, 101, 101, 101, 99	0	1	0	1	0	1
Bilirubin/ALT,No change,n=99,102,102,102,101,100	99	102	102	102	101	100
Bilirubin/ALT, High,n=99,102,102,102,101,100	0	0	0	0	0	0

Notes
[54] - mITT population.
[55] - mITT population.
[56] - mITT population.
[57] - mITT population.
[58] - mITT population.
[59] - mITT population.

No statistical analyses for this end point

Primary: Number of participants with worst case vital signs parameter results by PCI

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End point title

Number of participants with worst case vital signs parameter results by PCI ^[60]

End point description

Vital signs parameters includes systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate and respiration rate were measured in a semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges for vital signs parameters were as follows: <90 to >160 millimeters of mercury (mmHg) for SBP and <40 to >110 mmHg for DBP, <35 or >120 beats per minute for heart rate and <8 or >30 breaths per minute for respiration rate. Values above and below this range were considered of PCI. Only those participants with available data at the specified time points were analyzed.

End point type

Primary

End point timeframe

Up to Day 168

Notes
[60] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	96 ^[61]	102 ^[62]	101 ^[63]	101 ^[64]	102 ^[65]	99 ^[66]
Units: Participants
SBP, Low	0	0	0	0	0	1
SBP, No change	93	92	95	98	98	94
SBP, High	3	10	6	3	4	4
DBP, Low	0	0	0	0	0	0
DBP, No change	96	102	101	101	102	99
DBP, High	0	0	0	0	0	0
Pulse rate	0	0	0	0	0	0
Pulse rate,No change	96	102	99	100	102	98
Pulse rate, High	0	0	2	1	0	1
Respiratory rate,Low	0	0	0	0	0	0
Respiratory rate,No change	96	102	101	101	102	98
Respiratory rate, High	0	0	0	0	0	1

Notes
[61] - mITT population.
[62] - mITT population.
[63] - mITT population.
[64] - mITT population.
[65] - mITT population.
[66] - mITT population.

No statistical analyses for this end point

Primary: Number of participants with worst case post-Baseline abnormal 12-lead electrocardiogram (ECG) findings

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End point title

Number of participants with worst case post-Baseline abnormal 12-lead electrocardiogram (ECG) findings ^[67]

End point description

Triplicate 12-lead ECG obtained to measure PR, QRS, QT, and Corrected QT intervals. Only those participants with worst case post-Baseline data have been represented for abnormal - not clinical significant and abnormal - clinical significant. Day 1 was considered as Baseline. Only those participants with available data at the specified time points were analyzed.

End point type

Primary

End point timeframe

Baseline and Day 168

Notes
[67] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	96 ^[68]	102 ^[69]	101 ^[70]	101 ^[71]	102 ^[72]	99 ^[73]
Units: Participants
Not Clinical significant	52	65	68	67	62	53
Clinical significant	2	1	1	0	3	1

Notes
[68] - mITT population.
[69] - mITT population.
[70] - mITT population.
[71] - mITT population.
[72] - mITT population.
[73] - mITT population.

No statistical analyses for this end point

Secondary: Number of moderate or severe Healthcare Resource Utilization (HCRU) exacerbations per participant

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End point title

Number of moderate or severe Healthcare Resource Utilization (HCRU) exacerbations per participant

End point description

Participants with moderate or severe COPD exacerbations, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness analyzed. Mild exacerbations are defined as exacerbations that did not require treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, Emergency Room [ER] visit or resulting in death). Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, ER visit or resulting in death). Severe exacerbations are defined as exacerbations that required hospitalization, ER visit or resulted in death. Number of moderate or severe HCRU exacerbations per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.

End point type

Secondary

End point timeframe

Up to Day 196

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[74]	102 ^[75]	100 ^[76]	103 ^[77]	100 ^[78]	99 ^[79]
Units: Exacerbations per participant
Zero (0)	66	51	61	63	55	50
One (1)	28	34	23	28	30	36
>=2	7	17	16	12	15	13

Notes
[74] - Per Protocol Population.
[75] - Per Protocol Population.
[76] - Per Protocol Population.
[77] - Per Protocol Population.
[78] - Per Protocol Population.
[79] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Number of responders E-RS in COPD (E-RS): COPD Total Score

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End point title

Number of responders E-RS in COPD (E-RS): COPD Total Score

End point description

E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. E-RS is intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The E-RS has a scoring range of 0-40; higher scores indicate more severe symptoms. Response is defined as an E-RS: COPD total score of 2 units below baseline or lower. Non-response is defined as an E-RS: COPD total score higher than 2 units below Baseline. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Month 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	86 ^[80]	95 ^[81]	87 ^[82]	91 ^[83]	85 ^[84]	86 ^[85]
Units: Participants	33	48	33	30	29	32

Notes
[80] - Per Protocol Population.
[81] - Per Protocol Population.
[82] - Per Protocol Population.
[83] - Per Protocol Population.
[84] - Per Protocol Population.
[85] - Per Protocol Population.

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.089 ^[86]

Method

linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.71

Confidence interval

level

90%

sides

2-sided

lower limit

1.02

upper limit

2.86

Notes
[86] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, relevant baseline E-RS: COPD score, smoking status at Screening, country, month, baseline by month and treatment by month interactions.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

173

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.881 ^[87]

Method

linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.05

Confidence interval

level

90%

sides

2-sided

lower limit

0.62

upper limit

1.79

Notes
[87] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, relevant baseline E-RS: COPD score, smoking status at Screening, country, month, baseline by month and treatment by month interactions.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.674 ^[88]

Method

linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.87

Confidence interval

level

90%

sides

2-sided

lower limit

0.51

upper limit

1.48

Notes
[88] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, relevant baseline E-RS: COPD score, smoking status at Screening, country, month, baseline by month and treatment by month interactions.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.804 ^[89]

Method

linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.92

Confidence interval

level

90%

sides

2-sided

lower limit

0.54

upper limit

1.58

Notes
[89] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, relevant baseline E-RS: COPD score, smoking status at Screening, country, month, baseline by month and treatment by month interactions.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.987 ^[90]

Method

linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.01

Confidence interval

level

90%

sides

2-sided

lower limit

0.59

upper limit

1.71

Notes
[90] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, relevant baseline E-RS: COPD score, smoking status at Screening, country, month, baseline by month and treatment by month interactions.

Secondary: Number of EXACT events per participant

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End point title

Number of EXACT events per participant

End point description

EXACT is a 14 item patient reported outcome (PRO) instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Events were categorized as recovered, censored, or persistent worsening. Number of EXACT events per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.

End point type

Secondary

End point timeframe

Up to Day 196

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[91]	102 ^[92]	100 ^[93]	103 ^[94]	100 ^[95]	99 ^[96]
Units: Events
Zero (0)	92	92	92	92	86	86
One (1)	9	6	7	9	10	10
>=2	0	4	1	2	4	3

Notes
[91] - Per protocol Population
[92] - Per protocol Population
[93] - Per protocol Population
[94] - Per protocol Population
[95] - Per protocol Population
[96] - Per protocol Population

No statistical analyses for this end point

Secondary: Time to first EXACT event

Top of page

End point title

Time to first EXACT event

End point description

The time to first on-treatment EXACT event was calculated as the onset date of the first on-treatment EXACT event minus date of start of treatment plus 1. 99999 indicates, if <25% of participants experienced the event within a treatment then Q1 time to event are displayed as NA (not applicable) for that treatment. 88888 indicates, if <50% of participants experienced the event within a treatment then median time to event are displayed as NA (not applicable) for that treatment.

End point type

Secondary

End point timeframe

Up to Day 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[97]	102 ^[98]	100 ^[99]	103 ^[100]	100 ^[101]	99 ^[102]
Units: Days
First quartile (Q1) time to event	99999	99999	99999	99999	99999	99999
Median time to event	88888	88888	88888	88888	88888	88888

Notes
[97] - Per protocol population
[98] - Per protocol population
[99] - Per protocol population
[100] - Per protocol population
[101] - Per protocol population
[102] - Per protocol population

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other ^[103]

Method

Parameter type

Median Posterior Hazard Ratio

Point estimate

1.2

Confidence interval

level

90%

sides

2-sided

lower limit

0.5

upper limit

2.6

Notes
[103] - DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[104]

Method

Parameter type

Median Posterior Hazard Ratio

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

0.4

upper limit

2.4

Notes
[104] - DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

other ^[105]

Method

Parameter type

Median Posterior Hazard Ratio

Point estimate

1.4

Confidence interval

level

90%

sides

2-sided

lower limit

0.6

upper limit

3.2

Notes
[105] - DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[106]

Method

Parameter type

Median Posterior Hazard Ratio

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

4.3

Notes
[106] - DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

other ^[107]

Method

Parameter type

Median Posterior Hazard Ratio

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

4.5

Notes
[107] - DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Secondary: Severity of EXACT event

Top of page

End point title

Severity of EXACT event

End point description

EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery. Only those participants with data available at the specified data points were analyzed

End point type

Secondary

End point timeframe

Up to Day 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	9 ^[108]	15 ^[109]	9 ^[110]	13 ^[111]	19 ^[112]	16 ^[113]
Units: Scores on a scale
arithmetic mean (standard deviation)	22.1 ± 6.60	26.7 ± 3.71	22.9 ± 5.28	28.6 ± 5.68	25.0 ± 5.54	26.4 ± 6.36

Notes
[108] - Per Protocol Population.
[109] - Per Protocol Population.
[110] - Per Protocol Population.
[111] - Per Protocol Population.
[112] - Per Protocol Population.
[113] - Per Protocol Population.

No statistical analyses for this end point

Secondary: EXACT event duration for all events

Top of page

End point title

EXACT event duration for all events

End point description

EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery. Duration of EXACT events has been reported. Only those participants with data available at the specified data points were analyzed.

End point type

Secondary

End point timeframe

Up to Day 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	9 ^[114]	15 ^[115]	9 ^[116]	13 ^[117]	19 ^[118]	16 ^[119]
Units: Days
arithmetic mean (standard deviation)	45.3 ± 50.37	11.6 ± 10.15	45.8 ± 51.97	25.5 ± 42.11	17.6 ± 16.28	18.7 ± 37.75

Notes
[114] - Per Protocol Population.
[115] - Per Protocol Population.
[116] - Per Protocol Population.
[117] - Per Protocol Population.
[118] - Per Protocol Population.
[119] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Time to first HCRU-defined COPD exacerbation

Top of page

End point title

Time to first HCRU-defined COPD exacerbation

End point description

The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation – date of start of treatment +1. 99999 indicates, if <50% of participants experienced the event within a treatment then median time to event are displayed as NA (not applicable) for that treatment.

End point type

Secondary

End point timeframe

Up to Day 196

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[120]	102 ^[121]	100 ^[122]	103 ^[123]	100 ^[124]	99 ^[125]
Units: Days
Q1 time to event	110	47	63	79	70	57
Median time to event	99999	99999	99999	99999	99999	99999

Notes
[120] - Per Protocol Population
[121] - Per Protocol Population
[122] - Per Protocol Population
[123] - Per Protocol Population
[124] - Per Protocol Population
[125] - Per Protocol Population

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other ^[126]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.5

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

2.2

Notes
[126] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[127]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

90%

sides

2-sided

lower limit

0.8

upper limit

1.7

Notes
[127] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

other ^[128]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

1.6

Notes
[128] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[129]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.4

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

2.1

Notes
[129] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

other ^[130]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.6

Confidence interval

level

90%

sides

2-sided

lower limit

1.1

upper limit

2.3

Notes
[130] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Secondary: Time to first severe HCRU-defined COPD exacerbation

Top of page

End point title

Time to first severe HCRU-defined COPD exacerbation

End point description

A COPD exacerbation defined as a severe exacerbation if it requires hospitalization or emergency room visit or extended observation. The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation – date of start of treatment +1. 99999 indicates, if <25% of participants experienced the event within a treatment then Q1 time to event are displayed as NA (not applicable) for that treatment. 88888 indicates, if <50% of participants experienced the event within a treatment then median time to event are displayed as NA (not applicable) for that treatment.

End point type

Secondary

End point timeframe

Up to Day 196

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[131]	102 ^[132]	100 ^[133]	103 ^[134]	100 ^[135]	99 ^[136]
Units: Days
Q1 time to event	99999	99999	99999	99999	99999	99999
Median time to event	88888	88888	88888	88888	88888	88888

Notes
[131] - Per Protocol Population
[132] - Per Protocol Population
[133] - Per Protocol Population
[134] - Per Protocol Population
[135] - Per Protocol Population
[136] - Per Protocol Population

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other ^[137]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

5.5

Notes
[137] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[138]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.9

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

5.8

Notes
[138] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

other ^[139]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

5.6

Notes
[139] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other ^[140]

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.3

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

6.9

Notes
[140] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

other ^[141]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.2

upper limit

2.7

Notes
[141] - Bayesian proportional hazards model. DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Secondary: HCRU-defined exacerbation duration

Top of page

End point title

HCRU-defined exacerbation duration

End point description

The duration of HCRU exacerbation were determined. The duration of the exacerbation was calculated as (exacerbation resolution date or date of death - exacerbation onset date + 1). For exacerbations which were not resolved but where the participant later died from other causes, the duration was calculated using date of death as the end date of the event. Only those participants with data available at the specified data points were analyzed.

End point type

Secondary

End point timeframe

Up to Day 196

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	44 ^[142]	75 ^[143]	58 ^[144]	56 ^[145]	66 ^[146]	65 ^[147]
Units: Days
arithmetic mean (standard deviation)	10.3 ± 7.37	12.3 ± 8.95	12.9 ± 9.58	14.0 ± 8.71	10.7 ± 7.21	14.2 ± 9.29

Notes
[142] - Per Protocol Population.
[143] - Per Protocol Population.
[144] - Per Protocol Population.
[145] - Per Protocol Population.
[146] - Per Protocol Population.
[147] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score

Top of page

End point title

Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score

End point description

The SGRQ-C consists of 40 items aggregated into 3 component scores: Symptoms, Activity, Impacts, and a Total score. Each response to a question is assigned a weight. Component scores are calculated by summing the weights from all positive items in that component, dividing by the sum of weights for all items in that component, and multiplying this number by 100. Component scores could range from 0-100, with a higher component score indicating greater disease burden. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation is presented. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Baseline, Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[148]	102 ^[149]	100 ^[150]	103 ^[151]	100 ^[152]	99 ^[153]
Units: Scores on a scale
arithmetic mean (standard deviation)
Day 84, n=93, 97, 94, 96, 91, 90	-3.79 ± 1.172	-3.63 ± 1.150	-1.31 ± 1.146	-3.19 ± 1.148	-2.83 ± 1.189	-2.48 ± 1.175
Day 168, n=85, 96, 86, 90, 86, 85	-4.11 ± 1.292	-3.44 ± 1.246	-4.19 ± 1.292	-4.94 ± 1.251	-4.12 ± 1.287	-3.41 ± 1.302

Notes
[148] - Per Protocol Population.
[149] - Per Protocol Population.
[150] - Per Protocol Population.
[151] - Per Protocol Population.
[152] - Per Protocol Population.
[153] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Number of SGRQ responder

Top of page

End point title

Number of SGRQ responder

End point description

A participant was consider Responder according to SGRQ total score if their change from Baseline SGRQ total score of 4 units below Baseline or lower. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Secondary

End point timeframe

Day 84 and Day 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[154]	102 ^[155]	100 ^[156]	103 ^[157]	100 ^[158]	99 ^[159]
Units: Participants
Day 84, n=93, 97, 94, 96, 91, 90	39	40	35	49	35	38
Day 168, n=85, 96, 86, 90, 86, 85	35	47	40	47	41	34

Notes
[154] - Per Protocol Population.
[155] - Per Protocol Population.
[156] - Per Protocol Population.
[157] - Per Protocol Population.
[158] - Per Protocol Population.
[159] - Per Protocol Population.

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.208 ^[160]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.51

Confidence interval

level

90%

sides

2-sided

lower limit

0.88

upper limit

2.59

Notes
[160] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline SGRQ total score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.482 ^[161]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.27

Confidence interval

level

90%

sides

2-sided

lower limit

0.73

upper limit

2.2

Notes
[161] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline SGRQ total score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.239 ^[162]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.47

Confidence interval

level

90%

sides

2-sided

lower limit

0.86

upper limit

2.53

Notes
[162] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline SGRQ total score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.426 ^[163]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.31

Confidence interval

level

90%

sides

2-sided

lower limit

0.75

upper limit

2.26

Notes
[163] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline SGRQ total score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.763 ^[164]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.9

Confidence interval

level

90%

sides

2-sided

lower limit

0.52

upper limit

1.58

Notes
[164] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline SGRQ total score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Secondary: Change from Baseline COPD Assessment Test (CAT) total score

Top of page

End point title

Change from Baseline COPD Assessment Test (CAT) total score

End point description

CAT is 8 item questionnaire(cough,sputum,chest tightness,breathlessness,going up hills/stairs, activity limitation at home,confidence leaving home/sleep and energy)that measures health status of participants with COPD.Participants were completed each question by rating their experience on 6point scale ranging from 0(maximum impairment)to 5(no impairment) with total scoring range of 0-40;higher scores indicate worse health status.CAT score was calculated by summing non-missing scores on 8items.Individual items are scored from 0 to 5 with total score range from 0–40, higher scores indicate greater disease impact.Day1 was Baseline.Change from Baseline was calculated by subtracting Baseline value from specified time point value.Number of participants presented represent those with data available at time point being presented;however,all participants in per protocol population without missing covariate information and with at least 1 post Baseline measurement are included in analysis.

End point type

Secondary

End point timeframe

Baseline, Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[165]	102 ^[166]	100 ^[167]	103 ^[168]	100 ^[169]	99 ^[170]
Units: Scores on a scale
arithmetic mean (standard deviation)
Day 84, n=89, 97, 92, 89, 88, 85	-2.02 ± 0.536	-0.86 ± 0.525	-0.63 ± 0.524	-0.55 ± 0.542	-1.51 ± 0.543	-0.36 ± 0.549
Day 168, n=84, 94, 86, 87, 85, 83	-1.39 ± 0.557	-1.39 ± 0.537	-1.23 ± 0.548	-0.97 ± 0.560	-1.56 ± 0.560	-1.32 ± 0.565

Notes
[165] - Per Protocol Population.
[166] - Per Protocol Population.
[167] - Per Protocol Population.
[168] - Per Protocol Population.
[169] - Per Protocol Population.
[170] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Number of CAT responder

Top of page

End point title

Number of CAT responder

End point description

A participant was considered as a responder according to CAT score if their change from Baseline CAT score 2.0 units below Baseline or lower. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Secondary

End point timeframe

Day 84 and Day 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[171]	102 ^[172]	100 ^[173]	103 ^[174]	100 ^[175]	99 ^[176]
Units: Participants
Day 84, n=89, 97, 92, 89, 88, 85	46	44	38	37	43	36
Day 168, n=84, 94, 86, 87, 85, 83	41	44	39	42	46	44

Notes
[171] - Per Protocol Population.
[172] - Per Protocol Population.
[173] - Per Protocol Population.
[174] - Per Protocol Population.
[175] - Per Protocol Population.
[176] - Per Protocol Population.

Statistical Analysis of Placebo Vs Danirixin 5 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Comparison groups

Placebo v Danirixin 5 mg

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.973 ^[177]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.01

Confidence interval

level

90%

sides

2-sided

lower limit

0.58

upper limit

1.76

Notes
[177] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline CAT score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 10 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Comparison groups

Placebo v Danirixin 10 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.825 ^[178]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.93

Confidence interval

level

90%

sides

2-sided

lower limit

0.53

upper limit

1.63

Notes
[178] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline CAT score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 25 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Comparison groups

Placebo v Danirixin 25 mg

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.887 ^[179]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

0.95

Confidence interval

level

90%

sides

2-sided

lower limit

0.55

upper limit

1.66

Notes
[179] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline CAT score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 35 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Comparison groups

Placebo v Danirixin 35 mg

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.567 ^[180]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.21

Confidence interval

level

90%

sides

2-sided

lower limit

0.69

upper limit

2.13

Notes
[180] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline CAT score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Statistical Analysis of Placebo Vs Danirixin 50 mg

Statistical analysis description

Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Comparison groups

Placebo v Danirixin 50 mg

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.501 ^[181]

Method

Linear mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

90%

sides

2-sided

lower limit

0.72

upper limit

2.2

Notes
[181] - Analysis performed using a generalised linear mixed model with a logit link function including treatment, baseline CAT score, smoking status at Screening, country, visit, baseline by visit and treatment by visit interactions.

Secondary: Change from Baseline in post-bronchodilator FEV1 as a lung function assessment

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End point title

Change from Baseline in post-bronchodilator FEV1 as a lung function assessment

End point description

Spirometric analysis was done to determine FEV1. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Baseline, Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[182]	102 ^[183]	103 ^[184]	103 ^[185]	102 ^[186]	102 ^[187]
Units: Liters
least squares mean (standard error)
Day 84, n=94, 99, 98, 97, 92, 93	0.016 ± 0.0208	-0.031 ± 0.0203	-0.029 ± 0.0204	-0.018 ± 0.0206	-0.027 ± 0.0211	0.027 ± 0.0210
Day 168, n=88, 97, 90, 90, 88, 86	-0.016 ± 0.0199	-0.043 ± 0.0191	-0.033 ± 0.0197	-0.058 ± 0.0198	-0.012 ± 0.0201	-0.011 ± 0.0202

Notes
[182] - mITT Population.
[183] - mITT Population.
[184] - mITT Population.
[185] - mITT Population.
[186] - mITT Population.
[187] - mITT Population.

No statistical analyses for this end point

Secondary: Percent predicted normal FEV1

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End point title

Percent predicted normal FEV1

End point description

Spirometric analysis was done to determine percent predicted FEVI at screening. FEV1 is forced expiratory volume in one second. Percent predicted FEV1 is defined as the percent FEV1 of the participant is divided by average FEV1 percent in the population of any person similar age, sex and body composition. Only those participants with available data at the specified time points were analyzed.

End point type

Secondary

End point timeframe

At Screening

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	100 ^[188]	102 ^[189]	100 ^[190]	103 ^[191]	100 ^[192]	99 ^[193]
Units: Percent predicted FEV1
arithmetic mean (standard deviation)	58.98 ± 12.838	56.75 ± 12.038	56.62 ± 11.848	56.84 ± 12.813	57.51 ± 14.076	57.84 ± 12.794

Notes
[188] - Per Protocol Population.
[189] - Per Protocol Population.
[190] - Per Protocol Population.
[191] - Per Protocol Population.
[192] - Per Protocol Population.
[193] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Change from Baseline in post-bronchodilator Forced Vital Capacity (FVC) as a lung function assessment

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End point title

Change from Baseline in post-bronchodilator Forced Vital Capacity (FVC) as a lung function assessment

End point description

Spirometric analysis was done to determine FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Baseline, Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[194]	102 ^[195]	103 ^[196]	103 ^[197]	102 ^[198]	102 ^[199]
Units: Liters
least squares mean (standard error)
Day 84, n=94, 99, 98, 97, 92, 93	0.024 ± 0.0321	-0.054 ± 0.0313	-0.043 ± 0.0315	0.027 ± 0.0317	-0.049 ± 0.0326	0.014 ± 0.0323
Day 168, n=88, 97, 90, 90, 88, 86	-0.011 ± 0.0348	-0.079 ± 0.0335	-0.043 ± 0.0344	-0.024 ± 0.0345	-0.036 ± 0.0351	-0.016 ± 0.0353

Notes
[194] - mITT Population.
[195] - mITT Population.
[196] - mITT Population.
[197] - mITT Population.
[198] - mITT Population.
[199] - mITT Population.

No statistical analyses for this end point

Secondary: Change from Baseline in post-bronchodilator FEV1/FVC ratio as a lung function assessment

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End point title

Change from Baseline in post-bronchodilator FEV1/FVC ratio as a lung function assessment

End point description

Spirometric analysis was done to determine FEV1 and FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Baseline, Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[200]	102 ^[201]	103 ^[202]	103 ^[203]	102 ^[204]	102 ^[205]
Units: Ratio of FEV1/FVC
arithmetic mean (standard deviation)
Day 84, n=94, 99, 98, 97, 92, 93	-0.003 ± 0.0543	-0.001 ± 0.0554	-0.000 ± 0.0453	-0.013 ± 0.0630	-0.000 ± 0.0402	0.014 ± 0.1636
Day 168, n=88, 97, 90, 90, 88, 86	-0.007 ± 0.0622	-0.003 ± 0.0555	0.003 ± 0.0420	-0.015 ± 0.0610	0.002 ± 0.0495	-0.002 ± 0.0385

Notes
[200] - mITT Population.
[201] - mITT Population.
[202] - mITT Population.
[203] - mITT Population.
[204] - mITT Population.
[205] - mITT Population.

No statistical analyses for this end point

Secondary: Change from Baseline number of puffs of rescue medication per day

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End point title

Change from Baseline number of puffs of rescue medication per day

End point description

The mean number of puffs of rescue per day was calculated over the same time periods and using the same assumptions as rescue use via diary. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

End point type

Secondary

End point timeframe

Baseline, Months 1, 2, 3, 4, 5 and 6

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[206]	102 ^[207]	100 ^[208]	103 ^[209]	100 ^[210]	99 ^[211]
Units: Puffs per day
arithmetic mean (standard error)
Month 1, n=100, 102, 100, 102, 98, 99	0.00 ± 0.132	0.36 ± 0.130	0.28 ± 0.132	0.15 ± 0.130	-0.03 ± 0.133	0.28 ± 0.133
Month 2, n=96, 100, 98, 97, 98, 96	-0.22 ± 0.187	0.42 ± 0.184	0.18 ± 0.186	0.35 ± 0.185	0.07 ± 0.187	0.33 ± 0.188
Month 3, n=95, 100, 95, 97, 94, 92	-0.18 ± 0.184	0.29 ± 0.181	0.21 ± 0.184	0.25 ± 0.182	0.07 ± 0.185	0.27 ± 0.186
Month 4, n=92, 98, 92, 97, 90, 90	-0.18 ± 0.193	0.27 ± 0.189	0.27 ± 0.192	0.21 ± 0.190	-0.04 ± 0.194	0.44 ± 0.195
Month 5, n=88, 97, 88, 94, 87, 87	-0.16 ± 0.190	0.17 ± 0.186	0.19 ± 0.190	0.25 ± 0.187	-0.06 ± 0.191	0.29 ± 0.192
Month 6, n=86, 95, 88, 91, 85, 86	-0.17 ± 0.196	0.21 ± 0.191	0.10 ± 0.195	0.15 ± 0.193	0.04 ± 0.197	0.28 ± 0.198

Notes
[206] - Per Protocol Population.
[207] - Per Protocol Population.
[208] - Per Protocol Population.
[209] - Per Protocol Population.
[210] - Per Protocol Population.
[211] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire

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End point title

Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire

End point description

Clinical Visit PROactive Physical Activity in COPD(C-PPAC) tool is a designed for intermittent use within a clinical study.PROactive Total Score and 2domain scores(amount/difficulty) are derived using data from C-PPAC questionnaire and physical activity monitor worn for 7days prior to questionnaire.C-PPAC is 12 item questionnaire.PROactive tools are scored from0 to 100 with higher scores indicating greater disease impact.It was implemented in subset of approximately 50% of participants.Amount domain is calculated using 2items from C-PPAC questionnaire(amount of walking outside/chores outside) and 2activity monitor outputs(vector magnitude units per minute (VMU/min) and steps/day). Each domain score is based on the addition of items(0-15 for amount and 0-40 for difficulty) and then scaled from 0-100. Total score is calculated as (amount+difficulty)/2. Only those participants with data available at specified data points were analyzed(represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Days 84 and 168

End point values	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	101 ^[212]	102 ^[213]	100 ^[214]	103 ^[215]	100 ^[216]	99 ^[217]
Units: Scores on a scale
arithmetic mean (standard deviation)
Total score, Day 84, n=8, 4, 6, 6, 10, 6	3.00 ± 5.964	-5.75 ± 6.035	-3.83 ± 12.754	0.42 ± 2.635	-1.20 ± 8.453	2.33 ± 2.677
Total score, Day 168, n=13, 7, 9, 8, 6, 7	-0.96 ± 13.266	1.86 ± 9.344	2.11 ± 5.878	1.25 ± 3.423	4.08 ± 6.492	0.43 ± 7.607
Amount score, Day 84, n=8, 4, 6, 6, 10, 6	2.25 ± 5.825	-8.50 ± 7.937	-4.00 ± 19.204	0.00 ± 6.957	-4.20 ± 10.706	-0.83 ± 5.345
Amount score, Day 168, n=13, 7, 9, 8, 6, 7	-3.69 ± 14.733	-0.43 ± 8.810	2.11 ± 9.558	1.25 ± 9.161	3.67 ± 11.708	-4.14 ± 12.522
Difficult score, Day 84, n=29, 22, 18, 19, 24, 14	6.38 ± 9.511	1.64 ± 8.301	-0.17 ± 7.679	1.89 ± 11.704	2.79 ± 9.278	4.50 ± 9.598
Difficult score, Day 168, n=29, 20, 18, 19, 25, 15	3.03 ± 14.409	2.20 ± 11.039	2.11 ± 7.553	0.63 ± 11.413	1.52 ± 9.687	4.87 ± 8.887

Notes
[212] - Per Protocol Population.
[213] - Per Protocol Population.
[214] - Per Protocol Population.
[215] - Per Protocol Population.
[216] - Per Protocol Population.
[217] - Per Protocol Population.

No statistical analyses for this end point

Secondary: Danirixin Whole Blood Pharmacokinetic Concentration-Time Data

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End point title

Danirixin Whole Blood Pharmacokinetic Concentration-Time Data ^[218]

End point description

Blood samples were collected from the participants for the analysis of blood pharmacokinetic concentration-time data. All participants in the mITT population who had at least 1 non-missing Pharmacokinetic assessment obtained and analyzed whilst on treatment with danirixin were included Pharmacokinetic population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Secondary

End point timeframe

Pre-dose on Days 1, 56, 84 and 168; 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Days 1 and 168

Notes
[218] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[219]	103 ^[220]	102 ^[221]	102 ^[222]	101 ^[223]
Units: Nanogram per milliliter
arithmetic mean (standard deviation)
Day 1, Pre-dose, n=97, 99, 102, 102, 100	2.1 ± 19.41	0.4 ± 3.92	0.3 ± 3.06	17.2 ± 169.33	3.9 ± 39.10
Day 1, 0.5 hour, n=16, 19, 24, 26, 19	86.7 ± 85.73	210.4 ± 207.54	730.5 ± 1046.42	976.1 ± 839.37	1331.0 ± 1220.06
Day 1, 1 hour, n=16, 18, 24, 26, 19	148.3 ± 104.75	343.3 ± 228.66	822.0 ± 527.47	1183.5 ± 760.02	1846.2 ± 979.95
Day 1, 2 hours, n=16, 19, 24, 26, 19	115.3 ± 46.00	277.7 ± 245.32	707.7 ± 256.63	1011.2 ± 398.82	1472.8 ± 858.49
Day 1, 4 hours, n=16, 19, 24, 26, 19	59.2 ± 17.79	165.3 ± 136.50	401.5 ± 188.75	591.5 ± 302.96	904.6 ± 599.85
Day 1, 6 hours, n=16, 19, 24, 26, 19	34.4 ± 12.32	100.6 ± 84.26	270.0 ± 169.37	371.5 ± 335.23	594.9 ± 525.00
Day 1, 8 hours, n=15, 19, 24, 26, 19	26.1 ± 13.54	67.8 ± 61.02	213.8 ± 162.24	325.8 ± 359.79	428.2 ± 398.16
Day 1, 10 hours, n=16, 18, 22, 26, 19	42.5 ± 67.85	61.5 ± 56.67	265.0 ± 396.25	274.5 ± 328.04	302.3 ± 255.81
Day 1, 12 hours, n=16, 16, 21, 26, 18	87.2 ± 174.14	74.7 ± 82.51	188.2 ± 188.27	232.8 ± 316.67	459.3 ± 561.53
Day 56, Pre-dose, n=94, 91, 94, 95, 92	53.2 ± 73.19	91.8 ± 102.43	252.3 ± 295.15	372.1 ± 427.41	572.0 ± 738.28
Day 84, Pre-dose, n=97, 94, 96, 91, 90	50.2 ± 77.78	76.2 ± 106.86	212.3 ± 211.35	342.8 ± 411.28	484.3 ± 527.47
Day 168, Pre-dose, n=92, 85, 89, 85, 84	41.2 ± 38.02	99.5 ± 138.00	217.9 ± 221.92	350.7 ± 336.07	459.5 ± 421.30
Day 168, 0.5 hours, n=14, 12, 17, 18, 16	147.7 ± 91.51	248.3 ± 189.30	530.5 ± 536.75	1449.5 ± 949.00	1635.6 ± 1077.48
Day 168, 1 hours, n=14, 13, 17, 18, 16	162.1 ± 108.88	314.0 ± 157.04	681.2 ± 630.86	1590.3 ± 1019.32	1725.4 ± 870.79
Day 168, 2 hours, n=14, 13, 17, 18, 16	127.4 ± 88.80	331.9 ± 164.10	574.7 ± 445.85	1045.2 ± 414.21	1736.6 ± 592.51
Day 168, 4 hours, n=13, 11, 16, 18, 16	90.5 ± 53.67	190.9 ± 103.35	452.8 ± 289.44	805.0 ± 346.87	1459.9 ± 909.32
Day 168, 6 hours, n=13, 13, 16, 18, 15	55.6 ± 26.36	135.5 ± 87.39	289.6 ± 188.04	554.8 ± 313.52	960.4 ± 633.37
Day 168, 8 hours, n=13, 13, 17, 18, 15	41.5 ± 19.75	102.6 ± 60.14	245.1 ± 165.40	444.9 ± 298.69	760.8 ± 679.30
Day 168, 10 hours, n=13, 12, 17, 18, 15	42.4 ± 35.98	76.6 ± 56.95	193.9 ± 128.42	380.2 ± 285.81	715.0 ± 840.54
Day 168, 12 hours, n=13, 12, 17, 18, 15	42.2 ± 41.29	73.1 ± 41.21	169.7 ± 114.20	481.2 ± 640.17	662.4 ± 877.91

Notes
[219] - Pharmacokinetic Population.
[220] - Pharmacokinetic Population.
[221] - Pharmacokinetic Population.
[222] - Pharmacokinetic Population.
[223] - Pharmacokinetic Population.

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in whole blood using dried blood spot

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End point title

Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in whole blood using dried blood spot ^[224]

End point description

Blood samples were collected at indicated timepoints for the analysis of phamacokinetic parameter. All participants in the PK population who had at least 1 non-missing PK assessment obtained and analyzed whilst on treatment with danirixin from a dry blood spot sample and corresponding wet whole blood sample were included in Pharmacokinetic population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Secondary

End point timeframe

Days 1 and 168

Notes
[224] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[225]	103 ^[226]	102 ^[227]	102 ^[228]	101 ^[229]
Units: Hour*nanogram per milliliter
geometric mean (confidence interval 95%)
Day 1, n=17, 19, 24, 26, 19	543.0 (354.9 to 830.8)	1373.1 (1081.7 to 1743.0)	3851.5 (3136.7 to 4729.2)	5485.1 (4604.8 to 6533.8)	8073.4 (6591.3 to 9888.7)
Day 168, n=14, 13, 17, 18, 16	752.1 (546.8 to 1034.4)	1701.8 (1257.2 to 2303.7)	4170.1 (3198.1 to 5437.6)	7682.6 (6384.8 to 9244.0)	11538.0 (9313.4 to 14294.0)

Notes
[225] - Pharmacokinetic Population.
[226] - Pharmacokinetic Population.
[227] - Pharmacokinetic Population.
[228] - Pharmacokinetic Population.
[229] - Pharmacokinetic Population.

No statistical analyses for this end point

Secondary: Concentration maximum (Cmax) of Danirixin in whole blood using dried blood spots

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End point title

Concentration maximum (Cmax) of Danirixin in whole blood using dried blood spots ^[230]

End point description

Blood samples were collected from the participants for the analysis of pharmacokinetic parameter. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Secondary

End point timeframe

Days 1 and 168

Notes
[230] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[231]	103 ^[232]	102 ^[233]	102 ^[234]	101 ^[235]
Units: Nanogram per milliliter
geometric mean (confidence interval 95%)
Day 1, n=17, 19, 24, 26, 19	164.9 (119.5 to 227.5)	343.1 (264.1 to 445.6)	1028.8 (818.2 to 1293.7)	1386.2 (1172.1 to 1639.3)	2119.1 (1728.9 to 2597.4)
Day 168, n=14, 13, 17, 18, 16	171.9 (123.5 to 239.4)	357.3 (274.4 to 465.4)	821.2 (570.9 to 1181.2)	1695.0 (1285.8 to 2234.5)	2390.5 (2014.6 to 2836.5)

Notes
[231] - Pharmacokinetic Population.
[232] - Pharmacokinetic Population.
[233] - Pharmacokinetic Population.
[234] - Pharmacokinetic Population.
[235] - Pharmacokinetic Population.

No statistical analyses for this end point

Secondary: Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood using dried blood spots

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End point title

Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood using dried blood spots ^[236]

End point description

Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.

End point type

Secondary

End point timeframe

Days 1 and 168

Notes
[236] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Number of subjects analysed	102 ^[237]	103 ^[238]	102 ^[239]	102 ^[240]	101 ^[241]
Units: Hours
median (full range (min-max))
Day 1, n=17, 19, 24, 26, 19	1.000 (0.58 to 11.80)	1.000 (0.50 to 12.00)	1.000 (0.50 to 10.08)	1.000 (0.48 to 5.85)	1.000 (0.50 to 12.00)
Day 168, n=14, 13, 17, 18, 16	1.000 (0.50 to 11.78)	1.000 (0.50 to 2.00)	1.000 (0.33 to 10.00)	1.000 (0.48 to 11.87)	1.000 (0.50 to 11.77)

Notes
[237] - Pharmacokinetic Population.
[238] - Pharmacokinetic Population.
[239] - Pharmacokinetic Population.
[240] - Pharmacokinetic Population.
[241] - Pharmacokinetic Population.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAEs) and non serious AEs were collected from the start of study treatment up to 196 days

Adverse event reporting additional description

mITT population comprised of all randomized participants who were randomized apart from those randomized in error, received a treatment randomization number, modified and data for this population were based on actual treatment received. SAEs and AEs were reported for mITT Population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Placebo

Reporting group description

Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 5 mg

Reporting group description

Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 10 mg

Reporting group description

Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 25 mg

Reporting group description

Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 35 mg

Reporting group description

Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Reporting group title

Danirixin 50 mg

Reporting group description

Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.

Serious adverse events	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 102 (7.84%)	7 / 102 (6.86%)	13 / 103 (12.62%)	10 / 103 (9.71%)	7 / 102 (6.86%)	11 / 102 (10.78%)
number of deaths (all causes)	0	0	1	2	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder papilloma
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac neoplasm unspecified
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal adenocarcinoma
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	1 / 102 (0.98%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	2 / 103 (1.94%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	1 / 102 (0.98%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 102 (0.98%)	1 / 102 (0.98%)	1 / 103 (0.97%)	2 / 103 (1.94%)	2 / 102 (1.96%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Facial bones fracture
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	2 / 103 (1.94%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 102 (0.98%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	1 / 102 (0.98%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Diabetic neuropathy
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal prolapse
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic gastritis
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	1 / 102 (0.98%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic cyst
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	1 / 103 (0.97%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankylosing spondylitis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	2 / 103 (1.94%)	1 / 103 (0.97%)	1 / 102 (0.98%)	4 / 102 (3.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perichondritis
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pilonidal cyst
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 102 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 102 (0.98%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 103 (0.00%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 102 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 103 (0.97%)	0 / 102 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 102 (19.61%)	24 / 102 (23.53%)	22 / 103 (21.36%)	31 / 103 (30.10%)	27 / 102 (26.47%)	27 / 102 (26.47%)
Nervous system disorders
Headache
subjects affected / exposed	2 / 102 (1.96%)	4 / 102 (3.92%)	6 / 103 (5.83%)	5 / 103 (4.85%)	8 / 102 (7.84%)	8 / 102 (7.84%)
occurrences all number	2	4	6	8	9	8
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 102 (3.92%)	7 / 102 (6.86%)	4 / 103 (3.88%)	6 / 103 (5.83%)	5 / 102 (4.90%)	5 / 102 (4.90%)
occurrences all number	4	7	4	7	6	5
Infections and infestations
Nasopharyngitis
subjects affected / exposed	12 / 102 (11.76%)	8 / 102 (7.84%)	9 / 103 (8.74%)	12 / 103 (11.65%)	14 / 102 (13.73%)	10 / 102 (9.80%)
occurrences all number	13	8	11	14	16	14
Upper respiratory tract infection
subjects affected / exposed	5 / 102 (4.90%)	7 / 102 (6.86%)	7 / 103 (6.80%)	9 / 103 (8.74%)	5 / 102 (4.90%)	6 / 102 (5.88%)
occurrences all number	6	7	8	12	8	8

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Were there any global substantial amendments to the protocol? Yes

31 Oct 2017

This amendment adds a second, optional, detailed pharmacokinetic profiling at Visit 10 in a subset of participants to allow for a better understanding of danirixin pharmacokinetics. This amendment also removes the Participant Exit Interview from the exploratory endpoints. Additionally, this amendment provides additional information and clarification for the following: spirometry assessments, exclusion for cancers other than lung cancer, permitted use of supplemental oxygen, permitted uses of chronic steroids, participant numbering requirement for re-screening, additional text to explain the timing of the planned interim analysis and updates to the analysis populations.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in respiratory symptoms measured by evaluating respiratory symptoms (E-RS) in COPD. E-RS: COPD Total Score

Primary: Change from Baseline in respiratory symptoms measured by evaluating respiratory symptoms (E-RS) in COPD. E-RS: COPD Total Score

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Breathlessness Score)

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Breathlessness Score)

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)

Primary: Change from Baseline in respiratory symptoms measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)

Primary: Number of participants with adverse events (AE) and serious adverse events (SAE)

Primary: Number of participants with adverse events (AE) and serious adverse events (SAE)

Primary: Number of participants with worst case hematology parameter results by potential clinical importance (PCI)

Primary: Number of participants with worst case hematology parameter results by potential clinical importance (PCI)

Primary: Number of participants with worst case clinical chemistry parameter results by PCI

Primary: Number of participants with worst case clinical chemistry parameter results by PCI

Primary: Number of participants with worst case vital signs parameter results by PCI

Primary: Number of participants with worst case vital signs parameter results by PCI

Primary: Number of participants with worst case post-Baseline abnormal 12-lead electrocardiogram (ECG) findings

Primary: Number of participants with worst case post-Baseline abnormal 12-lead electrocardiogram (ECG) findings

Secondary: Number of moderate or severe Healthcare Resource Utilization (HCRU) exacerbations per participant

Secondary: Number of moderate or severe Healthcare Resource Utilization (HCRU) exacerbations per participant

Secondary: Number of responders E-RS in COPD (E-RS): COPD Total Score

Secondary: Number of responders E-RS in COPD (E-RS): COPD Total Score

Secondary: Number of EXACT events per participant

Secondary: Number of EXACT events per participant

Secondary: Time to first EXACT event

Secondary: Time to first EXACT event

Secondary: Severity of EXACT event

Secondary: Severity of EXACT event

Secondary: EXACT event duration for all events

Secondary: EXACT event duration for all events

Secondary: Time to first HCRU-defined COPD exacerbation

Secondary: Time to first HCRU-defined COPD exacerbation

Secondary: Time to first severe HCRU-defined COPD exacerbation

Secondary: Time to first severe HCRU-defined COPD exacerbation

Secondary: HCRU-defined exacerbation duration

Secondary: HCRU-defined exacerbation duration

Secondary: Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score

Secondary: Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score

Secondary: Number of SGRQ responder

Secondary: Number of SGRQ responder

Secondary: Change from Baseline COPD Assessment Test (CAT) total score

Secondary: Change from Baseline COPD Assessment Test (CAT) total score

Secondary: Number of CAT responder

Secondary: Number of CAT responder

Secondary: Change from Baseline in post-bronchodilator FEV1 as a lung function assessment

Secondary: Change from Baseline in post-bronchodilator FEV1 as a lung function assessment

Secondary: Percent predicted normal FEV1

Secondary: Percent predicted normal FEV1

Secondary: Change from Baseline in post-bronchodilator Forced Vital Capacity (FVC) as a lung function assessment

Secondary: Change from Baseline in post-bronchodilator Forced Vital Capacity (FVC) as a lung function assessment

Secondary: Change from Baseline in post-bronchodilator FEV1/FVC ratio as a lung function assessment

Secondary: Change from Baseline in post-bronchodilator FEV1/FVC ratio as a lung function assessment

Secondary: Change from Baseline number of puffs of rescue medication per day

Secondary: Change from Baseline number of puffs of rescue medication per day

Secondary: Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire

Secondary: Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire

Secondary: Danirixin Whole Blood Pharmacokinetic Concentration-Time Data

Secondary: Danirixin Whole Blood Pharmacokinetic Concentration-Time Data

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in whole blood using dried blood spot

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in whole blood using dried blood spot

Secondary: Concentration maximum (Cmax) of Danirixin in whole blood using dried blood spots

Secondary: Concentration maximum (Cmax) of Danirixin in whole blood using dried blood spots

Secondary: Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood using dried blood spots

Secondary: Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood using dried blood spots

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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