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Clinical Trial Results:
A 12-week, multinational, randomised, double blind, double dummy, 4-arm parallel-group study comparing the efficacy and safety of CHF 1535 (fixed combination of beclomethasone dipropionate + formoterol fumarate) 100 + 6 μg/actuation inhalation powder, administered via the NEXT™ inhaler, versus CHF 1535 (fixed combination of beclomethasone dipropionate + formoterol fumarate) 100 + 6 μg/actuation, via HFA pressurised inhalation solution, in moderate to severe symptomatic asthmatic patients aged ≥ 12 years under treatment with inhaled corticosteroids.

Summary
EudraCT number	2008-000401-11
Trial protocol	DE CZ HU BG
Global end of trial date	19 Oct 2009

Results information
Results version number	v1(current)
This version publication date	15 Jul 2017
First version publication date	15 Jul 2017
Other versions

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

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Trial information

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Sponsor protocol code

CCD-0705-PR-0027

ISRCTN number

US NCT number

NCT00862394

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici SpA

Sponsor organisation address

Via Palermo, 26/A, Parma, Italy, 43122

Public contact

Clinical Trial Transparency , Chiesi Farmaceutici SpA, 0521 2791, ClinicalTrial_info@chiesi.com

Scientific contact

Clinical Trial Transparency , Chiesi Farmaceutici SpA, 0521 2791, ClinicalTrial_info@chiesi.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000548-PIP01-09

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?

Yes

Analysis stage

Final

Date of interim/final analysis

19 Oct 2009

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Oct 2009

Global end of trial reached?

Yes

Global end of trial date

19 Oct 2009

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that CHF 1535 via NEXT™DPI (beclomethasone dipropionate + formoterol fumarate 100 + 6 μg), 1 inhalation or 2 inhalations twice daily, for 12 weeks is non-inferior to the corresponding dose of CHF 1535 via HFA-134a “extrafine” pMDI in terms of pulmonary function (change from baseline in pre-dose morning FEV1) in moderate to severe symptomatic asthmatic patients aged ≥ 12 years under treatment with inhaled corticosteroids (< 2000 µg BDP or equivalent).

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.

Background therapy

No background therapy is concerned.

Evidence for comparator

Actual start date of recruitment

19 Feb 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Romania: 67

Country: Number of subjects enrolled

Russian Federation: 101

Country: Number of subjects enrolled

Ukraine: 193

Country: Number of subjects enrolled

Bulgaria: 96

Country: Number of subjects enrolled

Czech Republic: 43

Country: Number of subjects enrolled

Germany: 93

Country: Number of subjects enrolled

Hungary: 103

Worldwide total number of subjects

696

EEA total number of subjects

402

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)

162

Adults (18-64 years)

481

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients of both sexes, aged > 12 years, non/ex-smokers, with a diagnosis of moderate to severe symptomatic asthma treated with a stable daily dose of inhaled corticosteroids < 2000 μg BDP or equivalent for at least 4 weeks prior to inclusion (plus additional criteria) were considered for recruitment.

Screening details

A total of 783 patients were screened, 87 (11.1%) patients were withdrawn before randomisation and were considered as screen failures. The study entailed a 2-week run-in period followed by a 12-week randomised active treatment. A total of 696 patients were randomised to receive one of the four study treatments between 05 March and 22 July 2009.

Period 1 title

Overall trial by treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The study was double-blind and double-dummy with respect to the formulations of the test product CHF 1535, NEXT DPI® and pMDI. No blinding was applied with respect to the dose intake. The randomisation list was provided to the labelling facility but was not available to patients, investigators, monitors or employees of the centres involved in the management of the trial before unblinding of the data, unless in case of emergency.

Are arms mutually exclusive

Yes

Arm A

Arm description

CHF 1535 NEXT DPI®, 1 inhalation bid + placebo pMDI, 1 inhalation bid

Arm type

Experimental

Investigational medicinal product name

CHF 1535 NEXT DPI

Investigational medicinal product code

Other name

beclomethasone dipropionate, formoterol fumarate

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

1 inhalation bid Daily dose: beclomethasone dipropionate (BDP) 200 μg/formoterol fumarate (FF) 12 μg

Investigational medicinal product name

placebo pMDI

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

1 inhalation bid

Arm B

Arm description

CHF 1535 pMDI, 1 inhalation bid + placebo NEXT DPI®, 1 inhalation bid.

Arm type

Active comparator

Investigational medicinal product name

CHF 1535 pMDI

Investigational medicinal product code

Other name

beclomethasone dipropionate, formoterol fumarate

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

1 inhalation bid Daily dose: beclometasone (BDP) 200 μg/formoterol fumarate (FF) 12 μg

Investigational medicinal product name

placebo NEXT DPI

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

1 inhalation bid

Arm C

Arm description

CHF 1535 NEXT DPI®, 2 inhalations bid + placebo pMDI, 2 inhalations bid

Arm type

Experimental

Investigational medicinal product name

CHF 1535 NEXT DPI

Investigational medicinal product code

Other name

beclomethasone dipropionate, formoterol fumarate

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

2 inhalations bid Daily dose: beclomethasone dipropionate (BDP) 400 μg/formoterol fumarate (FF) 24 μg

Investigational medicinal product name

placebo pMDI

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

2 inhalations bid

Arm D

Arm description

CHF 1535 pMDI, 2 inhalations bid + placebo NEXT DPI®, 2 inhalations bid

Arm type

Active comparator

Investigational medicinal product name

CHF 1535 pMDI

Investigational medicinal product code

Other name

beclomethasone dipropionate (BDP) 400 μg/formoterol fumarate

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

2 inhalations bid Daily dose: beclomethasone dipropionate (BDP) 400 μg/formoterol fumarate (FF) 24 μg

Investigational medicinal product name

placebo NEXT DPI

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

2 inhalations bid

Number of subjects in period 1	Arm A	Arm B	Arm C	Arm D
Started	173	173	176	174
Completed	161	159	163	160
Not completed	12	14	13	14
Consent withdrawn by subject	3	-	1	1
Adverse event, non-fatal	3	4	3	2
Non compliance	1	1	-	-
Unspecified	2	3	6	3
Discontinuation criteria	-	6	-	-
Protocol deviation	3	-	3	8

Baseline characteristics

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Reporting group title

Arm A

Reporting group description

CHF 1535 NEXT DPI®, 1 inhalation bid + placebo pMDI, 1 inhalation bid

Reporting group title

Arm B

Reporting group description

CHF 1535 pMDI, 1 inhalation bid + placebo NEXT DPI®, 1 inhalation bid.

Reporting group title

Arm C

Reporting group description

CHF 1535 NEXT DPI®, 2 inhalations bid + placebo pMDI, 2 inhalations bid

Reporting group title

Arm D

Reporting group description

CHF 1535 pMDI, 2 inhalations bid + placebo NEXT DPI®, 2 inhalations bid

Reporting group values	Arm A	Arm B	Arm C	Arm D	Total
Number of subjects	173	173	176	174	696
Age categorical
Units: Subjects
12 ≤ Age < 18	42	38	47	35	162
Age ≥ 18	131	135	129	139	534
Gender categorical
Units: Subjects
Female	111	101	91	100	403
Male	62	72	85	74	293

Subject analysis set title

Arm A - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm A who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm B - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm B who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm C - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm C who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm D - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm D who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm A - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm A who took at least one dose of study medication

Subject analysis set title

Arm B - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm B who took at least one dose of study medication

Subject analysis set title

Arm C - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm C who took at least one dose of study medication

Subject analysis set title

Arm D - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm D who took at least one dose of study medication

Subject analysis set title

Arm A - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm A included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm B - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm B included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm C - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm C included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm D - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm D included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis sets values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population	Arm A - Safety population	Arm B - Safety population	Arm C - Safety population	Arm D - Safety population	Arm A - PP population	Arm B - PP population	Arm C - PP population	Arm D - PP population
Number of subjects	173	173	176	172	172	173	177	173	159	154	161	158
Age categorical
Units: Subjects
12 ≤ Age < 18	42	38	47	35	42	38	47	35	41	34	44	34
Age ≥ 18	131	135	129	137	130	135	130	138	118	120	117	124
Age continuous
Units:
	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	111	101	91	99	111	100	92	99	100	87	81	91
Male	62	72	85	73	62	72	85	74	59	67	80	67

End points

Top of page

Reporting group title

Arm A

Reporting group description

CHF 1535 NEXT DPI®, 1 inhalation bid + placebo pMDI, 1 inhalation bid

Reporting group title

Arm B

Reporting group description

CHF 1535 pMDI, 1 inhalation bid + placebo NEXT DPI®, 1 inhalation bid.

Reporting group title

Arm C

Reporting group description

CHF 1535 NEXT DPI®, 2 inhalations bid + placebo pMDI, 2 inhalations bid

Reporting group title

Arm D

Reporting group description

CHF 1535 pMDI, 2 inhalations bid + placebo NEXT DPI®, 2 inhalations bid

Subject analysis set title

Arm A - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm A who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm B - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm B who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm C - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm C who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm D - ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomised to Arm D who received at least one dose of the study medications and with at least one post-baseline evaluation for any efficacy variable.

Subject analysis set title

Arm A - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm A who took at least one dose of study medication

Subject analysis set title

Arm B - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm B who took at least one dose of study medication

Subject analysis set title

Arm C - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm C who took at least one dose of study medication

Subject analysis set title

Arm D - Safety population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects randomised to Arm D who took at least one dose of study medication

Subject analysis set title

Arm A - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm A included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm B - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm B included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm C - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm C included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Subject analysis set title

Arm D - PP population

Subject analysis set type

Per protocol

Subject analysis set description

All subjects randomised to Arm D included in the ITT population who also met all inclusion/exclusion criteria and who did not have any major protocol deviations.

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - ITT population

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End point title

Change in Pre-Dose FEV1 from Baseline to End of Treatment - ITT population

End point description

Change from baseline measured at clinic visit V2 (end of run-in) to the end of treatment period (V5) in pre-dose morning Forced Expiratory Volume in the 1st second (FEV1) measured at clinic.

End point type

Primary

End point timeframe

From visit 2 (end of run-in) to Visit 5 (end of treatment period)

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[1]	166 ^[2]	175 ^[3]	170 ^[4]
Units: liters
arithmetic mean (standard deviation)	0.29 ( 0.41 )	0.39 ( 0.5 )	0.38 ( 0.42 )	0.45 ( 0.46 )

Notes
[1] - The one reported is the real number of patients analyzed
[2] - The one reported is the real number of patients analyzed
[3] - The one reported is the real number of patients analyzed
[4] - The one reported is the real number of patients analyzed

Arm A vs Arm B

Statistical analysis description

Non-inferiority comparison of CHF 1535 NEXT DPI® versus the corresponding dose (1 inhalation bid) of CHF 1535 pMDI

Comparison groups

Arm B - ITT population v Arm A - ITT population

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

Method

Parameter type

least square means difference

Point estimate

-0.109

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

-0.017

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[5] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate.

Arm C vs Arm D

Statistical analysis description

Non-inferiority comparison of CHF 1535 NEXT DPI® versus the corresponding dose (2 inhalations bid) of CHF 1535 pMDI

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

345

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

least square means difference

Point estimate

-0.076

Confidence interval

level

95%

sides

2-sided

lower limit

-0.166

upper limit

0.014

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[6] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate

Arm C vs Arm A

Comparison groups

Arm A - ITT population v Arm C - ITT population

Number of subjects included in analysis

345

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

P-value

= 0.069

Method

ANCOVA

Parameter type

least square means difference

Point estimate

0.084

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.174

Notes
[7] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate.

Arm D vs Arm B

Comparison groups

Arm D - ITT population v Arm B - ITT population

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

P-value

= 0.272

Method

ANCOVA

Parameter type

least square means difference

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.143

Notes
[8] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate.

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - PP population

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End point title

Change in Pre-Dose FEV1 from Baseline to End of Treatment - PP population

End point description

Change from baseline measured at clinic visit V2 (end of run-in) to the end of treatment period (V5) in pre-dose morning Forced Expiratory Volume in the 1st second (FEV1) measured at clinic.

End point type

Primary

End point timeframe

From visit 2 (end of run-in) to Visit 5 (end of treatment period)

End point values	Arm A - PP population	Arm B - PP population	Arm C - PP population	Arm D - PP population
Number of subjects analysed	159 ^[9]	154 ^[10]	161 ^[11]	158 ^[12]
Units: liters
least squares mean (standard error)	0.26 ( 0.03 )	0.36 ( 0.04 )	0.34 ( 0.03 )	0.43 ( 0.04 )

Notes
[9] - The one reported is the real number of patients analyzed
[10] - The one reported is the real number of patients analyzed
[11] - The one reported is the real number of patients analyzed
[12] - The one reported is the real number of patients analyzed

Arm A vs Arm B - PP population

Statistical analysis description

Non-inferiority comparison of CHF 1535 NEXT DPI® versus the corresponding dose (1 inhalation bid) of CHF 1535 pMDI

Comparison groups

Arm A - PP population v Arm B - PP population

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

Method

Parameter type

least square means difference

Point estimate

-0.104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.199

upper limit

-0.009

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[13] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate.

Arm C vs Arm D - PP population

Statistical analysis description

Non-inferiority comparison of CHF 1535 NEXT DPI® versus the corresponding dose (2 inhalations bid) of CHF 1535 pMDI

Comparison groups

Arm C - PP population v Arm D - PP population

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

Method

Parameter type

least square means difference

Point estimate

-0.082

Confidence interval

level

95%

sides

2-sided

lower limit

-0.176

upper limit

0.011

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[14] - The primary efficacy variable was submitted to an ANCOVA model, including terms for country and treatment as factors and baseline value as a covariate.

Secondary: Pre-dose FEV1 at Visit 2

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End point title

Pre-dose FEV1 at Visit 2

End point description

End point type

Secondary

End point timeframe

Lung Function Tests – FEV1, FVC, FEF25-75% – were measured pre-dose at each clinic visit: Visit 1 (Week –2), Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12). Data from Visit 2 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	173	173	176	172
Units: liters
arithmetic mean (standard deviation)	2.03 ( 0.59 )	2.03 ( 0.53 )	2.12 ( 0.55 )	2.06 ( 0.59 )

No statistical analyses for this end point

Secondary: Pre-dose FEV1 at Visit 3

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End point title

Pre-dose FEV1 at Visit 3

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[15]	164 ^[16]	170 ^[17]	166 ^[18]
Units: liters
arithmetic mean (standard deviation)	2.33 ( 0.77 )	2.37 ( 0.79 )	2.46 ( 0.73 )	2.46 ( 0.72 )

Notes
[15] - The one reported is the real number of patients analyzed
[16] - The one reported is the real number of patients analyzed
[17] - The one reported is the real number of patients analyzed
[18] - The one reported is the real number of patients analyzed

No statistical analyses for this end point

Secondary: Pre-dose FEV1 at Visit 4

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End point title

Pre-dose FEV1 at Visit 4

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[19]	165 ^[20]	170 ^[21]	166 ^[22]
Units: liters
arithmetic mean (standard deviation)	2.32 ( 0.77 )	2.41 ( 0.8 )	2.51 ( 0.71 )	2.54 ( 0.76 )

Notes
[19] - The one reported is the real number of patients analyzed
[20] - The one reported is the real number of patients analyzed
[21] - The one reported is the real number of patients analyzed
[22] - The one reported is the real number of patients analyzed

No statistical analyses for this end point

Secondary: Pre-dose FEV1 at Visit 5

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End point title

Pre-dose FEV1 at Visit 5

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[23]	166 ^[24]	175 ^[25]	170 ^[26]
Units: liters
arithmetic mean (standard deviation)	2.31 ( 0.78 )	2.43 ( 0.82 )	2.5 ( 0.7 )	2.51 ( 78 )

Notes
[23] - The one reported is the real number of patients analyzed
[24] - The one reported is the real number of patients analyzed
[25] - The one reported is the real number of patients analyzed
[26] - The one reported is the real number of patients analyzed

No statistical analyses for this end point

Secondary: Post-dose FEV1 AUC0-8 h at Visit 2

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End point title

Post-dose FEV1 AUC0-8 h at Visit 2

End point description

Area under the curve was calculated using the linear trapezoidal rule in the subgroup of patients performing spirometry until 8 hours post-dose.

End point type

Secondary

End point timeframe

Post-dose FEV1 AUC0-8 h standardised by time (FEV1 at 10 min, 30 min, 1, 2, 3 , 4 , 6 and 8 h) was measured at Visit 2 (Week 0) and Visit 5 (End of treatment period). Data from Visit 2 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	61 ^[27]	56 ^[28]	60 ^[29]	63 ^[30]
Units: ng*h/mL
arithmetic mean (standard deviation)	2.35 ( 0.73 )	2.55 ( 0.68 )	2.62 ( 0.67 )	2.65 ( 0.78 )

Notes
[27] - The real number of patients analyzed out of 67 who underwent serial spirometry until 8 hr post-dose.
[28] - The real number of patients analyzed out of 65 who underwent serial spirometry until 8 hr post-dose.
[29] - The real number of patients analyzed out of 63 who underwent serial spirometry until 8 hr post-dose.
[30] - The real number of patients analyzed out of 66 who underwent serial spirometry until 8 hr post-dose.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm C - ITT population

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.009

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.167

Confidence interval

level

95%

sides

2-sided

lower limit

-0.292

upper limit

-0.043

Notes
[31] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FEV1 (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm B vs Arm D

Comparison groups

Arm B - ITT population v Arm D - ITT population

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.242

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.073

Confidence interval

level

95%

sides

2-sided

lower limit

-0.195

upper limit

0.049

Notes
[32] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FEV1 (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Post-dose FEV1 AUC0-8 h at Visit 5

Top of page

End point title

Post-dose FEV1 AUC0-8 h at Visit 5

End point description

Area under the curve was calculated using the linear trapezoidal rule in the subgroup of patients performing spirometry until 8 hours post-dose.

End point type

Secondary

End point timeframe

Post-dose FEV1 AUC0-8 h standardised by time (FEV1 at 10 min, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours) was measured at Visit V2 (Wek 0) and Visit 5 (End of treatment period). data from Visit 5 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	62 ^[33]	53 ^[34]	60 ^[35]	61 ^[36]
Units: ng*h/mL
arithmetic mean (standard deviation)	2.5 ( 0.81 )	2.8 ( 0.8 )	2.74 ( 0.64 )	2.78 ( 0.7 )

Notes
[33] - The real number of patients analyzed out of 67 who underwent serial spirometry until 8 hr post-dose.
[34] - The real number of patients analyzed out of 65 who underwent serial spirometry until 8 hr post-dose.
[35] - The real number of patients analyzed out of 63 who underwent serial spirometry until 8 hr post-dose.
[36] - The real number of patients analyzed out of 66 who underwent serial spirometry until 8 hr post-dose.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.206

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.054

Confidence interval

level

95%

sides

2-sided

lower limit

-0.139

upper limit

0.03

Notes
[37] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FEV1 (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[38]

P-value

= 0.568

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.106

upper limit

0.058

Notes
[38] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FEV1 (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose FVC at Visit 2

Top of page

End point title

Pre-dose FVC at Visit 2

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	173	173	176	172
Units: liters
arithmetic mean (standard deviation)	2.87 ( 0.81 )	2.94 ( 0.77 )	3 ( 0.86 )	2.96 ( 0.9 )

No statistical analyses for this end point

Secondary: Pre-dose FVC at Visit 3

Top of page

End point title

Pre-dose FVC at Visit 3

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[39]	164 ^[40]	170 ^[41]	166 ^[42]
Units: liters
arithmetic mean (standard deviation)	3.15 ( 0.95 )	3.24 ( 0.93 )	3.31 ( 0.88 )	3.34 ( 0.93 )

Notes
[39] - This is the real number of patients analyzed.
[40] - This is the real number of patients analyzed.
[41] - This is the real number of patients analyzed.
[42] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose FVC at Visit 4

Top of page

End point title

Pre-dose FVC at Visit 4

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[43]	165 ^[44]	170 ^[45]	166 ^[46]
Units: liters
arithmetic mean (standard deviation)	3.16 ( 0.88 )	3.32 ( 1.05 )	3.39 ( 0.89 )	3.46 ( 0.99 )

Notes
[43] - This is the real number of patients analyzed.
[44] - This is the real number of patients analyzed.
[45] - This is the real number of patients analyzed.
[46] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose FVC at Visit 5

Top of page

End point title

Pre-dose FVC at Visit 5

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[47]	166 ^[48]	175 ^[49]	170 ^[50]
Units: liters
arithmetic mean (standard deviation)	3.17 ( 0.94 )	3.32 ( 0.96 )	3.37 ( 0.86 )	3.42 ( 0.94 )

Notes
[47] - This is the real number of patients analyzed.
[48] - This is the real number of patients analyzed.
[49] - This is the real number of patients analyzed.
[50] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Change in Pre-Dose FVC from Baseline to End of Treatment

Top of page

End point title

Change in Pre-Dose FVC from Baseline to End of Treatment

End point description

End point type

Secondary

End point timeframe

Lung Function Tests – FEV1, FVC, FEF25-75% – were measured pre-dose at each clinic visit: Visit 1 (Week –2), Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12).

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[51]	166 ^[52]	175 ^[53]	170 ^[54]
Units: liters
arithmetic mean (standard deviation)	0.3 ( 0.49 )	0.38 ( 0.61 )	0.37 ( 0.46 )	0.47 ( 0.55 )

Notes
[51] - This is the real number of patients analyzed.
[52] - This is the real number of patients analyzed.
[53] - This is the real number of patients analyzed.
[54] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

= 0.127

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.086

Confidence interval

level

95%

sides

2-sided

lower limit

-0.197

upper limit

0.024

Notes
[55] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

345

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

= 0.076

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.098

Confidence interval

level

95%

sides

2-sided

lower limit

-0.207

upper limit

0.01

Notes
[56] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose FEF25-75% at Visit 2

Top of page

End point title

Pre-dose FEF25-75% at Visit 2

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	173
Units: L/sec
arithmetic mean (standard deviation)	1.74 ( 1.16 )	1.61 ( 0.95 )	1.68 ( 0.81 )	1.69 ( 0.98 )

No statistical analyses for this end point

Secondary: Pre-dose FEF25-75% at Visit 3

Top of page

End point title

Pre-dose FEF25-75% at Visit 3

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[57]	164 ^[58]	170 ^[59]	166 ^[60]
Units: L/sec
arithmetic mean (standard deviation)	2.12 ( 1.41 )	2.07 ( 1.32 )	2.15 ( 1.24 )	2.17 ( 1.25 )

Notes
[57] - This is the real number of patients analyzed.
[58] - This is the real number of patients analyzed.
[59] - This is the real number of patients analyzed.
[60] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose FEF25-75% at Visit 4

Top of page

End point title

Pre-dose FEF25-75% at Visit 4

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[61]	165 ^[62]	170 ^[63]	166 ^[64]
Units: L/sec
arithmetic mean (standard deviation)	2.1 ( 1.39 )	2.12 ( 1.33 )	2.17 ( 1.2 )	2.21 ( 1.28 )

Notes
[61] - This is the real number of patients analyzed.
[62] - This is the real number of patients analyzed.
[63] - This is the real number of patients analyzed.
[64] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose FEF25-75% at Visit 5

Top of page

End point title

Pre-dose FEF25-75% at Visit 5

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[65]	166 ^[66]	175 ^[67]	170 ^[68]
Units: L/sec
arithmetic mean (standard deviation)	2.06 ( 1.28 )	2.11 ( 1.35 )	2.18 ( 1.24 )	2.18 ( 1.29 )

Notes
[65] - This is the real number of patients analyzed.
[66] - This is the real number of patients analyzed.
[67] - This is the real number of patients analyzed.
[68] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Change in Pre-Dose FEF25-75% from Baseline to End of Treatment

Top of page

End point title

Change in Pre-Dose FEF25-75% from Baseline to End of Treatment

End point description

End point type

Secondary

End point timeframe

Lung Function Tests – FEV1, FVC, FEF25-75% – were measured pre-dose at each clinic visit: Visit 1 (Week –2), Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12).

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[69]	166 ^[70]	175 ^[71]	170 ^[72]
Units: L/sec
arithmetic mean (standard deviation)	0.32 ( 0.99 )	0.51 ( 0.78 )	0.49 ( 0.89 )	0.48 ( 0.74 )

Notes
[69] - This is the real number of patients analyzed.
[70] - This is the real number of patients analyzed.
[71] - This is the real number of patients analyzed.
[72] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.042

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.188

Confidence interval

level

95%

sides

2-sided

lower limit

-0.369

upper limit

-0.007

Notes
[73] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

345

Analysis specification

Pre-specified

Analysis type

other ^[74]

P-value

= 0.884

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.165

upper limit

0.192

Notes
[74] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Post-dose FVC AUC0-8 h at Visit 2

Top of page

End point title

Post-dose FVC AUC0-8 h at Visit 2

End point description

Area under the curve was calculated using the linear trapezoidal rule in the subgroup of patients performing spirometry until 8 hours post-dose.

End point type

Secondary

End point timeframe

Post-dose FVC AUC0-8 h standardised by time (FEV1 at 10 min, 30 min, 1, 2, 3 , 4 , 6 and 8 h) was measured at Visit 2 (Week 0) and Visit 5 (End of treatment period). Data from Visit 2 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	61 ^[75]	56 ^[76]	60 ^[77]	63 ^[78]
Units: ng*h/mL
arithmetic mean (standard deviation)	3.18 ( 0.94 )	3.4 ( 0.84 )	3.54 ( 0.92 )	3.56 ( 1.04 )

Notes
[75] - The real number of patients analyzed out of 67 who underwent serial spirometry until 8 hr post-dose.
[76] - The real number of patients analyzed out of 65 who underwent serial spirometry until 8 hr post-dose.
[77] - The real number of patients analyzed out of 63 who underwent serial spirometry until 8 hr post-dose.
[78] - The real number of patients analyzed out of 66 who underwent serial spirometry until 8 hr post-dose.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

117

Analysis specification

Pre-specified

Analysis type

other ^[79]

P-value

= 0.183

Method

ANCOVA

Parameter type

least square means difference

Point estimate

-0.108

Confidence interval

level

95%

sides

2-sided

lower limit

-0.268

upper limit

0.052

Notes
[79] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FVC (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

other ^[80]

P-value

= 0.352

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.074

Confidence interval

level

95%

sides

2-sided

lower limit

-0.231

upper limit

0.083

Notes
[80] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FVC (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Post-dose FVC AUC0-8 h at Visit 5

Top of page

End point title

Post-dose FVC AUC0-8 h at Visit 5

End point description

Area under the curve was calculated using the linear trapezoidal rule in the subgroup of patients performing spirometry until 8 hours post-dose.

End point type

Secondary

End point timeframe

Post-dose FVC AUC0-8 h standardised by time (FEV1 at 10 min, 30 min, 1, 2, 3 , 4 , 6 and 8 h) was measured at Visit 2 (Week 0) and Visit 5 (End of treatment period). Data from Visit 5 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	62 ^[81]	53 ^[82]	60 ^[83]	61 ^[84]
Units: ng*h/mL
arithmetic mean (standard deviation)	3.31 ( 0.91 )	3.6 ( 0.88 )	3.64 ( 0.87 )	3.62 ( 0.9 )

Notes
[81] - The real number of patients analyzed out of 67 who underwent serial spirometry until 8 hr post-dose.
[82] - The real number of patients analyzed out of 65 who underwent serial spirometry until 8 hr post-dose.
[83] - The real number of patients analyzed out of 63 who underwent serial spirometry until 8 hr post-dose.
[84] - The real number of patients analyzed out of 66 who underwent serial spirometry until 8 hr post-dose.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

other ^[85]

P-value

= 0.647

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.023

Confidence interval

level

95%

sides

2-sided

lower limit

-0.121

upper limit

0.075

Notes
[85] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FVC (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

other ^[86]

P-value

= 0.843

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.105

upper limit

0.086

Notes
[86] - AUCs were compared between treatments at both V2 and V5 using ANCOVA with baseline FVC (pre-dose at visit 2) as covariate and country as factor. Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose morning PEF - Run-in period

Top of page

End point title

Pre-dose morning PEF - Run-in period

End point description

PEF was measured at home by a portable electronic peak flow meter.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	112 ^[87]	100 ^[88]	107 ^[89]	108
Units: L/min
arithmetic mean (standard deviation)	307.18 ( 81.71 )	322.18 ( 94.95 )	331.9 ( 96.22 )	336.79 ( 95.13 )

Notes
[87] - This is the real number of patients analyzed.
[88] - This is the real number of patients analyzed.
[89] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose morning PEF - End-of-treatment period

Top of page

End point title

Pre-dose morning PEF - End-of-treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. End-of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	111 ^[90]	105 ^[91]	104 ^[92]	107 ^[93]
Units: L/min
arithmetic mean (standard deviation)	313.96 ( 92.48 )	339.79 ( 106.57 )	352.78 ( 98.37 )	361.99 ( 103.07 )

Notes
[90] - This is the real number of patients analyzed.
[91] - This is the real number of patients analyzed.
[92] - This is the real number of patients analyzed.
[93] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose morning PEF - Overall treatment period

Top of page

End point title

Pre-dose morning PEF - Overall treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	166 ^[94]	163 ^[95]	170 ^[96]	168 ^[97]
Units: L/min
arithmetic mean (standard deviation)	313.34 ( 92.81 )	328.15 ( 106.01 )	336.37 ( 96.5 )	351.12 ( 100.35 )

Notes
[94] - This is the real number of patients analyzed.
[95] - This is the real number of patients analyzed.
[96] - This is the real number of patients analyzed.
[97] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose morning PEF - Change from Run-in period to End-of-treatment period

Top of page

End point title

Pre-dose morning PEF - Change from Run-in period to End-of-treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. End-of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily at home. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the change from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	84 ^[98]	75 ^[99]	80 ^[100]	80
Units: L/min
arithmetic mean (standard deviation)	9.3 ( 55.24 )	19 ( 47.63 )	27.77 ( 54.76 )	29.19 ( 56.82 )

Notes
[98] - This is the real number of patients analyzed.
[99] - This is the real number of patients analyzed.
[100] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

other ^[101]

P-value

= 0.301

Method

ANCOVA

Parameter type

Least square means ratio

Point estimate

-8.623

Confidence interval

level

95%

sides

2-sided

lower limit

-24.983

upper limit

7.738

Notes
[101] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

other ^[102]

P-value

= 0.806

Method

ANCOVA

Parameter type

Leats square means difference

Point estimate

-2.032

Confidence interval

level

95%

sides

2-sided

lower limit

-18.266

upper limit

14.203

Notes
[102] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose morning PEF - Change from Run-in periodo to Overall treatment period

Top of page

End point title

Pre-dose morning PEF - Change from Run-in periodo to Overall treatment period

End point description

PEF was measured daily at home by a portable electronic peak flow meter. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for change from Run-in period to Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	111 ^[103]	98 ^[104]	105 ^[105]	107 ^[106]
Units: L/min
arithmetic mean (standard deviation)	10.47 ( 47.38 )	9.87 ( 38.34 )	25.68 ( 42.92 )	27.77 ( 44.9 )

Notes
[103] - This is the real number of patients analyzed.
[104] - This is the real number of patients analyzed.
[105] - This is the real number of patients analyzed.
[106] - This is the real number of patients analyzed.

Arm A vs Arm B

Statistical analysis description

Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

other ^[107]

P-value

= 0.864

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

1.006

Confidence interval

level

95%

sides

2-sided

lower limit

-10.568

upper limit

12.581

Notes
[107] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

212

Analysis specification

Pre-specified

Analysis type

other ^[108]

P-value

= 0.656

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-2.592

Confidence interval

level

95%

sides

2-sided

lower limit

-14.026

upper limit

8.842

Notes
[108] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose evening PEF - Run-in period

Top of page

End point title

Pre-dose evening PEF - Run-in period

End point description

PEF was measured at home by a portable electronic peak flow meter.

End point type

Secondary

End point timeframe

Pre-dose evening PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	102 ^[109]	108 ^[110]	100 ^[111]	100 ^[112]
Units: L/min
arithmetic mean (standard deviation)	321.14 ( 88.74 )	334.75 ( 106.46 )	343.24 ( 104.77 )	352.22 ( 101.96 )

Notes
[109] - This is the real number of patients analyzed.
[110] - This is the real number of patients analyzed.
[111] - This is the real number of patients analyzed.
[112] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose evening PEF - End-of-treatment period

Top of page

End point title

Pre-dose evening PEF - End-of-treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. End-of-treatment period is the last 14 days of treatment

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	103 ^[113]	104 ^[114]	94 ^[115]	97 ^[116]
Units: L/min
arithmetic mean (standard deviation)	319.33 ( 88.86 )	352.3 ( 106.42 )	356.07 ( 92.95 )	367.31 ( 98.03 )

Notes
[113] - This is the real number of patients analyzed.
[114] - This is the real number of patients analyzed.
[115] - This is the real number of patients analyzed.
[116] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose evening PEF - Overall treatment period

Top of page

End point title

Pre-dose evening PEF - Overall treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Pre-dose morning PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	166 ^[117]	166 ^[118]	169 ^[119]	166 ^[120]
Units: L/min
arithmetic mean (standard deviation)	322.43 ( 95.17 )	340.29 ( 104.84 )	347.17 ( 97.59 )	359.71 ( 101.51 )

Notes
[117] - This is the real number of patients analyzed.
[118] - This is the real number of patients analyzed.
[119] - This is the real number of patients analyzed.
[120] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Pre-dose evening PEF - Change from Run-in period to End-of-treatment period

Top of page

End point title

Pre-dose evening PEF - Change from Run-in period to End-of-treatment period

End point description

PEF was measured at home by a portable electronic peak flow meter. End-of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Pre-dose evening PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the change from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	73 ^[121]	76 ^[122]	65 ^[123]	69 ^[124]
Units: L/min
arithmetic mean (standard deviation)	4.51 ( 38.19 )	17.18 ( 47.79 )	16.43 ( 45.81 )	23.17 ( 55.32 )

Notes
[121] - This is the real number of patients analyzed.
[122] - This is the real number of patients analyzed.
[123] - This is the real number of patients analyzed.
[124] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

other ^[125]

P-value

= 0.076

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-13.428

Confidence interval

level

95%

sides

2-sided

lower limit

-28.287

upper limit

1.431

Notes
[125] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[126]

P-value

= 0.484

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-5.582

Confidence interval

level

95%

sides

2-sided

lower limit

-21.255

upper limit

10.091

Notes
[126] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Pre-dose evening PEF - Change from Run-in period to Overall treatment period

Top of page

End point title

Pre-dose evening PEF - Change from Run-in period to Overall treatment period

End point description

Evening PEF was measured at home by a portable electronic peak flow meter. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Pre-dose evening PEF was measured daily. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for change from Run-in period to Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	101 ^[127]	107 ^[128]	100 ^[129]	99 ^[130]
Units: L/min
arithmetic mean (standard deviation)	8.33 ( 40.74 )	12.53 ( 42.23 )	16.8 ( 37.34 )	24.21 ( 46.17 )

Notes
[127] - This is the real number of patients analyzed.
[128] - This is the real number of patients analyzed.
[129] - This is the real number of patients analyzed.
[130] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

208

Analysis specification

Pre-specified

Analysis type

other ^[131]

P-value

= 0.384

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-4.917

Confidence interval

level

95%

sides

2-sided

lower limit

-15.998

upper limit

6.164

Notes
[131] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

other ^[132]

P-value

= 0.171

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-7.872

Confidence interval

level

95%

sides

2-sided

lower limit

-19.163

upper limit

3.419

Notes
[132] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Daily PEF variability - Run-in period

Top of page

End point title

Daily PEF variability - Run-in period

End point description

During each measurement session (morning or evening before the intake of the study medication) the patient had to perform 3 blows and only the best PEF parameter was saved into the peak flow meter memory. The device automatically calculated the daily PEF variability.

End point type

Secondary

End point timeframe

Morning and evening PEF was measured daily at home by a portable electronic peak flow meter. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	94 ^[133]	95 ^[134]	98 ^[135]	100 ^[136]
Units: L/min
arithmetic mean (standard deviation)	12.79 ( 8.61 )	12.97 ( 8.74 )	11.78 ( 8 )	12.14 ( 7.74 )

Notes
[133] - This is the real number of patients analyzed.
[134] - This is the real number of patients analyzed.
[135] - This is the real number of patients analyzed.
[136] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Daily PEF variability - End-of-treatment period

Top of page

End point title

Daily PEF variability - End-of-treatment period

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	97 ^[137]	102 ^[138]	93 ^[139]	92 ^[140]
Units: L/min
arithmetic mean (standard deviation)	10.2 ( 6.47 )	10.76 ( 5.83 )	8.23 ( 4.63 )	9.35 ( 6.27 )

Notes
[137] - This is the real number of patients analyzed.
[138] - This is the real number of patients analyzed.
[139] - This is the real number of patients analyzed.
[140] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Daily PEF variability - Overall treatment period

Top of page

End point title

Daily PEF variability - Overall treatment period

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	159 ^[141]	157 ^[142]	164 ^[143]	158 ^[144]
Units: L/min
arithmetic mean (standard deviation)	11.11 ( 6.03 )	12.87 ( 10.32 )	10.83 ( 6.51 )	10.74 ( 6.36 )

Notes
[141] - This is the real number of patients analyzed.
[142] - This is the real number of patients analyzed.
[143] - This is the real number of patients analyzed.
[144] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Daily PEF variability - Change from Run-in period to End-of-treatment period

Top of page

End point title

Daily PEF variability - Change from Run-in period to End-of-treatment period

End point description

End point type

Secondary

End point timeframe

Morning and evening PEF was measured daily at home. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the change from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	67 ^[145]	76 ^[146]	69 ^[147]	68 ^[148]
Units: L/min
arithmetic mean (standard deviation)	-2.18 ( 8.13 )	-1.76 ( 8.92 )	-3.21 ( 8.26 )	-2.54 ( 8.25 )

Notes
[145] - This is the real number of patients analyzed.
[146] - This is the real number of patients analyzed.
[147] - This is the real number of patients analyzed.
[148] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

other ^[149]

P-value

= 0.488

Method

ANCOVA

Parameter type

Leats square means difference

Point estimate

-0.644

Confidence interval

level

95%

sides

2-sided

lower limit

-2.467

upper limit

1.18

Notes
[149] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

other ^[150]

P-value

= 0.092

Method

ANCOVA

Parameter type

Leats square means difference

Point estimate

-1.599

Confidence interval

level

95%

sides

2-sided

lower limit

-3.464

upper limit

0.265

Notes
[150] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Daily PEF variability - Change from Run-in period to Overall treatment period

Top of page

End point title

Daily PEF variability - Change from Run-in period to Overall treatment period

End point description

End point type

Secondary

End point timeframe

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	91 ^[151]	91 ^[152]	97 ^[153]	98 ^[154]
Units: L/min
arithmetic mean (standard deviation)	-1.88 ( 7.15 )	-1.76 ( 6.7 )	-2.08 ( 7.09 )	-2.28 ( 6.74 )

Notes
[151] - This is the real number of patients analyzed.
[152] - This is the real number of patients analyzed.
[153] - This is the real number of patients analyzed.
[154] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

other ^[155]

P-value

= 0.559

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.366

Confidence interval

level

95%

sides

2-sided

lower limit

-1.598

upper limit

0.866

Notes
[155] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other ^[156]

P-value

= 0.98

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-1.175

upper limit

1.204

Notes
[156] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm A

Comparison groups

Arm C - ITT population v Arm A - ITT population

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority ^[157]

P-value

= 0.151

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.887

Confidence interval

level

95%

sides

2-sided

lower limit

-2.099

upper limit

0.326

Notes
[157] - Within-treatment comparison in the change from Run-in period to End-of-treatment period was performed using the same ANCOVA model as for the primary efficacy analysis.

Secondary: Morning Asthma Symptom Score - Run-in period

Top of page

End point title

Morning Asthma Symptom Score - Run-in period

End point description

The asthma symptom scores were recorded with a portable peak flow meter twice daily in the morning and in the evening, before PEF measurements.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the Run-in period are reported here.

End point values	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population	Arm A - Safety population
Number of subjects analysed	169 ^[158]	167 ^[159]	168 ^[160]	171 ^[161]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	3.11 ( 2.19 )	3.34 ( 2.14 )	3.27 ( 2.22 )	3.31 ( 2.29 )

Notes
[158] - This is the real number of patients analyzed.
[159] - This is the real number of patients analyzed.
[160] - This is the real number of patients analyzed.
[161] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Morning Asthma Symptom Score - End-of-treatment period

Top of page

End point title

Morning Asthma Symptom Score - End-of-treatment period

End point description

The asthma symptom scores were recorded with a portable peak flow meter twice daily in the morning and in the evening, before PEF measurements. End-of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	161 ^[162]	158 ^[163]	158 ^[164]	160 ^[165]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	1.93 ( 2.23 )	2.12 ( 2.45 )	1.74 ( 2.3 )	1.94 ( 2.29 )

Notes
[162] - This is the real number of patients analyzed.
[163] - This is the real number of patients analyzed.
[164] - This is the real number of patients analyzed.
[165] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Morning Asthma Symptom Score - Overall treatment period

Top of page

End point title

Morning Asthma Symptom Score - Overall treatment period

End point description

The asthma symptom scores were recorded with the above described portable peak flow meter twice daily in the morning and in the evening, before PEF measurements. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	171 ^[166]	168 ^[167]	175 ^[168]	171 ^[169]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	2.12 ( 1.99 )	2.31 ( 2.21 )	2.03 ( 2.19 )	2.22 ( 2.1 )

Notes
[166] - This is the real number of patients analyzed.
[167] - This is the real number of patients analyzed.
[168] - This is the real number of patients analyzed.
[169] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Morning Asthma Symptom Score - Change from Run-in period to End-of-treatment period

Top of page

End point title

Morning Asthma Symptom Score - Change from Run-in period to End-of-treatment period

End point description

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Change in the scores from Run-in period to the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	159 ^[170]	156 ^[171]	153 ^[172]	159 ^[173]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	-1.18 ( 2.23 )	-1.16 ( 2.23 )	-1.59 ( 2.08 )	-1.37 ( 2.22 )

Notes
[170] - This is the real number of patients analyzed.
[171] - This is the real number of patients analyzed.
[172] - This is the real number of patients analyzed.
[173] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

other ^[174]

P-value

= 0.632

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.101

Confidence interval

level

95%

sides

2-sided

lower limit

-0.517

upper limit

0.314

Notes
[174] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other ^[175]

P-value

= 0.24

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.667

upper limit

0.167

Notes
[175] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Morning Asthma Symptom Score - Change from Run-in period to Overall treatment period

Top of page

End point title

Morning Asthma Symptom Score - Change from Run-in period to Overall treatment period

End point description

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Change in the scores from Run-in period to the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	169 ^[176]	165 ^[177]	168 ^[178]	170 ^[179]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	-0.96 ( 1.81 )	-1.04 ( 1.87 )	-1.38 ( 1.8 )	-1.12 ( 1.94 )

Notes
[176] - This is the real number of patients analyzed.
[177] - This is the real number of patients analyzed.
[178] - This is the real number of patients analyzed.
[179] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm B - ITT population v Arm A - ITT population

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

other ^[180]

P-value

= 0.962

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.008

Confidence interval

level

95%

sides

2-sided

lower limit

-0.341

upper limit

0.325

Notes
[180] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm D - ITT population v Arm C - ITT population

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

other ^[181]

P-value

= 0.101

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.276

Confidence interval

level

95%

sides

2-sided

lower limit

-0.607

upper limit

0.054

Notes
[181] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Evening Asthma Symptom Score - Run-in period

Top of page

End point title

Evening Asthma Symptom Score - Run-in period

End point description

The asthma symptom scores were recorded with a portable peak flow meter twice daily in the morning and in the evening, before PEF measurements.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[182]	161 ^[183]	162 ^[184]	163 ^[185]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	3.44 ( 2.22 )	3.55 ( 2.18 )	3.4 ( 2.3 )	3.59 ( 2.15 )

Notes
[182] - This is the real number of patients analyzed.
[183] - This is the real number of patients analyzed.
[184] - This is the real number of patients analyzed.
[185] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Evening Asthma Symptom Score - End-of-treatment period

Top of page

End point title

Evening Asthma Symptom Score - End-of-treatment period

End point description

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	158 ^[186]	152 ^[187]	156 ^[188]	152 ^[189]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	2.08 ( 2.26 )	2.21 ( 2.41 )	1.91 ( 2.43 )	2.12 ( 2.45 )

Notes
[186] - This is the real number of patients analyzed.
[187] - This is the real number of patients analyzed.
[188] - This is the real number of patients analyzed.
[189] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Evening Asthma Symptom score - Overall treatment period

Top of page

End point title

Evening Asthma Symptom score - Overall treatment period

End point description

The asthma symptom scores were recorded with a portable peak flow meter twice daily in the morning and in the evening, before PEF measurements. Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Scores for the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	171 ^[190]	171 ^[191]	174 ^[192]	171 ^[193]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	2.32 ( 2.01 )	2.46 ( 2.2 )	2.15 ( 2.18 )	2.35 ( 2.16 )

Notes
[190] - This is the real number of patients analyzed.
[191] - This is the real number of patients analyzed.
[192] - This is the real number of patients analyzed.
[193] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Evening Asthma Symptoms score - Change from Run-in period to End-of-treatment period

Top of page

End point title

Evening Asthma Symptoms score - Change from Run-in period to End-of-treatment period

End point description

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Change in the scores from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	154 ^[194]	148 ^[195]	149 ^[196]	147 ^[197]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	-1.31 ( 2.24 )	-1.28 ( 2.15 )	-1.68 ( 2.18 )	-1.48 ( 2.53 )

Notes
[194] - This is the real number of patients analyzed.
[195] - This is the real number of patients analyzed.
[196] - This is the real number of patients analyzed.
[197] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.665

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.097

Confidence interval

level

95%

sides

2-sided

lower limit

-0.535

upper limit

0.341

Arm C vs Arm D

Comparison groups

Arm D - ITT population v Arm C - ITT population

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.312

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.228

Confidence interval

level

95%

sides

2-sided

lower limit

-0.671

upper limit

0.215

Secondary: Evening Asthma Symptom score - Change from Run-in period to Overall treatment period

Top of page

End point title

Evening Asthma Symptom score - Change from Run-in period to Overall treatment period

End point description

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Change in the scores from the Run-in period to the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	167 ^[198]	161 ^[199]	162 ^[200]	162 ^[201]
Units: integer from 0 to 3
arithmetic mean (standard deviation)	-1.11 ( 1.81 )	-1.1 ( 1.78 )	-1.36 ( 1.89 )	-1.28 ( 2.11 )

Notes
[198] - This is the real number of patients analyzed.
[199] - This is the real number of patients analyzed.
[200] - This is the real number of patients analyzed.
[201] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

other ^[202]

P-value

= 0.769

Method

ANCOVA

Parameter type

Leeast square means difference

Point estimate

-0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-0.393

upper limit

0.291

Notes
[202] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

other ^[203]

P-value

= 0.414

Method

ANCOVA

Parameter type

Leeast square means difference

Point estimate

-0.143

Confidence interval

level

95%

sides

2-sided

lower limit

-0.488

upper limit

0.201

Notes
[203] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm A

Comparison groups

Arm C - ITT population v Arm A - ITT population

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

superiority ^[204]

P-value

= 0.123

Method

ANCOVA

Parameter type

Leeast square means difference

Point estimate

-0.269

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

0.073

Notes
[204] - Within-treatment comparison in the change from Run-in period to End-of-treatment period was performed using the same ANCOVA model as for the primary efficacy analysis.

Arm D vs Arm B

Comparison groups

Arm B - ITT population v Arm D - ITT population

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority ^[205]

P-value

= 0.315

Method

ANCOVA

Parameter type

Leeast square means difference

Point estimate

-0.177

Confidence interval

level

95%

sides

2-sided

lower limit

-0.521

upper limit

0.168

Notes
[205] - Within-treatment comparison in the change from Run-in period to End-of-treatment period was performed using the same ANCOVA model as for the primary efficacy analysis.

Secondary: Asthma Control Questionnaire score - Baseline

Top of page

End point title

Asthma Control Questionnaire score - Baseline

End point description

End point type

Secondary

End point timeframe

At Visit 2 (Baseline) and Visit 5 (End of treatment) Data from Visit 2 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	173 ^[206]	173 ^[207]	176 ^[208]	172 ^[209]
Units: digit
arithmetic mean (standard deviation)	2.51 ( 0.56 )	2.44 ( 0.6 )	2.47 ( 0.58 )	2.52 ( 0.59 )

Notes
[206] - This is the real number of patients analyzed.
[207] - This is the real number of patients analyzed.
[208] - This is the real number of patients analyzed.
[209] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Asthma Control Questionnaire score - End of treatment

Top of page

End point title

Asthma Control Questionnaire score - End of treatment

End point description

End point type

Secondary

End point timeframe

At Visit 2 (Baseline) and Visit 5 (End of treatment) Data from Visit 5 are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	164 ^[210]	160 ^[211]	168 ^[212]	166 ^[213]
Units: digit
arithmetic mean (standard deviation)	1.43 ( 0.93 )	1.33 ( 0.98 )	1.24 ( 0.87 )	1.16 ( 0.84 )

Notes
[210] - This is the real number of patients analyzed.
[211] - This is the real number of patients analyzed.
[212] - This is the real number of patients analyzed.
[213] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Asthma Control Questionnaire score - Change from Baseline to End of treatment

Top of page

End point title

Asthma Control Questionnaire score - Change from Baseline to End of treatment

End point description

End point type

Secondary

End point timeframe

Asthma Control Questionnaire was administered at Visit 2 (Baseline) and Visit 5 (End of treatment) Change in score from Visit 2 (Baseline) to Visit 5 (End of treatment) is reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	164 ^[214]	160 ^[215]	168 ^[216]	166 ^[217]
Units: digit
arithmetic mean (standard deviation)	-1.08 ( 0.91 )	-1.08 ( 0.91 )	-1.24 ( 0.73 )	-1.36 ( 0.87 )

Notes
[214] - This is the real number of patients analyzed.
[215] - This is the real number of patients analyzed.
[216] - This is the real number of patients analyzed.
[217] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

other ^[218]

P-value

= 0.349

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.24

Notes
[218] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

other ^[219]

P-value

= 0.276

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.25

Notes
[219] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Asthma Control Days - Run-in period

Top of page

End point title

Asthma Control Days - Run-in period

End point description

Asthma control day was defined as a day with symptom score = 0 daytime and night, and no use of rescue medication.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Data from the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	162 ^[220]	157 ^[221]	157 ^[222]	160 ^[223]
Units: percentage
arithmetic mean (standard deviation)	7.29 ( 16.35 )	5.78 ( 12.69 )	6.09 ( 14.36 )	6.24 ( 14.28 )

Notes
[220] - This is the real number of patients analyzed.
[221] - This is the real number of patients analyzed.
[222] - This is the real number of patients analyzed.
[223] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Asthma Control days - End of Treatment period

Top of page

End point title

Asthma Control days - End of Treatment period

End point description

Asthma control day was defined as a day with symptom score = 0 daytime and night, and no use of rescue medication.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Data from the End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	138 ^[224]	144 ^[225]	141 ^[226]	140 ^[227]
Units: percentage
arithmetic mean (standard deviation)	26.22 ( 34.09 )	27.4 ( 34.77 )	33.63 ( 37.83 )	27.94 ( 35.56 )

Notes
[224] - This is the real number of patients analyzed.
[225] - This is the real number of patients analyzed.
[226] - This is the real number of patients analyzed.
[227] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Asthma Control days - Overall Treatment period

Top of page

End point title

Asthma Control days - Overall Treatment period

End point description

Asthma control day was defined as a day with symptom score = 0 daytime and night, and no use of rescue medication.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Data from the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	169 ^[228]	163 ^[229]	172 ^[230]	169 ^[231]
Units: percentage
arithmetic mean (standard deviation)	20.83 ( 28.53 )	22.16 ( 28.36 )	24.84 ( 30.23 )	21.13 ( 28.18 )

Notes
[228] - This is the real number of patients analyzed.
[229] - This is the real number of patients analyzed.
[230] - This is the real number of patients analyzed.
[231] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Asthma Control days - Change from Run-in period to End of Treatment period

Top of page

End point title

Asthma Control days - Change from Run-in period to End of Treatment period

End point description

The asthma symptom scores were recorded with a portable peak flow meter twice daily in the morning and in the evening, before PEF measurements.

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Changes from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	133 ^[232]	139 ^[233]	132 ^[234]	133 ^[235]
Units: percentage
arithmetic mean (standard deviation)	18.76 ( 30.49 )	21.22 ( 31.52 )	28.53 ( 35.02 )	21.82 ( 32.64 )

Notes
[232] - This is the real number of patients analyzed.
[233] - This is the real number of patients analyzed.
[234] - This is the real number of patients analyzed.
[235] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

272

Analysis specification

Pre-specified

Analysis type

other ^[236]

P-value

= 0.613

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-1.891

Confidence interval

level

95%

sides

2-sided

lower limit

-9.237

upper limit

5.455

Notes
[236] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[237]

P-value

= 0.119

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

5.91

Confidence interval

level

95%

sides

2-sided

lower limit

-1.52

upper limit

13.339

Notes
[237] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Asthma control days - Change from Run-in period to Overall Treatment period

Top of page

End point title

Asthma control days - Change from Run-in period to Overall Treatment period

End point description

Asthma control day was defined as a day with symptom score = 0 daytime and night, and no use of rescue medication

End point type

Secondary

End point timeframe

Daily before morning and evening PEF measurements. Changes from the Run-in period to the Overall Treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	160 ^[238]	151 ^[239]	155 ^[240]	158 ^[241]
Units: percentage
arithmetic mean (standard deviation)	13.99 ( 24.3 )	17.05 ( 24.95 )	19.27 ( 26.08 )	15.81 ( 25.39 )

Notes
[238] - This is the real number of patients analyzed.
[239] - This is the real number of patients analyzed.
[240] - This is the real number of patients analyzed.
[241] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

311

Analysis specification

Pre-specified

Analysis type

other ^[242]

P-value

= 0.205

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-3.461

Confidence interval

level

95%

sides

2-sided

lower limit

-8.819

upper limit

1.897

Notes
[242] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

other ^[243]

P-value

= 0.233

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

3.248

Confidence interval

level

95%

sides

2-sided

lower limit

-2.09

upper limit

8.585

Notes
[243] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm A

Comparison groups

Arm C - ITT population v Arm A - ITT population

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

superiority ^[244]

P-value

= 0.047

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

5.385

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

10.706

Notes
[244] - Within-treatment comparison in the change from Run-in period to Overall Treatment period was performed using the same ANCOVA model as for the primary efficacy analysis.

Arm D vs Arm B

Comparison groups

Arm D - ITT population v Arm B - ITT population

Number of subjects included in analysis

309

Analysis specification

Pre-specified

Analysis type

superiority ^[245]

P-value

= 0.629

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-1.323

Confidence interval

level

95%

sides

2-sided

lower limit

-6.694

upper limit

4.047

Notes
[245] - Within-treatment comparison in the change from Run-in period to Overall Treatment period was performed using the same ANCOVA model as for the primary efficacy analysis.

Secondary: Asthma exacerbations

Top of page

End point title

Asthma exacerbations

End point description

Moderate asthma exacerbations were defined as need for systemic corticosteroids and unscheduled medical visit, and severe asthma exacerbations were defined as emergency room attendance or hospitalisation (GINA definitions).

End point type

Secondary

End point timeframe

Throughout the study/At each visit

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	173 ^[246]	173 ^[247]	176 ^[248]	172 ^[249]
Units: number of events
Moderate	0	4	5	2
Severe	0	4	5	1

Notes
[246] - No subjects experienced asthma exacerbations.
[247] - Four subjects experienced moderate asthma exacerbations.
[248] - Five subjects experienced moderate asthma exacerbations.
[249] - Two/one subjects experienced moderate/severe asthma exacerbations.

No statistical analyses for this end point

Secondary: Use of rescue salbutamol - Run-in period

Top of page

End point title

Use of rescue salbutamol - Run-in period

End point description

End point type

Secondary

End point timeframe

Daily throughout the study. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Run-in period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[250]	169 ^[251]	169 ^[252]	171 ^[253]
Units: puffs/day
arithmetic mean (standard deviation)	1.66 ( 1.82 )	1.72 ( 2.12 )	1.58 ( 1.66 )	1.64 ( 1.67 )

Notes
[250] - This is the real number of patients analyzed.
[251] - This is the real number of patients analyzed.
[252] - This is the real number of patients analyzed.
[253] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Use of rescue salbutamol - End-of-treatment period

Top of page

End point title

Use of rescue salbutamol - End-of-treatment period

End point description

End.of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Daily trhoughout the study. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the End.of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	166 ^[254]	159 ^[255]	167 ^[256]	163 ^[257]
Units: puffs/day
arithmetic mean (standard deviation)	1.02 ( 1.9 )	0.83 ( 1.55 )	0.55 ( 1.03 )	0.74 ( 1.43 )

Notes
[254] - This is the real number of patients analyzed.
[255] - This is the real number of patients analyzed.
[256] - This is the real number of patients analyzed.
[257] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Use of rescue salbutamol - Overall treatment period

Top of page

End point title

Use of rescue salbutamol - Overall treatment period

End point description

Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Daily throughout the study. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for the Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	171 ^[258]	171 ^[259]	175 ^[260]	171 ^[261]
Units: puffs/day
arithmetic mean (standard deviation)	1.08 ( 1.56 )	0.99 ( 1.49 )	0.78 ( 1.39 )	0.9 ( 1.42 )

Notes
[258] - This is the real number of patients analyzed.
[259] - This is the real number of patients analyzed.
[260] - This is the real number of patients analyzed.
[261] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Use of rescue salbutamol - Change from Run-in period to End-of-treatment period

Top of page

End point title

Use of rescue salbutamol - Change from Run-in period to End-of-treatment period

End point description

End-of-treatment period is the last 14 days of treatment.

End point type

Secondary

End point timeframe

Daily throughout the study. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for change from Run-in period to End-of-treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	165 ^[262]	158 ^[263]	163 ^[264]	162 ^[265]
Units: puffs/day
arithmetic mean (standard deviation)	-0.66 ( 2.04 )	-0.94 ( 2.06 )	-1.03 ( 1.5 )	-0.95 ( 1.91 )

Notes
[262] - This is the real number of patients analyzed.
[263] - This is the real number of patients analyzed.
[264] - This is the real number of patients analyzed.
[265] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

other ^[266]

P-value

= 0.168

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.208

Confidence interval

level

95%

sides

2-sided

lower limit

-0.088

upper limit

0.503

Notes
[266] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

other ^[267]

P-value

= 0.39

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.129

Confidence interval

level

95%

sides

2-sided

lower limit

-0.424

upper limit

0.166

Notes
[267] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Use of rescue salbutamol - Change from Run-in period to Overall treatment period

Top of page

End point title

Use of rescue salbutamol - Change from Run-in period to Overall treatment period

End point description

Overall treatment period is from Day 1 to Last day of treatment.

End point type

Secondary

End point timeframe

Daily throughout the study. Data are available for the Run-in period and for 2-week periods over the 12-week treatment. Data for change from Run-in period to Overall treatment period are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[268]	169 ^[269]	169 ^[270]	170 ^[271]
Units: puffs/day
arithmetic mean (standard deviation)	-0.58 ( 1.77 )	-0.72 ( 1.84 )	-0.77 ( 1.61 )	-0.76 ( 1.69 )

Notes
[268] - This is the real number of patients analyzed.
[269] - This is the real number of patients analyzed.
[270] - This is the real number of patients analyzed.
[271] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

other ^[272]

P-value

= 0.518

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

0.088

Confidence interval

level

95%

sides

2-sided

lower limit

-0.179

upper limit

0.355

Notes
[272] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

other ^[273]

P-value

= 0.687

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-0.055

Confidence interval

level

95%

sides

2-sided

lower limit

-0.322

upper limit

0.212

Notes
[273] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Secondary: Patients Achieving the Level of 'Controlled' Asthma - Baseline

Top of page

End point title

Patients Achieving the Level of 'Controlled' Asthma - Baseline

End point description

End point type

Secondary

End point timeframe

At Baseline and at the End-of-treatment period. Data are available as number of patients and percentage. Number of patients with controlled asthma at Baseline are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	170 ^[274]	168 ^[275]	170 ^[276]	169 ^[277]
Units: number of patients	0	0	0	0

Notes
[274] - This is the real number of patients analyzed.
[275] - This is the real number of patients analyzed.
[276] - This is the real number of patients analyzed.
[277] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Patients Achieving the Level of 'Controlled' Asthma - End of treatment

Top of page

End point title

Patients Achieving the Level of 'Controlled' Asthma - End of treatment

End point description

End point type

Secondary

End point timeframe

At Baseline and at the End-of-treatment period. Data are available as number of patients and percentage. Number of patients achieving a total control of asthma at the End of treatment are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	156 ^[278]	151 ^[279]	160 ^[280]	156 ^[281]
Units: number of patients	15	22	13	16

Notes
[278] - This is the real number of patients analyzed.
[279] - This is the real number of patients analyzed.
[280] - This is the real number of patients analyzed.
[281] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Induced Sputum Eosinophils Count - Baseline

Top of page

End point title

Induced Sputum Eosinophils Count - Baseline

End point description

End point type

Secondary

End point timeframe

Induced sputum eosinophil count was performed locally in a subgroup of 48 patients (at Visiit 2 and Visit 5) at selected sites. Data for Visit 2 (Baseline, i.e. the last available value before first inhalation of study drug) are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	11 ^[282]	11 ^[283]	9 ^[284]	10 ^[285]
Units: percentage
arithmetic mean (standard deviation)	5 ( 5.85 )	5.36 ( 5.18 )	6.22 ( 8.01 )	7.6 ( 9.07 )

Notes
[282] - This is the real number of patients analyzed.
[283] - This is the real number of patients analyzed.
[284] - This is the real number of patients analyzed.
[285] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Induced sputum eosinophil count - End of treatment

Top of page

End point title

Induced sputum eosinophil count - End of treatment

End point description

End point type

Secondary

End point timeframe

Induced sputum eosinophil count was performed locally in a subgroup of 48 patients (at Visiit 2 and Visit 5) at selected sites. Data for Visit 5 (End of treatment, i.e. the last available post-baseline value) are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	10 ^[286]	10 ^[287]	7 ^[288]	10 ^[289]
Units: percentage
arithmetic mean (standard deviation)	4.4 ( 8.19 )	8.9 ( 14.44 )	8.14 ( 5.84 )	5 ( 11.73 )

Notes
[286] - This is the real number of patients analyzed.
[287] - This is the real number of patients analyzed.
[288] - This is the real number of patients analyzed.
[289] - This is the real number of patients analyzed.

No statistical analyses for this end point

Secondary: Induced sputum eosinophil cont - Change from Baseline to End of treatment

Top of page

End point title

Induced sputum eosinophil cont - Change from Baseline to End of treatment

End point description

End point type

Secondary

End point timeframe

Induced sputum eosinophil count was performed locally in a subgroup of 48 patients (at V2 and V5) at selected sites. Data for change from Baseline to End of treatment are reported here.

End point values	Arm A - ITT population	Arm B - ITT population	Arm C - ITT population	Arm D - ITT population
Number of subjects analysed	10 ^[290]	10 ^[291]	7 ^[292]	8 ^[293]
Units: percentage
arithmetic mean (standard deviation)	-0.9 ( 11.47 )	3 ( 15.54 )	0.71 ( 8.73 )	-0.63 ( 16.24 )

Notes
[290] - This is the real number of patients analyzed.
[291] - This is the real number of patients analyzed.
[292] - This is the real number of patients analyzed.
[293] - This is the real number of patients analyzed.

Arm A vs Arm B

Comparison groups

Arm A - ITT population v Arm B - ITT population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[294]

P-value

= 0.576

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

-3.15

Confidence interval

level

95%

sides

2-sided

lower limit

-14.56

upper limit

8.26

Notes
[294] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Arm C vs Arm D

Comparison groups

Arm C - ITT population v Arm D - ITT population

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[295]

P-value

= 0.818

Method

ANCOVA

Parameter type

Least square means difference

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-10.97

upper limit

13.78

Notes
[295] - Comparisons between treatments were done using the same ANCOVA model as for the primary analysis without testing for non-inferiority.

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were assessed at Weeks –2 (run in, Visit 1), 0 ( Visit 2), 4 ( Visit 3), 8 ( Visit 4), and 12 (Visit 5) , and at Week 14 by phone call.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

11.1

Reporting group title

Arm A - Safety analysis

Reporting group description

All subjects randomised to treatment with CHF 1535 NEXT DPI®, 1 inhalation bid (daily dose: BDP 200 μg/FF 12 μg) + placebo pMDI, 1 inhalation bid who took at least one dose of study medication.

Reporting group title

Arm B - Safety analysis

Reporting group description

All subjects randomised to treatment with CHF 1535 pMDI, 1 inhalation bid (daily dose: BDP 200 μg/FF 12 μg) + placebo NEXT DPI®, 1 inhalation bid who took at least one dose of study medication.

Reporting group title

Arm C - Safety analysis

Reporting group description

All subjects randomised to treatment with CHF 1535 NEXT DPI®, 2 inhalations bid (daily dose: BDP 400 μg/FF 24 μg) + placebo pMDI, 2 inhalations bid who took at least one dose of study medication.

Reporting group title

Arm D - Safety analysis

Reporting group description

All subjects randomised to treatment with CHF 1535 pMDI, 2 inhalations bid (daily dose: BDP 400 μg/FF 24 μg) + placebo NEXT DPI®, 2 inhalations bid who took at least one dose of study medication.

Serious adverse events	Arm A - Safety analysis	Arm B - Safety analysis	Arm C - Safety analysis	Arm D - Safety analysis
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	0 / 177 (0.00%)	1 / 173 (0.58%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Reproductive system and breast disorders
Uterine polyp
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Hepatitis B
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.1%

Non-serious adverse events	Arm A - Safety analysis	Arm B - Safety analysis	Arm C - Safety analysis	Arm D - Safety analysis
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 172 (35.47%)	65 / 173 (37.57%)	56 / 177 (31.64%)	62 / 173 (35.84%)
Vascular disorders
Hypertension
subjects affected / exposed	3 / 172 (1.74%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	3	1	0	0
Circulatory collapse
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Hyperthermia
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	3 / 173 (1.73%)
occurrences all number	1	0	0	3
Asthenia
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	0	1	1
Chest pain
subjects affected / exposed	2 / 172 (1.16%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	3	0	0	0
Fatigue
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	0	1	1
Chest discomfort
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Irritability
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Oedema peripheral
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Prostatitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 172 (1.16%)	2 / 173 (1.16%)	6 / 177 (3.39%)	3 / 173 (1.73%)
occurrences all number	2	2	6	3
Dysphonia
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	3 / 173 (1.73%)
occurrences all number	0	1	0	3
Throat irritation
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	2 / 177 (1.13%)	1 / 173 (0.58%)
occurrences all number	0	1	2	2
Bronchospasm
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Nasal congestion
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Rhinitis allergic
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	16 / 172 (9.30%)	20 / 173 (11.56%)	13 / 177 (7.34%)	12 / 173 (6.94%)
occurrences all number	22	20	13	14
Blood glucose increased
subjects affected / exposed	3 / 172 (1.74%)	5 / 173 (2.89%)	3 / 177 (1.69%)	4 / 173 (2.31%)
occurrences all number	3	5	3	4
Electrocardiogram T wave abnormal
subjects affected / exposed	3 / 172 (1.74%)	2 / 173 (1.16%)	1 / 177 (0.56%)	5 / 173 (2.89%)
occurrences all number	3	3	1	5
Blood cortisol decreased
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 172 (1.16%)	1 / 173 (0.58%)	2 / 177 (1.13%)	2 / 173 (1.16%)
occurrences all number	2	1	2	2
Blood triglycerides increased
subjects affected / exposed	0 / 172 (0.00%)	2 / 173 (1.16%)	3 / 177 (1.69%)	2 / 173 (1.16%)
occurrences all number	0	2	3	2
Gamma-glutamyl transferase increased
subjects affected / exposed	0 / 172 (0.00%)	4 / 173 (2.31%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	4	1	1
Blood potassium increased
subjects affected / exposed	1 / 172 (0.58%)	3 / 173 (1.73%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	1	3	0	1
Cortisol free urine decreased
subjects affected / exposed	3 / 172 (1.74%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	3	0	1	1
Cortisol free urine increased
subjects affected / exposed	0 / 172 (0.00%)	2 / 173 (1.16%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	2	0	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	0	1	1
Creatinine urine increased
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	1	0	1	0
Blood cholesterol increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Electrocardiogram normal
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Electrocardiogram poor r-wave progression
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Electrocardiogram Q wave abnormal
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Urea urine increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
White blood cell count increased
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Arthropod sting
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Concussion
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Contusion
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Joint dislocation
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Postoperative fever
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	2 / 172 (1.16%)	1 / 173 (0.58%)	1 / 177 (0.56%)	9 / 173 (5.20%)
occurrences all number	3	2	1	10
Tachycardia
subjects affected / exposed	0 / 172 (0.00%)	2 / 173 (1.16%)	2 / 177 (1.13%)	0 / 173 (0.00%)
occurrences all number	0	2	2	0
Bradycardia
subjects affected / exposed	1 / 172 (0.58%)	2 / 173 (1.16%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	2	0	0
Bundle branch block
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	2 / 173 (1.16%)
occurrences all number	0	0	1	2
Bundle branch block right
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	2 / 173 (1.16%)
occurrences all number	1	0	0	2
Synus arrhytmia
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	1	0	1	1
Angina pectoris
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	2 / 177 (1.13%)	0 / 173 (0.00%)
occurrences all number	0	0	2	0
Atrioventricular block first degree
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	0	1	1
Sinus tachycardia
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	1	1	0
Bundle branch block left
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Myocardial ischaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Supraventricular extrasystoles
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 172 (1.74%)	4 / 173 (2.31%)	2 / 177 (1.13%)	4 / 173 (2.31%)
occurrences all number	3	6	4	4
Tremor
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	7 / 177 (3.95%)	0 / 173 (0.00%)
occurrences all number	0	0	7	0
Dizziness
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	2 / 173 (1.16%)
occurrences all number	0	0	1	2
Syncope
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Eye disorders
Conjunctivitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	2 / 177 (1.13%)	0 / 173 (0.00%)
occurrences all number	1	0	3	0
Abdominal pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	2 / 173 (1.16%)
occurrences all number	0	0	0	2
Abdominal pain upper
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	1	0	0
Food poisoning
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	2 / 177 (1.13%)	0 / 173 (0.00%)
occurrences all number	0	0	2	0
Aphthous stomatitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Diarrhoea
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Dry mouth
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Dyspepsia
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Enteritis
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Toothache
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Vomiting
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Hepatitis toxic
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Liver disorder
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Eczema
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Rash
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Urticaria
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	1	1	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 172 (2.91%)	3 / 173 (1.73%)	7 / 177 (3.95%)	5 / 173 (2.89%)
occurrences all number	5	3	7	6
Respiratory tract infection
subjects affected / exposed	2 / 172 (1.16%)	1 / 173 (0.58%)	3 / 177 (1.69%)	1 / 173 (0.58%)
occurrences all number	2	1	3	1
Rhinitis
subjects affected / exposed	0 / 172 (0.00%)	5 / 173 (2.89%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	6	1	0
Respiratory tract infection viral
subjects affected / exposed	2 / 172 (1.16%)	1 / 173 (0.58%)	0 / 177 (0.00%)	2 / 173 (1.16%)
occurrences all number	2	1	0	2
Bronchitis
subjects affected / exposed	1 / 172 (0.58%)	2 / 173 (1.16%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	1	2	0	1
Acute sinusitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	2 / 177 (1.13%)	1 / 173 (0.58%)
occurrences all number	0	0	2	1
Pharyngitis
subjects affected / exposed	2 / 172 (1.16%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	3	0	0	1
Tracheobronchitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 173 (1.16%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	3	0	1
Acute tonsillitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	1	0	1
Bronchitis bacterial
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	1	0	1	0
Gastroenteristis
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	1	0	0
Cystitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Ear infection
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Infected cyst
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Influenza
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Oral herpes
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Pharyngotonsillitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Rhinotracheitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	0	0	1
Urinary tract infection
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Viral rhinitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	0	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 172 (0.58%)	0 / 173 (0.00%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	0	0	0
Metabolism and nutrition disorders
Hyperglycemia
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	2 / 177 (1.13%)	1 / 173 (0.58%)
occurrences all number	1	1	2	1
Hypertriglyceridaemia
subjects affected / exposed	2 / 172 (1.16%)	0 / 173 (0.00%)	2 / 177 (1.13%)	0 / 173 (0.00%)
occurrences all number	2	0	2	0
Diabetes mellitus
subjects affected / exposed	1 / 172 (0.58%)	1 / 173 (0.58%)	0 / 177 (0.00%)	0 / 173 (0.00%)
occurrences all number	1	1	0	0
Glucose tolerance impaired
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	1 / 173 (0.58%)
occurrences all number	0	0	1	1
Hypercholesterolaemia
subjects affected / exposed	0 / 172 (0.00%)	1 / 173 (0.58%)	0 / 177 (0.00%)	1 / 173 (0.58%)
occurrences all number	0	1	0	2
Hyperkalaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 172 (0.00%)	0 / 173 (0.00%)	1 / 177 (0.56%)	0 / 173 (0.00%)
occurrences all number	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

08 Jul 2008

To substitute the CRO in charge of monitoring, the central laboratory being used for this trial and other minor changes surrounding the Interactive Voice Response System.

16 Jan 2009

The aim of this amendment is to clarify several aspects in the conduct of the CCD-0705-PR-0027 Next DPI protocol

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.

There are no limitation or caveats applicable to this summary of results

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - ITT population

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - ITT population

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - PP population

Primary: Change in Pre-Dose FEV1 from Baseline to End of Treatment - PP population

Secondary: Pre-dose FEV1 at Visit 2

Secondary: Pre-dose FEV1 at Visit 2

Secondary: Pre-dose FEV1 at Visit 3

Secondary: Pre-dose FEV1 at Visit 3

Secondary: Pre-dose FEV1 at Visit 4

Secondary: Pre-dose FEV1 at Visit 4

Secondary: Pre-dose FEV1 at Visit 5

Secondary: Pre-dose FEV1 at Visit 5

Secondary: Post-dose FEV1 AUC0-8 h at Visit 2

Secondary: Post-dose FEV1 AUC0-8 h at Visit 2

Secondary: Post-dose FEV1 AUC0-8 h at Visit 5

Secondary: Post-dose FEV1 AUC0-8 h at Visit 5

Secondary: Pre-dose FVC at Visit 2

Secondary: Pre-dose FVC at Visit 2

Secondary: Pre-dose FVC at Visit 3

Secondary: Pre-dose FVC at Visit 3

Secondary: Pre-dose FVC at Visit 4

Secondary: Pre-dose FVC at Visit 4

Secondary: Pre-dose FVC at Visit 5

Secondary: Pre-dose FVC at Visit 5

Secondary: Change in Pre-Dose FVC from Baseline to End of Treatment

Secondary: Change in Pre-Dose FVC from Baseline to End of Treatment

Secondary: Pre-dose FEF25-75% at Visit 2

Secondary: Pre-dose FEF25-75% at Visit 2

Secondary: Pre-dose FEF25-75% at Visit 3

Secondary: Pre-dose FEF25-75% at Visit 3

Secondary: Pre-dose FEF25-75% at Visit 4

Secondary: Pre-dose FEF25-75% at Visit 4

Secondary: Pre-dose FEF25-75% at Visit 5

Secondary: Pre-dose FEF25-75% at Visit 5

Secondary: Change in Pre-Dose FEF25-75% from Baseline to End of Treatment

Secondary: Change in Pre-Dose FEF25-75% from Baseline to End of Treatment

Secondary: Post-dose FVC AUC0-8 h at Visit 2

Secondary: Post-dose FVC AUC0-8 h at Visit 2

Secondary: Post-dose FVC AUC0-8 h at Visit 5

Secondary: Post-dose FVC AUC0-8 h at Visit 5

Secondary: Pre-dose morning PEF - Run-in period

Secondary: Pre-dose morning PEF - Run-in period

Secondary: Pre-dose morning PEF - End-of-treatment period

Secondary: Pre-dose morning PEF - End-of-treatment period

Secondary: Pre-dose morning PEF - Overall treatment period

Secondary: Pre-dose morning PEF - Overall treatment period

Secondary: Pre-dose morning PEF - Change from Run-in period to End-of-treatment period

Secondary: Pre-dose morning PEF - Change from Run-in period to End-of-treatment period

Secondary: Pre-dose morning PEF - Change from Run-in periodo to Overall treatment period

Secondary: Pre-dose morning PEF - Change from Run-in periodo to Overall treatment period

Secondary: Pre-dose evening PEF - Run-in period

Secondary: Pre-dose evening PEF - Run-in period

Secondary: Pre-dose evening PEF - End-of-treatment period

Secondary: Pre-dose evening PEF - End-of-treatment period

Secondary: Pre-dose evening PEF - Overall treatment period

Secondary: Pre-dose evening PEF - Overall treatment period

Secondary: Pre-dose evening PEF - Change from Run-in period to End-of-treatment period

Secondary: Pre-dose evening PEF - Change from Run-in period to End-of-treatment period

Secondary: Pre-dose evening PEF - Change from Run-in period to Overall treatment period

Secondary: Pre-dose evening PEF - Change from Run-in period to Overall treatment period

Secondary: Daily PEF variability - Run-in period

Secondary: Daily PEF variability - Run-in period

Secondary: Daily PEF variability - End-of-treatment period

Secondary: Daily PEF variability - End-of-treatment period

Secondary: Daily PEF variability - Overall treatment period

Secondary: Daily PEF variability - Overall treatment period

Secondary: Daily PEF variability - Change from Run-in period to End-of-treatment period

Secondary: Daily PEF variability - Change from Run-in period to End-of-treatment period

Secondary: Daily PEF variability - Change from Run-in period to Overall treatment period

Secondary: Daily PEF variability - Change from Run-in period to Overall treatment period

Secondary: Morning Asthma Symptom Score - Run-in period