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Clinical Trial Results:
A 52-week, double blind, double dummy, randomized, multinational, multicentre, 3-arm parallel group, active controlled clinical trial of fixed combination of beclometasone dipropionate plus formoterol fumarate plus glycopyrrolate bromide administered via pMDI (CHF 5993) versus tiotropium bromide and versus fixed combination of beclometasone dipropionate plus formoterol fumarate administered via pMDI and tiotropium bromide in patients with chronic obstructive pulmonary disease

Summary
EudraCT number	2013-000063-91
Trial protocol	HU IT GB SK BG PL HR
Global end of trial date	18 Mar 2016

Results information
Results version number	v1(current)
This version publication date	14 Apr 2017
First version publication date	14 Apr 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-1208-PR-0090

ISRCTN number

US NCT number

NCT01911364

WHO universal trial number (UTN)

Other trial identifiers

TRINITY: Trinity

Sponsor organisation name

Chiesi Farmaceutici S.p.A.

Sponsor organisation address

Via Palermo 26/A, Parma, Italy, 43122

Public contact

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com

Scientific contact

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

11 Jul 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

Primary objective: Demonstrate superiority of CHF 5993 pMDI over tiotropium in terms of moderate and severe COPD exacerbation rate over 52 weeks of treatment. Key secondary objectives: Demonstrate superiority of CHF 5993 pMDI over Tiotropium in terms of pulmonary function (change from baseline in pre-dose morning forced expiratory volume in the 1st second [FEV1] at Week 52); Demonstrate non-inferiority of CHF 5993 pMDI relative to CHF 1535 pMDI + Tiotropium in terms of pulmonary function (change from baseline in pre-dose morning FEV1 at Week 52). CHF 5993=Fixed combination of BDP and FF and GB CHF 1535=Fixed combination of BDP and FF BDP=Beclometasone dipropionate FF=Formoterol fumarate GB=Glycopyrronium bromide pMDI=Pressurised metered dose inhaler

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices (GCP) guidelines, and national legal requirements. At all visits, from screening onwards, concomitant medication, AEs and vital signs were recorded, COPD exacerbations were assessed, pre-dose spirometry (including inspiratory capacity [IC], FEV1 and forced vital capacity [FVC]), and physical examinations were carried out. From screening, the electronic diary (eDiary) was completed to record rescue medication use, compliance with treatment and EXAcerbations of Chronic pulmonary disease Tool (EXACT)-Patient-Reported Outcome (PRO) questionnaire. Furthermore, 12-lead electrocardiogram (ECG) parameters: heart rate (HR), Fridericia-corrected QT interval (QTcF), PR interval (PR), and QRS interval (QRS) were evaluated at screening, week 26, and week 52 of treatment. At screening, 12-lead ECG measurements were done pre-bronchodilator, while at week 26, and week 52, they were done pre-dose and 10 minutes post-dose.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 275

Country: Number of subjects enrolled

Romania: 219

Country: Number of subjects enrolled

Russian Federation: 658

Country: Number of subjects enrolled

Slovakia: 48

Country: Number of subjects enrolled

Turkey: 60

Country: Number of subjects enrolled

Ukraine: 816

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Argentina: 50

Country: Number of subjects enrolled

Belarus: 65

Country: Number of subjects enrolled

Bulgaria: 181

Country: Number of subjects enrolled

Croatia: 18

Country: Number of subjects enrolled

Germany: 143

Country: Number of subjects enrolled

Hungary: 126

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Mexico: 12

Worldwide total number of subjects

2691

EEA total number of subjects

1030

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1500

From 65 to 84 years

1188

85 years and over

Subject disposition

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Recruitment details

Overall, 3433 patients were screened according to inclusion and exclusion criteria; of these, 2691 patients were randomized.

Screening details

At the screening visit, inclusion/exclusion criteria were assessed. The screening visit was followed by a 2-week, open-label, run-in period during which patients self-administered Tiotropium (18μg daily) as 1 capsule once daily.

Period 1 title

Treatment period (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

Interactive Response Technology (IRT) was used to assign study medication kits to have an inventory control and patient dosing tracking. The IRT maintained quantities, kit numbers, drug types,batch/code number, expiration dates and it monitored inventory levels at all sites and managed the drug re-supply. Double dummy design of the study was ensured; patients randomised to CHF 5993 pMDI received Tiotropium matched placebo and patients randomised to Tiotropium received pMDI placebo.

Are arms mutually exclusive

Yes

Treatment A: CHF 5993 pMDI (100/6/12.5μg)

Arm description

Arm type

Experimental

Investigational medicinal product name

CHF 5993 pMDI (100/6/12.5μg)

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

Test product: CHF 5993 pMDI, fixed-dose combination of BDP + FF + GB. Dose: BDP 100 μg, FF 6 μg, GB 12.5 μg per actuation, 2 puffs, bid. Total daily dose: BDP 400 μg, FF 24 μg, GB 50 μg. Mode of administration: pMDI using a standard actuator. If patients inhaled their usual COPD pMDI medications with a spacer device, they were provided with the AeroChamber Plus™ Flow-Vu antistatic valved holding chamber (simply referred to as AeroChamber Plus™) to be used when taking the pMDI study treatments. CHF 5993=Fixed combination of BDP and FF and GB BDP=Beclometasone dipropionate bid=Twice daily FF=Formoterol fumarate GB=Glycopyrronium bromide pMDI=Pressurised metered dose inhaler

Treatment B: Tiotropium (18µg)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Tiotropium (18µg)

Investigational medicinal product code

Other name

Spiriva®, Tiotropium bromide

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Reference product: Tiotropium Bromide (Spiriva®) inhalation powder, hard capsule. Dose: 18 μg per capsule, one capsule, once daily. Total daily dose: 18 μg. Mode of administration: Dry powder inhaler, HandiHaler® inhaler.

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Arm description

Arm type

Active comparator

Investigational medicinal product name

CHF 1535 pMDI (100/6µg)

Investigational medicinal product code

Other name

Foster®

Pharmaceutical forms

Pressurised inhalation, solution

Routes of administration

Inhalation use

Dosage and administration details

Reference product: CHF 1535 pMDI, FDC of BDP + FF Dose: BDP 100 μg, FF 6 μg per actuation, 2 puffs, bid Total daily dose: BDP 400 μg, FF 24 μg Mode of administration: pMDI (for CHF 1535), using a standard actuator. If patients inhaled their usual COPD pMDI medications with a spacer device, they were provided with the AeroChamber Plus™ to be used when taking the pMDI study treatments. CHF 1535=Fixed combination of BDP and FF BDP = Beclometasone dipropionate bid=Twice daily FF=Formoterol fumarate pMDI=Pressurised metered dose inhaler

Investigational medicinal product name

Tiotropium (18µg)

Investigational medicinal product code

Other name

Spiriva®, Tiotropium bromide

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Number of subjects in period 1	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Started	1078	1075	538
Completed	986	914	496
Not completed	92	161	42
Consent withdrawn by subject	49	92	19
Adverse event, non-fatal	13	26	5
Protocol violation	2	1	3
Death	19	29	8
Other	1	1	-
Lost to follow-up	7	2	5
Lack of efficacy	1	10	2

Baseline characteristics

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Reporting group title

Treatment A: CHF 5993 pMDI (100/6/12.5μg)

Reporting group description

Reporting group title

Treatment B: Tiotropium (18µg)

Reporting group description

Reporting group title

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Reporting group description

Reporting group values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)	Total
Number of subjects	1078	1075	538	2691
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	594	600	306	1500
From 65-84 years	482	475	231	1188
85 years and over	2	0	1	3
Age continuous
Units: years
arithmetic mean (standard deviation)	63.4 ( 8.7 )	63.3 ( 8.4 )	62.6 ( 8.9 )	-
Gender categorical
Units: Subjects
Female	249	246	140	635
Male	829	829	398	2056
Race
Units: Subjects
Black or African American	1	0	0	1
White	1068	1070	533	2671
Other	9	5	5	19

End points

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Reporting group title

Treatment A: CHF 5993 pMDI (100/6/12.5μg)

Reporting group description

Reporting group title

Treatment B: Tiotropium (18µg)

Reporting group description

Reporting group title

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Reporting group description

Primary: 1_Moderate and severe COPD exacerbation rate over 52 weeks of treatment, CHF 5993 vs Tiotropium

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End point title

1_Moderate and severe COPD exacerbation rate over 52 weeks of treatment, CHF 5993 vs Tiotropium

End point description

Rate of moderate or severe COPD exacerbation. Evaluate the rate of moderate or severe COPD exacerbation over 52 weeks of treatment. Data are presented as Adjusted Exacerbation Rate per Patient per Year (95% CI). Shown are the number of subjects included in the model and the number of subjects with available results. A COPD exacerbation was defined as treated with systemic corticosteroids if this treatment was recorded. COPD=Chronic obstructive pulmonary disease

End point type

Primary

End point timeframe

Baseline to Week 52 (entire treatment period).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[1]	1074 ^[2]	538 ^[3]
Units: exacerbation/patient/year
number (confidence interval 95%)	0.457 (0.412 to 0.508)	0.571 (0.517 to 0.632)	0.452 (0.389 to 0.524)

Notes
[1] - ITT population
[2] - ITT population
[3] - ITT population

1_Adj rate ratio mod & sev exacerbations; A vs B

Statistical analysis description

Adjusted rate ratio for moderate and severe exacerbations. Primary efficacy analysis.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.003

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.801

Confidence interval

level

95%

sides

2-sided

lower limit

0.693

upper limit

0.925

Notes
[4] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset. Superiority of CHF 5993 pMDI over Tiotropium was demonstrated by a statistically significant adjusted rate ratio (defined as p<0.05) favouring CHF 5993 pMDI.

2_Adj rate ratio mod & sev exacerbations; A vs C

Statistical analysis description

Adjusted rate ratio for moderate and severe exacerbations. Secondary efficacy analysis.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.887

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

1.013

Confidence interval

level

95%

sides

2-sided

lower limit

0.846

upper limit

1.214

Notes
[5] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset.

3_Adj rate ratio mod & sev exacerbations; C vs B

Statistical analysis description

Adjusted rate ratio for moderate and severe exacerbations. Secondary efficacy analysis.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.01

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.661

upper limit

0.944

Notes
[6] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset.

Secondary: 2_Change from baseline in pre-dose morning FEV1 at week 52

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End point title

2_Change from baseline in pre-dose morning FEV1 at week 52

End point description

Key secondary endpoint. Change from baseline in pre-dose morning FEV1, at Week 52. FEV1=Forced expiratory volume in the 1st second. It is the volume of air that can be forced out in one second after taking a deep breath.

End point type

Secondary

End point timeframe

Baseline to Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	985 ^[7]	921 ^[8]	495 ^[9]
Units: litre(s)
least squares mean (confidence interval 95%)	0.082 (0.065 to 0.1)	0.021 (0.003 to 0.039)	0.085 (0.061 to 0.11)

Notes
[7] - ITT population, available for change from baseline
[8] - ITT population, available for change from baseline
[9] - ITT population, available for change from baseline

1_Adj mean difference between treatment; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1906

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.061

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.086

Notes
[10] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. Superiority of CHF 5993 pMDI over Tiotropium was demonstrated by a statistically significant adjusted mean difference between treatments favouring CHF 5993 pMDI.

2_Adj mean difference between treatments; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. Non-inferiority of CHF 5993 pMDI relative to CHF 1535 pMDI + Tiotropium was demonstrated by a 95% confidence interval of the adjusted mean difference between treatments lying entirely to the right of the pre-defined non inferiority margin of -50 mL.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1480

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

P-value

= 0.852

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.033

upper limit

0.027

Notes
[11] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates. Non-inferiority of CHF 5993 pMDI relative to CHF 1535 pMDI + Tiotropium was demonstrated.

3_Adj mean difference between treatments; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1416

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.064

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

0.094

Notes
[12] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 3_Time to first moderate or severe COPD exacerbation

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End point title

3_Time to first moderate or severe COPD exacerbation

End point description

Time to first moderate or severe COPD exacerbation. Shown are the number of subjects included in the model and the number of subjects with available results. COPD=Chronic obstructive pulmonary disease

End point type

Secondary

End point timeframe

Baseline to Week 52 (entire treatment period).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[13]	1074 ^[14]	538 ^[15]
Units: Subjects, at least 1 mod or sev exacerbt	351	383	167

Notes
[13] - ITT population
[14] - ITT population
[15] - ITT population

1_Time to first mod or sev COPD exacerbation; AvsB

Statistical analysis description

Time to first moderate or severe COPD exacerbation.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.015

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.836

Confidence interval

level

95%

sides

2-sided

lower limit

0.723

upper limit

0.966

Notes
[16] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

2_Time to first mod or sev COPD exacerbation; AvsC

Statistical analysis description

Time to first moderate or severe COPD exacerbation.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.569

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.055

Confidence interval

level

95%

sides

2-sided

lower limit

0.877

upper limit

1.269

Notes
[17] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

3_Time to first mod or sev COPD exacerbation; CvsB

Statistical analysis description

Time to first moderate or severe COPD exacerbation.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.012

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.792

Confidence interval

level

95%

sides

2-sided

lower limit

0.661

upper limit

0.951

Notes
[18] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

Secondary: 4_Rate of severe COPD exacerbations over 52 weeks of treatment

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End point title

4_Rate of severe COPD exacerbations over 52 weeks of treatment

End point description

Rate of severe COPD exacerbations over 52 weeks of treatment. Data are presented as Adjusted Exacerbation Rate per Patient per Year (95% CI). Shown are the number of subjects included in the model and the number of subjects with available results.

End point type

Secondary

End point timeframe

Baseline to Week 52 (entire treatment period).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[19]	1074 ^[20]	538 ^[21]
Units: exacerbation/patient/year
number (confidence interval 95%)	0.067 (0.052 to 0.086)	0.098 (0.078 to 0.123)	0.057 (0.039 to 0.082)

Notes
[19] - ITT population
[20] - ITT population
[21] - ITT population

1_Adj rate ratio of severe exacerbations; A vs B

Statistical analysis description

Adjusted rate ratio for severe exacerbations.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.017

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.495

upper limit

0.935

Notes
[22] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation, and smoking status at screening as fixed effects, and log-time on study as an offset.

2_Adj rate ratio of severe exacerbations; A vs C

Statistical analysis description

Adjusted rate ratio for severe exacerbations.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.447

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

1.179

Confidence interval

level

95%

sides

2-sided

lower limit

0.771

upper limit

1.804

Notes
[23] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation, and smoking status at screening as fixed effects, and log-time on study as an offset.

3_Adj rate ratio of severe exacerbations; C vs B

Statistical analysis description

Adjusted rate ratio for severe exacerbations.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.009

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.577

Confidence interval

level

95%

sides

2-sided

lower limit

0.382

upper limit

0.87

Notes
[24] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation, and smoking status at screening as fixed effects, and log-time on study as an offset.

Secondary: 5_Time to first severe COPD exacerbation

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End point title

5_Time to first severe COPD exacerbation

End point description

Time to first severe COPD exacerbation. Shown are the number of subjects included in the model and the number of subjects with available results.

End point type

Secondary

End point timeframe

Baseline to Week 52 (entire treatment period).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[25]	1074 ^[26]	538 ^[27]
Units: Subjects, at least 1 severe exacerbation	75	99	35

Notes
[25] - ITT population
[26] - ITT population
[27] - ITT population

1_Time to first sev COPD exacerbation; A vs B

Statistical analysis description

Time to first severe COPD exacerbation.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

= 0.021

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.702

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.948

Notes
[28] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

2_Time to first sev COPD exacerbation; A vs C

Statistical analysis description

Time to first severe COPD exacerbation.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.822

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.047

Confidence interval

level

95%

sides

2-sided

lower limit

0.701

upper limit

1.565

Notes
[29] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

3_Time to first sev COPD exacerbation; C vs B

Statistical analysis description

Time to first severe COPD exacerbation.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.042

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.456

upper limit

0.986

Notes
[30] - Analysis is based on a Cox proportional hazards model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors.

Secondary: 6_Rate of moderate COPD exacerbations over 52 weeks of treatment

Top of page

End point title

6_Rate of moderate COPD exacerbations over 52 weeks of treatment

End point description

Rate of moderate COPD exacerbations over 52 weeks of treatment. Data are presented as Adjusted Exacerbation Rate per Patient per Year (95% CI). Shown are the number of subjects included in the model and the number of subjects with available results.

End point type

Secondary

End point timeframe

Baseline to Week 52 (entire treatment period).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[31]	1074 ^[32]	538 ^[33]
Units: exacerbation/patient/year
number (confidence interval 95%)	0.37 (0.329 to 0.416)	0.442 (0.395 to 0.495)	0.376 (0.32 to 0.443)

Notes
[31] - ITT population (analysed)
[32] - ITT population (analysed)
[33] - ITT population (analysed)

1_Adj rate ratio of moderate exacerbations; A vs B

Statistical analysis description

Adjusted rate ratio for moderate exacerbations.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

= 0.03

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.837

Confidence interval

level

95%

sides

2-sided

lower limit

0.713

upper limit

0.983

Notes
[34] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset.

2_Adj rate ratio of moderate exacerbation; A vs C

Statistical analysis description

Adjusted rate ratio for moderate exacerbations.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.871

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.984

Confidence interval

level

95%

sides

2-sided

lower limit

0.806

upper limit

1.2

Notes
[35] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset.

3_Adj rate ratio of moderate exacerbation; C vs B

Statistical analysis description

Adjusted rate ratio for moderate exacerbations.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[36]

P-value

= 0.108

Method

Negative binomial model

Parameter type

Adjusted Rate Ratio

Point estimate

0.851

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.036

Notes
[36] - Analysis is based on a negative binomial model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and log-time on study as an offset.

Secondary: 7_Change from baseline in pre-dose morning FEV1 at all other clinic visits

Top of page

End point title

7_Change from baseline in pre-dose morning FEV1 at all other clinic visits

End point description

Change from baseline in pre-dose morning FEV1 at all other study visits. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (Wk).

End point type

Secondary

End point timeframe

Baseline and study visit (Week 4, 12, 26, 40).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1068 ^[37]	1055 ^[38]	536 ^[39]
Units: litre(s)
least squares mean (confidence interval 95%)
Week 4	0.081 (0.067 to 0.095)	0.012 (-0.002 to 0.026)	0.091 (0.071 to 0.111)
Week 12	0.082 (0.066 to 0.097)	0.03 (0.015 to 0.046)	0.101 (0.08 to 0.123)
Week 26	0.075 (0.059 to 0.092)	0.024 (0.007 to 0.041)	0.086 (0.063 to 0.109)
Week 40	0.08 (0.063 to 0.097)	0.025 (0.007 to 0.042)	0.093 (0.069 to 0.117)

Notes
[37] - ITT (available for change from baseline) Wk 04 n=1067 Wk 12 n=1047 Wk 26 n=1027 Wk 40 n=998
[38] - ITT (available for change from baseline) Wk 04 n=1052 Wk 12 n=1019 Wk 26 n=977 Wk 40 n=944
[39] - ITT (available for change from baseline) Wk 04 n=536 Wk 12 n=526 Wk 26 n=510 Wk 40 n=502

1_Adj mean diffr btw treatment, wk 4; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (2123) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2123

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.049

upper limit

0.089

Notes
[40] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 4; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1604) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1604

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.443

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.034

upper limit

0.015

Notes
[41] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 4; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1591) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1591

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.079

Confidence interval

level

95%

sides

2-sided

lower limit

0.055

upper limit

0.103

Notes
[42] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

4_Adj mean diffr btw treatment, wk 12; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (2123) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2123

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

0.073

Notes
[43] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 12; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1604) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1604

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.145

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.046

upper limit

0.007

Notes
[44] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 12; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1591) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1591

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.044

upper limit

0.098

Notes
[45] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

7_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2123) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2123

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

0.028

upper limit

0.075

Notes
[46] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

8_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1604) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1604

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.461

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.039

upper limit

0.018

Notes
[47] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

9_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1591) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1591

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

0.034

upper limit

0.091

Notes
[48] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

10_Adj mean diffr btw treatment, wk 40; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (2123) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2123

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.032

upper limit

0.08

Notes
[49] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

11_Adj mean diffr btw treatment, wk 40; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1604) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1604

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.384

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.016

Notes
[50] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

12_Adj mean diffr btw treatment, wk 40; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1591) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1591

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.098

Notes
[51] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 8_Change from baseline to the average over the treatment period in pre-dose morning FEV1

Top of page

End point title

8_Change from baseline to the average over the treatment period in pre-dose morning FEV1

End point description

Change from baseline to the average over the treatment period in pre-dose morning FEV1. Shown are the number of subjects included in the model and the number of subjects with available results.

End point type

Secondary

End point timeframe

Baseline to the overall treatment period (Week 4 to Week 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1068 ^[52]	1055 ^[53]	536 ^[54]
Units: litre(s)
least squares mean (confidence interval 95%)	0.08 (0.067 to 0.093)	0.022 (0.009 to 0.036)	0.091 (0.073 to 0.11)

Notes
[52] - ITT (available for change from baseline)
[53] - ITT (available for change from baseline)
[54] - ITT (available for change from baseline)

1_Adj mean diffr btw treatment, average; A vs B

Statistical analysis description

Adjusted mean difference between treatments - average over treatment period.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2123

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.058

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.077

Notes
[55] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, average; A vs C

Statistical analysis description

Adjusted mean difference between treatments - average over treatment period.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1604

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

= 0.337

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.011

Confidence interval

level

95%

sides

2-sided

lower limit

-0.034

upper limit

0.012

Notes
[56] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, average; C vs B

Statistical analysis description

Adjusted mean difference between treatments - average over treatment period.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1591

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.092

Notes
[57] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 9_FEV1 response (change from baseline in pre-dose morning FEV1 ≥ 100 mL) at Week 26 and Week 52

Top of page

End point title

9_FEV1 response (change from baseline in pre-dose morning FEV1 ≥ 100 mL) at Week 26 and Week 52

End point description

FEV1 response is defined as a change from baseline in pre-dose morning FEV1 ≥100 mL. If the change from baseline was <100 mL, the patient was classed as a non-responder in terms of FEV1. Subjects with missing pre-dose morning FEV1 value at the relevant time points were also classified as non-responders. Results are shown as the number of responders at Week 26 and Week 52.

End point type

Secondary

End point timeframe

Baseline to study visit at Week 26, Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[58]	1074 ^[59]	538 ^[60]
Units: subject
Week 26	421	306	204
Week 52	408	295	210

Notes
[58] - ITT population
[59] - ITT population
[60] - ITT population

1_Btw grp analysis, FEV1 ≥100 mL, Wk 26; A vs B

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 26).

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

1.34

upper limit

1.93

Notes
[61] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

2_Btw grp analysis, FEV1 ≥100 mL, Wk 26; A vs C

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 26).

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[62]

P-value

= 0.694

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.3

Notes
[62] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

3_Btw grp analysis, FEV1 ≥100 mL, Wk 26; C vs B

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 26).

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

1.23

upper limit

1.92

Notes
[63] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

4_Btw grp analysis, FEV1 ≥100 mL, Wk 52; A vs B

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 52).

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[64]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

1.35

upper limit

1.95

Notes
[64] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

5_Btw grp analysis, FEV1 ≥100 mL, Wk 26; A vs C

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 26).

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

= 0.627

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.18

Notes
[65] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

6_Btw grp analysis, FEV1 ≥100 mL, Wk 52; C vs B

Statistical analysis description

Between group analysis (change from baseline in pre-dose morning FEV1 ≥100 mL, at Week 52).

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[66]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.71

Confidence interval

level

95%

sides

2-sided

lower limit

1.37

upper limit

2.13

Notes
[66] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline FEV1 value as a covariate.

Secondary: 10_Change from baseline in pre-dose morning inspiratory capacity (IC) at all clinic visits

Top of page

End point title

10_Change from baseline in pre-dose morning inspiratory capacity (IC) at all clinic visits

End point description

Change from baseline in pre-dose morning inspiratory capacity (IC) at all clinic visits. IC is the volume change recorded at the mouth when taking a slow full inspiration with no hesitation, from a position of passive end-tidal expiration (i.e. functional residual capacity [FRC]), to a position to maximum inspiration. The average of at least 3 acceptable slow vital capacity manoeuvres was recorded for IC. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (W).

End point type

Secondary

End point timeframe

Baseline and study visit (Week 4, 12, 26, 40, 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1063 ^[67]	1054 ^[68]	533 ^[69]
Units: litre(s)
least squares mean (confidence interval 95%)
Week 4	0.068 (0.047 to 0.09)	-0.002 (-0.023 to 0.019)	0.088 (0.059 to 0.118)
Week 12	0.07 (0.047 to 0.093)	0.012 (-0.011 to 0.035)	0.128 (0.096 to 0.16)
Week 26	0.078 (0.054 to 0.102)	0.039 (0.014 to 0.063)	0.083 (0.049 to 0.117)
Week 40	0.072 (0.047 to 0.096)	0.033 (0.008 to 0.058)	0.082 (0.047 to 0.117)
Week 52	0.071 (0.046 to 0.096)	0.012 (-0.014 to 0.037)	0.072 (0.037 to 0.108)

Notes
[67] - ITT (avail for change from baseline) W 04 n=1060 W 12 n=1043 W 26 n=1022 W 40 n=991 W 52 n=975
[68] - ITT (avail for change from baseline) W 04 n=1051 W 12 n=1016 W 26 n=973 W 40 n=943 W 52 n=918
[69] - ITT (avail for change from baseline) W 04 n=533 W 12 n=521 W 26 n=507 W 40 n=500 W 52 n=492

1_Adj mean diffr btw treatment, wk 4; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (2117) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2117

Analysis specification

Pre-specified

Analysis type

other ^[70]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

0.1

Notes
[70] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 4; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1596) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other ^[71]

P-value

= 0.284

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

0.017

Notes
[71] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 4; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1587) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1587

Analysis specification

Pre-specified

Analysis type

other ^[72]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.091

Confidence interval

level

95%

sides

2-sided

lower limit

0.054

upper limit

0.127

Notes
[72] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

4_Adj mean diffr btw treatment, wk 12; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (2117) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2117

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.057

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.09

Notes
[73] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 12; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1596) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other ^[74]

P-value

= 0.004

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.058

Confidence interval

level

95%

sides

2-sided

lower limit

-0.098

upper limit

-0.019

Notes
[74] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 12; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1587) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1587

Analysis specification

Pre-specified

Analysis type

other ^[75]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.116

Confidence interval

level

95%

sides

2-sided

lower limit

0.076

upper limit

0.156

Notes
[75] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

7_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2117) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2117

Analysis specification

Pre-specified

Analysis type

other ^[76]

P-value

= 0.025

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.039

Confidence interval

level

95%

sides

2-sided

lower limit

0.005

upper limit

0.074

Notes
[76] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

8_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1596) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other ^[77]

P-value

= 0.808

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.005

Confidence interval

level

95%

sides

2-sided

lower limit

-0.047

upper limit

0.037

Notes
[77] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

9_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1587) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1587

Analysis specification

Pre-specified

Analysis type

other ^[78]

P-value

= 0.038

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

0.002

upper limit

0.086

Notes
[78] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

10_Adj mean diffr btw treatment, wk 40; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (2117) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2117

Analysis specification

Pre-specified

Analysis type

other ^[79]

P-value

= 0.03

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.039

Confidence interval

level

95%

sides

2-sided

lower limit

0.004

upper limit

0.074

Notes
[79] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

11_Adj mean diffr btw treatment, wk 40; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1596) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other ^[80]

P-value

= 0.642

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.053

upper limit

0.033

Notes
[80] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

12_Adj mean diffr btw treatment, wk 40; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1587) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1587

Analysis specification

Pre-specified

Analysis type

other ^[81]

P-value

= 0.025

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.049

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.092

Notes
[81] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

13_Adj mean diffr btw treatment, wk 52; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (2117) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2117

Analysis specification

Pre-specified

Analysis type

other ^[82]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.024

upper limit

0.095

Notes
[82] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

14_Adj mean diffr btw treatment, wk 52; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1596) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other ^[83]

P-value

= 0.961

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.044

upper limit

0.042

Notes
[83] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

15_Adj mean diffr btw treatment, wk 52; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1587) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1587

Analysis specification

Pre-specified

Analysis type

other ^[84]

P-value

= 0.006

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.061

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.104

Notes
[84] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 11_Change from baseline in SGRQ at all study visits: Total Score

Top of page

End point title

11_Change from baseline in SGRQ at all study visits: Total Score

End point description

SGRQ Total Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0=baseline, 4, 12, 26, 40, 52). The Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were also calculated and include the domains: i) Symptoms, ii) Activity, and iii) Impacts on daily life. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (W). SGRQ=Saint George’s Respiratory Questionnaire

End point type

Secondary

End point timeframe

Baseline and each study visit (Week 4, 12, 26, 40, 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1012 ^[85]	1018 ^[86]	519 ^[87]
Units: score
least squares mean (confidence interval 95%)
Week 4	-4.27 (-4.96 to -3.59)	-2.12 (-2.8 to -1.43)	-4.73 (-5.69 to -3.77)
Week 12	-5.58 (-6.33 to -4.82)	-3.75 (-4.51 to -2.99)	-6.19 (-7.25 to -5.13)
Week 26	-5.44 (-6.26 to -4.62)	-4.41 (-5.24 to -3.59)	-7.2 (-8.35 to -6.05)
Week 40	-5.87 (-6.71 to -5.02)	-4.05 (-4.91 to -3.2)	-6.89 (-8.08 to -5.71)
Week 52	-5.74 (-6.6 to -4.88)	-4.14 (-5.01 to -3.27)	-7.32 (-8.51 to -6.12)

Notes
[85] - ITT (avail for change from baseline) W 04 n=982 W 12 n=954 W 26 n=944 W 40 n=915 W 52 n=899
[86] - ITT (avail for change from baseline) W 04 n=983 W 12 n=949 W 26 n=919 W 40 n=877 W 52 n=860
[87] - ITT (avail for change from baseline) W 04 n=497 W 12 n=494 W 26 n=474 W 40 n=467 W 52 n=463

1_Adj mean diffr btw treatment, wk 4; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (2030) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2030

Analysis specification

Pre-specified

Analysis type

other ^[88]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.16

Confidence interval

level

95%

sides

2-sided

lower limit

-3.13

upper limit

-1.19

Notes
[88] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 4; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1531) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1531

Analysis specification

Pre-specified

Analysis type

other ^[89]

P-value

= 0.451

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

1.64

Notes
[89] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 4; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 4. The number of subjects in this analysis (1537) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1537

Analysis specification

Pre-specified

Analysis type

other ^[90]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.61

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

-1.43

Notes
[90] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

4_Adj mean diffr btw treatment, wk 12; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (2030) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2030

Analysis specification

Pre-specified

Analysis type

other ^[91]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.83

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

-0.75

Notes
[91] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 12; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1531) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1531

Analysis specification

Pre-specified

Analysis type

other ^[92]

P-value

= 0.352

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-0.69

upper limit

1.92

Notes
[92] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 12; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 12. The number of subjects in this analysis (1537) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1537

Analysis specification

Pre-specified

Analysis type

other ^[93]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.45

Confidence interval

level

95%

sides

2-sided

lower limit

-3.75

upper limit

-1.14

Notes
[93] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

7_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2030) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2030

Analysis specification

Pre-specified

Analysis type

other ^[94]

P-value

= 0.083

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.03

Confidence interval

level

95%

sides

2-sided

lower limit

-2.19

upper limit

0.14

Notes
[94] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

8_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1531) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1531

Analysis specification

Pre-specified

Analysis type

other ^[95]

P-value

= 0.014

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

3.17

Notes
[95] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

9_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1537) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1537

Analysis specification

Pre-specified

Analysis type

other ^[96]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.79

Confidence interval

level

95%

sides

2-sided

lower limit

-4.21

upper limit

-1.37

Notes
[96] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

10_Adj mean diffr btw treatment, wk 40; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (2030) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2030

Analysis specification

Pre-specified

Analysis type

other ^[97]

P-value

= 0.003

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.82

Confidence interval

level

95%

sides

2-sided

lower limit

-3.02

upper limit

-0.61

Notes
[97] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

11_Adj mean diffr btw treatment, wk 40; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1531) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1531

Analysis specification

Pre-specified

Analysis type

other ^[98]

P-value

= 0.166

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

2.48

Notes
[98] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

12_Adj mean diffr btw treatment, wk 40; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 40. The number of subjects in this analysis (1537) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1537

Analysis specification

Pre-specified

Analysis type

other ^[99]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.84

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

-1.38

Notes
[99] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

13_Adj mean diffr btw treatment, wk 52; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (2030) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2030

Analysis specification

Pre-specified

Analysis type

other ^[100]

P-value

= 0.01

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.82

upper limit

-0.38

Notes
[100] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

14_Adj mean diffr btw treatment, wk 52; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1531) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1531

Analysis specification

Pre-specified

Analysis type

other ^[101]

P-value

= 0.036

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

3.05

Notes
[101] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

15_Adj mean diffr btw treatment, wk 52; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1537) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1537

Analysis specification

Pre-specified

Analysis type

other ^[102]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-3.18

Confidence interval

level

95%

sides

2-sided

lower limit

-4.66

upper limit

-1.69

Notes
[102] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 12_Change from baseline in SGRQ at all study visits: Symptoms Score

Top of page

End point title

12_Change from baseline in SGRQ at all study visits: Symptoms Score

End point description

SGRQ Symptoms Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0=baseline, 4, 12, 26, 40, 52). The Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were also calculated and include the domains: i) Symptoms, ii) Activity, and iii) Impacts on daily life. Shown are the number of subjects included in the model and the number of subjects with available results at week (Wk). SGRQ=Saint George’s Respiratory Questionnaire

End point type

Secondary

End point timeframe

Baseline and each study visit (Week 4, 12, 26, 40, 52); data shown are for Week 26 and Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1045 ^[103]	1047 ^[104]	533 ^[105]
Units: score
least squares mean (confidence interval 95%)
Week 26	-7.65 (-8.69 to -6.62)	-5.41 (-6.46 to -4.36)	-9.87 (-11.33 to -8.41)
Week 52	-9.07 (-10.14 to -7.99)	-6.65 (-7.74 to -5.55)	-11.07 (-12.58 to -9.57)

Notes
[103] - ITT (available for change from baseline) Wk 26 n=994 Wk 52 n=947
[104] - ITT (available for change from baseline) Wk 26 n=967 Wk 52 n=900
[105] - ITT (available for change from baseline) Wk 26 n=497 Wk 52 n=483

1_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2092) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2092

Analysis specification

Pre-specified

Analysis type

other ^[106]

P-value

= 0.003

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.24

Confidence interval

level

95%

sides

2-sided

lower limit

-3.72

upper limit

-0.77

Notes
[106] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1578) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1578

Analysis specification

Pre-specified

Analysis type

other ^[107]

P-value

= 0.015

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

2.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

4.01

Notes
[107] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1580) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1580

Analysis specification

Pre-specified

Analysis type

other ^[108]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-4.46

Confidence interval

level

95%

sides

2-sided

lower limit

-6.26

upper limit

-2.66

Notes
[108] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

4_Adj mean diffr btw treatment, wk 52; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (2092) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2092

Analysis specification

Pre-specified

Analysis type

other ^[109]

P-value

= 0.002

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.42

Confidence interval

level

95%

sides

2-sided

lower limit

-3.95

upper limit

-0.88

Notes
[109] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 52; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1578) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1578

Analysis specification

Pre-specified

Analysis type

other ^[110]

P-value

= 0.034

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

2.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

3.86

Notes
[110] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 52; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1580) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1580

Analysis specification

Pre-specified

Analysis type

other ^[111]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-4.43

Confidence interval

level

95%

sides

2-sided

lower limit

-6.29

upper limit

-2.56

Notes
[111] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 13_Change from baseline in SGRQ at all study visits: Activity Score

Top of page

End point title

13_Change from baseline in SGRQ at all study visits: Activity Score

End point description

SGRQ Activity Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0=baseline, 4, 12, 26, 40, 52). The Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were also calculated and include the domains: i) Symptoms, ii) Activity, and iii) Impacts on daily life. Shown are the number of subjects included in the model and the number of subjects with available results at week (Wk). SGRQ=Saint George’s Respiratory Questionnaire

End point type

Secondary

End point timeframe

Baseline and each study visit (Week 4, 12, 26, 40, 52); data shown are for Week 26 and Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1036 ^[112]	1026 ^[113]	527 ^[114]
Units: score
least squares mean (confidence interval 95%)
Week 26	-3.74 (-4.76 to -2.73)	-3.51 (-4.55 to -2.48)	-5.93 (-7.36 to -4.5)
Week 52	-4.43 (-5.46 to -3.41)	-2.64 (-3.69 to -1.59)	-6.04 (-7.48 to -4.6)

Notes
[112] - ITT (available for change from baseline) Wk 26 n=976 Wk 52 n=940
[113] - ITT (available for change from baseline) Wk 26 n=933 Wk 52 n=889
[114] - ITT (available for change from baseline) Wk 26 n=493 Wk 52 n=481

1_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2062) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2062

Analysis specification

Pre-specified

Analysis type

other ^[115]

P-value

= 0.755

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.68

upper limit

1.22

Notes
[115] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1563) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1563

Analysis specification

Pre-specified

Analysis type

other ^[116]

P-value

= 0.015

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

2.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

3.94

Notes
[116] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1553) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1553

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.007

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.41

Confidence interval

level

95%

sides

2-sided

lower limit

-4.18

upper limit

-0.65

4_Adj mean diffr btw treatment, wk 52; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (2062) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2062

Analysis specification

Pre-specified

Analysis type

other ^[117]

P-value

= 0.017

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.79

Confidence interval

level

95%

sides

2-sided

lower limit

-3.26

upper limit

-0.32

Notes
[117] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 52; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1563) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1563

Analysis specification

Pre-specified

Analysis type

other ^[118]

P-value

= 0.075

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

3.37

Notes
[118] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 52; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1553) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1553

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-3.39

Confidence interval

level

95%

sides

2-sided

lower limit

-5.18

upper limit

-1.61

Secondary: 14_Change from baseline in SGRQ at all study visits: Impact on daily life Score

Top of page

End point title

14_Change from baseline in SGRQ at all study visits: Impact on daily life Score

End point description

SGRQ Impact on daily life Score. SGRQ is a questionnaire developed to measure health in chronic airflow limitation. SGRQ questionnaire was completed by the patients at all study visits (Week 0=baseline, 4, 12, 26, 40, 52). The Total Score for SGRQ was calculated, whereby lower scores correspond to better health. Moreover, 3 component scores of SGRQ were also calculated and include the domains: i) Symptoms, ii) Activity, and iii) Impacts on daily life. Shown are the number of subjects included in the model and the number of subjects with available results at week (Wk). SGRQ=Saint George’s Respiratory Questionnaire

End point type

Secondary

End point timeframe

Baseline and each study visit (Week 4, 12, 26, 40, 52); data shown are for Week 26 and Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1041 ^[119]	1032 ^[120]	527 ^[121]
Units: score
least squares mean (confidence interval 95%)
Week 26	-5.73 (-6.66 to -4.81)	-4.67 (-5.61 to -3.72)	-7.04 (-8.34 to -5.73)
Week 52	-5.58 (-6.55 to -4.61)	-4.29 (-5.29 to -3.3)	-7.23 (-8.59 to -5.86)

Notes
[119] - ITT (available for change from baseline) Wk 26 n=991 Wk 52 n=951
[120] - ITT (available for change from baseline) Wk 26 n=943 Wk 52 n=890
[121] - ITT (available for change from baseline) Wk 26 n=496 Wk 52 n=483

1_Adj mean diffr btw treatment, wk 26; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (2073) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2073

Analysis specification

Pre-specified

Analysis type

other ^[122]

P-value

= 0.115

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.07

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

0.26

Notes
[122] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

2_Adj mean diffr btw treatment, wk 26; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1568) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1568

Analysis specification

Pre-specified

Analysis type

other ^[123]

P-value

= 0.112

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

2.91

Notes
[123] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

3_Adj mean diffr btw treatment, wk 26; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 26. The number of subjects in this analysis (1559) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1559

Analysis specification

Pre-specified

Analysis type

other ^[124]

P-value

= 0.004

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.37

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

-0.75

Notes
[124] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

4_Adj mean diffr btw treatment, wk 52; A vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (2073) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2073

Analysis specification

Pre-specified

Analysis type

other ^[125]

P-value

= 0.07

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-2.68

upper limit

0.11

Notes
[125] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

5_Adj mean diffr btw treatment, wk 52; A vs C

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1568) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1568

Analysis specification

Pre-specified

Analysis type

other ^[126]

P-value

= 0.054

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

3.32

Notes
[126] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

6_Adj mean diffr btw treatment, wk 52; C vs B

Statistical analysis description

Adjusted mean difference between treatments at week 52. The number of subjects in this analysis (1559) is due to an innate validation error within the EudraCT database. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1559

Analysis specification

Pre-specified

Analysis type

other ^[127]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-2.93

Confidence interval

level

95%

sides

2-sided

lower limit

-4.62

upper limit

-1.24

Notes
[127] - Analysis is based on a linear mixed model for repeated measures including treatment, visit, treatment by visit interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by visit interaction as covariates.

Secondary: 15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52

Top of page

End point title

15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52

End point description

SGRQ response is defined as a change from baseline in SGRQ total score ≤ -4. If the change from baseline was > -4, the patient was classed as a non-responder in terms of SGRQ. Patients with missing value for the change from baseline at the relevant time points were also classified as non-responders. Results are shown as the number of subjects Included in model and the number of responders in each of the treatment groups. SGRQ=Saint George’s respiratory questionnaire

End point type

Secondary

End point timeframe

Baseline, Week 26, Week 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[128]	1074 ^[129]	538 ^[130]
Units: subject
Week 26	508	438	276
Week 52	494	423	254

Notes
[128] - ITT population
[129] - ITT population
[130] - ITT population

1_Btw grp analysis, SGRQ score ≤-4, Wk 26; A vs B

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 26). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 26.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[131]

P-value

= 0.002

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.57

Notes
[131] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

2_Btw grp analysis, SGRQ score ≤-4, Wk 26; A vs C

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 26). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 26.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[132]

P-value

= 0.049

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

Notes
[132] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

3_Btw grp analysis, SGRQ score ≤-4, Wk 26; C vs B

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 26). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 26.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[133]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.63

Confidence interval

level

95%

sides

2-sided

lower limit

1.32

upper limit

2.02

Notes
[133] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

4_Btw grp analysis, SGRQ score ≤-4, Wk 52; A vs B

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 52). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 52.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2151

Analysis specification

Pre-specified

Analysis type

other ^[134]

P-value

= 0.002

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

1.59

Notes
[134] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

5_Btw grp analysis, SGRQ score ≤-4, Wk 52; A vs C

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 52). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 52.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1615

Analysis specification

Pre-specified

Analysis type

other ^[135]

P-value

= 0.373

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.13

Notes
[135] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

6_Btw grp analysis, SGRQ score ≤-4, Wk 52; C vs B

Statistical analysis description

Between group analysis (change from baseline in SGRQ Total score ≤-4, Week 52). SGRQ response = Subjects with a change from baseline in Total Score ≤-4, at week 52.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other ^[136]

P-value

< 0.001

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

1.18

upper limit

1.83

Notes
[136] - Analysis is based on a logistic model including treatment, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as factors and the baseline SGRQ total score value as a covariate.

Secondary: 16_Change from baseline for percentage of days without intake of rescue medication

Top of page

End point title

16_Change from baseline for percentage of days without intake of rescue medication

End point description

Days without intake of rescue medication. Change from baseline to each inter-visit period and for the entire treatment period (Week 1-52) in the percentage of days without intake of rescue medication. Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (W) interval.

End point type

Secondary

End point timeframe

Baseline, Week 4, 12, 26, 40, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1038 ^[137]	1015 ^[138]	513 ^[139]
Units: days
least squares mean (confidence interval 95%)
Week 1-4	13.89 (12.14 to 15.63)	5.81 (4.05 to 7.57)	13.08 (10.6 to 15.56)
Week 5-12	14.51 (12.6 to 16.42)	6.22 (4.28 to 8.16)	14.48 (11.76 to 17.19)
Week 13-26	14.14 (12.12 to 16.17)	5.47 (3.41 to 7.53)	15.03 (12.16 to 17.9)
Week 27-40	14.23 (12.12 to 16.33)	5.06 (2.91 to 7.22)	15.62 (12.63 to 18.61)
Week 41-52	12.89 (10.77 to 15.01)	4.11 (1.94 to 6.29)	14.13 (11.12 to 17.14)
Week 1-52	13.91 (12.04 to 15.79)	5.19 (3.28 to 7.1)	14.75 (12.08 to 17.41)

Attachments

Untitled (Filename: Figure 15_Trinity_without rescue med.pdf)

Notes
[137] - ITT W 1-4 n=1034 W 5-12 n=1018 W 13-26 n=1004 W 27-40 n=978 W 41-52 n=964 W 1-52 n=1038
[138] - ITT W 1-4 n=1009 W 5-12 n=970 W 13-26 n=954 W 27-40 n=907 W 41-52 n=894 W 1-52 n=1015
[139] - ITT W 1-4 n=509 W 5-12 n=507 W 13-26 n=497 W 27-40 n=486 W 41-52 n=480 W 1-52 n=513

1_Adj mean diffr btw treat groups W 1-52; A vs B

Statistical analysis description

Adjusted mean difference between treatment groups during Week 1-52. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'. Adjusted mean change from baseline in percentage of days without rescue medication use for each inter-visit period in the ITT population, is shown in the attached Figure.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2053

Analysis specification

Pre-specified

Analysis type

other ^[140]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

8.72

Confidence interval

level

95%

sides

2-sided

lower limit

6.05

upper limit

11.4

Notes
[140] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates

2_Adj mean diffr btw treat groups W 1-52; A vs C

Statistical analysis description

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1551

Analysis specification

Pre-specified

Analysis type

other ^[141]

P-value

= 0.616

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.83

Confidence interval

level

95%

sides

2-sided

lower limit

-4.09

upper limit

2.42

Notes
[141] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates

3_Adj mean diffr btw treat groups W 1-52; C vs B

Statistical analysis description

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1528

Analysis specification

Pre-specified

Analysis type

other ^[142]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

9.56

Confidence interval

level

95%

sides

2-sided

lower limit

6.28

upper limit

12.83

Notes
[142] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates

Secondary: 17_Change from baseline for the average use of rescue medication

Top of page

End point title

17_Change from baseline for the average use of rescue medication

End point description

Average use of rescue medication. Change from baseline to each inter-visit period and for the entire treatment period (Week 1-52) in the average use of rescue medication (number of puffs/day). Shown are the number of subjects included in the model and the number of subjects with available results at the indicated week (W) interval.

End point type

Secondary

End point timeframe

Baseline, Week 4, 12, 26, 40, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1038 ^[143]	1015 ^[144]	513 ^[145]
Units: puffs/day
least squares mean (confidence interval 95%)
Week 1-4	-0.53 (-0.62 to -0.45)	-0.03 (-0.11 to 0.06)	-0.56 (-0.68 to -0.44)
Week 5-12	-0.51 (-0.61 to -0.41)	0 (-0.1 to 0.1)	-0.59 (-0.73 to -0.45)
Week 13-26	-0.5 (-0.61 to -0.4)	0.06 (-0.05 to 0.16)	-0.57 (-0.71 to -0.42)
Week 27-40	-0.47 (-0.59 to -0.36)	0.14 (0.02 to 0.25)	-0.54 (-0.7 to -0.38)
Week 41-52	-0.42 (-0.53 to -0.3)	0.2 (0.08 to 0.32)	-0.46 (-0.63 to -0.3)
Week 1-52	-0.48 (-0.58 to -0.38)	0.1 (-0.01 to 0.2)	-0.54 (-0.68 to -0.4)

Attachments

Untitled (Filename: Figure 16_Trinity_with rescue med.pdf)

Notes
[143] - ITT W 1-4 n=1034 W 5-12 n=1018 W 13-26 n=1004 W 27-40 n=978 W 41-52 n=964 W 1-52 n=1038
[144] - ITT W 1-4 n=1009 W 5-12 n=970 W 13-26 n=954 W 27-40 n=907 W 41-52 n=894 W 1-52 n=1015
[145] - ITT W 1-4 n=509 W 5-12 n=507 W 13-26 n=497 W 27-40 n=486 W 41-52 n=480 W 1-52 n=513

1_Adj mean diffr btw treat groups W 1-52; A vs B

Statistical analysis description

Adjusted mean difference between treatment groups during Week 1-52. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'. Adjusted mean change from baseline in average use of rescue medication (puffs/day) for each inter-visit period in the ITT population, is shown in the attached Figure.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

2053

Analysis specification

Pre-specified

Analysis type

other ^[146]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.57

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

-0.43

Notes
[146] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.

2_Adj mean diffr btw treat groups W 1-52; A vs C

Statistical analysis description

Adjusted mean difference between treatment groups during Week 1-52. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'. Adjusted mean change from baseline in average use of rescue medication (puffs/day) for each inter-visit period in the ITT population, is shown in the attached Figure.

Comparison groups

Treatment A: CHF 5993 pMDI (100/6/12.5μg) v Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)

Number of subjects included in analysis

1551

Analysis specification

Pre-specified

Analysis type

other ^[147]

P-value

= 0.495

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.23

Notes
[147] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.

3_Adj mean diffr btw treat groups W 1-52; C vs B

Statistical analysis description

Adjusted mean difference between treatment groups during Week 1-52. The correct number of participating subjects for this statistical comparison is shown in the footnote of the table containing 'End point values'. Adjusted mean change from baseline in average use of rescue medication (puffs/day) for each inter-visit period in the ITT population, is shown in the attached Figure.

Comparison groups

Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg) v Treatment B: Tiotropium (18µg)

Number of subjects included in analysis

1528

Analysis specification

Pre-specified

Analysis type

other ^[148]

P-value

< 0.001

Method

Mixed model for repeated measures

Parameter type

Mean difference (net)

Point estimate

-0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-0.81

upper limit

-0.46

Notes
[148] - Analysis is based on a linear mixed model for repeated measures including treatment, inter-visit period, treatment by inter-visit period interaction, country, number of COPD exacerbations in the previous year, severity of airflow limitation and smoking status at screening as fixed effects, and baseline value and baseline by inter-visit period interaction as covariates.

Secondary: 18_Vital signs: Systolic blood pressure

Top of page

End point title

18_Vital signs: Systolic blood pressure

End point description

Systolic Blood Pressure. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 0, Week 26, and Week 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[149]	1075 ^[150]	537 ^[151]
Units: mmHg
arithmetic mean (confidence interval 95%)
Week 0, 10 min post-dose	0.3 (0 to 0.7)	0.4 (0 to 0.8)	0.4 (-0.1 to 0.9)
Week 26, pre-dose	0.2 (-0.5 to 0.8)	0.5 (-0.2 to 1.2)	-0.1 (-1 to 0.8)
Week 26, 10 min post-dose	0.3 (-0.4 to 0.9)	0.4 (-0.3 to 1.1)	0.1 (-0.8 to 1)
Week 52, pre-dose	0.5 (-0.2 to 1.2)	0.1 (-0.6 to 0.9)	-0.2 (-1.2 to 0.8)
Week 52, 10 min post-dose	0.4 (-0.3 to 1.1)	0.3 (-0.5 to 1)	0.1 (-0.9 to 1.1)

Notes
[149] - Safety pop W 0 post n=1069 W 26 pre n=1028 W 26 post n=1018 W 52 pre n=988 W 52 post n=986
[150] - Safety pop N=1076 W 0 post n=1071 W 26 pre n=978 W 26 post n=954 W 52 pre n=923 W 52 post n=911
[151] - Safety pop W 0 post n=536 W 26 pre n=512 W 26 post n=507 W 52 pre n=497 W 52 post n=495

No statistical analyses for this end point

Secondary: 19_Vital signs: Diastolic blood pressure

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End point title

19_Vital signs: Diastolic blood pressure

End point description

Diastolic Blood Pressure. Results represent changes from baseline (Week 0, pre-dose), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 0, Week 26, and Week 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[152]	1075 ^[153]	537 ^[154]
Units: mmHg
arithmetic mean (confidence interval 95%)
Week 0, 10 min post-dose	-0.2 (-0.5 to 0.1)	0 (-0.3 to 0.3)	0.4 (-0.1 to 0.8)
Week 26, pre-dose	-0.1 (-0.6 to 0.4)	0.3 (-0.2 to 0.8)	-0.5 (-1.2 to 0.2)
Week 26, 10 min post-dose	-0.1 (-0.6 to 0.3)	0.1 (-0.4 to 0.6)	-0.4 (-1.1 to 0.3)
Week 52, pre-dose	0 (-0.5 to 0.5)	0.4 (-0.2 to 0.9)	0.1 (-0.7 to 0.8)
Week 52, 10 min post-dose	-0.5 (-1 to 0)	0.1 (-0.4 to 0.6)	-0.2 (-1 to 0.5)

Notes
[152] - Safety pop W 0 post n=1069 W 26 pre n=1028 W 26 post n=1018 W 52 pre n=988 W 52 post n=986
[153] - Saf pop N=1076 W 0 post n=1071 W 26 pre n=978 W 26 post n=954 W 52 pre n=923 W 52 post n=911
[154] - Safety pop W 0 post n=536 W 26 pre n=512 W 26 post n=507 W 52 pre n=497 W 52 post n=495

No statistical analyses for this end point

Secondary: 20_Vital signs: Body mass index

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End point title

20_Vital signs: Body mass index

End point description

Body Mass Index. Results represent changes from baseline (Week 0), on Week 26 and Week 52. Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Baseline to Week 4, 12, 26, 40, 52 (data shown are for Week 26 and Week 52).

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[155]	1075 ^[156]	537 ^[157]
Units: kg/m2
arithmetic mean (confidence interval 95%)
Week 26	0.04 (-0.02 to 0.1)	0.05 (-0.02 to 0.12)	0.02 (-0.06 to 0.11)
Week 52	0.01 (-0.07 to 0.09)	0.06 (-0.01 to 0.14)	-0.04 (-0.16 to 0.08)

Notes
[155] - Safety population Wk 26 n=1028 Wk 52 n=988
[156] - Safety population actual N=1076 Wk 26 n=976 Wk 52 n=923
[157] - Safety population Wk 26 n=512 Wk 52 n=497

No statistical analyses for this end point

Secondary: 21_Electrocardiogram parameters: Heart rate

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End point title

21_Electrocardiogram parameters: Heart rate

End point description

Electrocardiogram parameter: Heart Rate. Results represent changes from screening (Week -2), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Screening (Week -2) to Week 26, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[158]	1075 ^[159]	537 ^[160]
Units: bpm
arithmetic mean (standard deviation)
Week 26, pre-dose	-1.42 ( 11.59 )	1.54 ( 11.81 )	-0.11 ( 11.31 )
Week 26, 10 min post-dose	-3.4 ( 11.41 )	-1.3 ( 11.93 )	-2.03 ( 12 )
Week 52, pre-dose	-0.6 ( 11.61 )	2.5 ( 12.21 )	0.63 ( 12.25 )
Week 52, 10 min post-dose	-1.9 ( 11.65 )	0.42 ( 12.21 )	-1.25 ( 12.28 )

Notes
[158] - Safety population W 26 pre n=1015 W 26 post n=983 W 52 pre n=963 W 52 post n=958
[159] - Safety population actual N=1076 W 26 pre n=978 W 26 post n=911 W 52 pre n=903 W 52 post n=880
[160] - Safety population W 26 pre n=504 W 26 post n=491 W 52 pre n=486 W 52 post n=485

No statistical analyses for this end point

Secondary: 22_Electrocardiogram parameters: QTcF interval

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End point title

22_Electrocardiogram parameters: QTcF interval

End point description

Electrocardiogram parameter: QTcF (Fridericia’s Corrected QT Interval). Results represent changes from screening (Week -2), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Screening (Week -2) to Week 26, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[161]	1075 ^[162]	537 ^[163]
Units: msec
arithmetic mean (standard deviation)
Week 26, pre-dose	-0.54 ( 17.17 )	0.85 ( 16.24 )	-0.63 ( 17.3 )
Week 26, 10 min post-dose	-0.14 ( 18.93 )	-0.95 ( 17.55 )	-0.64 ( 19.47 )
Week 52, pre-dose	0.1 ( 17.08 )	-0.51 ( 17.68 )	-1.83 ( 19.89 )
Week 52, 10 min post-dose	0.23 ( 17.63 )	-0.58 ( 17.65 )	-1.19 ( 17.84 )

Notes
[161] - Safety population W 26 pre n=1015 W 26 post n=983 W 52 pre n=963 W 52 post n=958
[162] - Safety population actual N=1076 W 26 pre n=977 W 26 post n=911 W 52 pre n=903 W 52 post n=880
[163] - Safety population W 26 pre n=503 W 26 post n=490 W 52 pre n=486 W 52 post n=485

No statistical analyses for this end point

Secondary: 23_Electrocardiogram parameters: PR interval

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End point title

23_Electrocardiogram parameters: PR interval

End point description

Electrocardiogram parameter: PR interval Results represent changes from screening (Week -2), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Screening (Week -2) to Week 26, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[164]	1075 ^[165]	537 ^[166]
Units: msec
arithmetic mean (standard deviation)
Week 26, pre-dose	0.56 ( 15.23 )	0.25 ( 13.72 )	1 ( 14.79 )
Week 26, 10 min post-dose	0.31 ( 14.67 )	0.53 ( 13.57 )	0.78 ( 15.38 )
Week 52, pre-dose	1.46 ( 14.92 )	0.39 ( 15.84 )	2.27 ( 15.96 )
Week 52, 10 min post-dose	0.35 ( 15.19 )	0.5 ( 16.13 )	1.94 ( 15.6 )

Notes
[164] - Safety population W 26 pre n=1014 W 26 post n=982 W 52 pre n=962 W 52 post n=958
[165] - Safety population actual N=1076 W 26 pre n=976 W 26 post n=910 W 52 pre n=901 W 52 post n=878
[166] - Safety population W 26 pre n=502 W 26 post n=490 W 52 pre n=486 W 52 post n=485

No statistical analyses for this end point

Secondary: 24_Electrocardiogram parameters: QRS interval

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End point title

24_Electrocardiogram parameters: QRS interval

End point description

Electrocardiogram parameter: QRS interval Results represent changes from screening (Week -2), on Week 26 and Week 52 (pre-dose and 10-minute post-dose). Shown are the number of subjects included in the safety population and the number of subjects with available results. Due to the limitations of the EudraCT database, the number of subjects analysed in the Treatment B group cannot be correctly reported in the table below. The correct number is specified in a note to the table.

End point type

Secondary

End point timeframe

Screening (Week -2) to Week 26, 52.

End point values	Treatment A: CHF 5993 pMDI (100/6/12.5μg)	Treatment B: Tiotropium (18µg)	Treatment C: CHF 1535 pMDI (100/6µg) + Tiotropium (18µg)
Number of subjects analysed	1077 ^[167]	1075 ^[168]	537 ^[169]
Units: msec
arithmetic mean (standard deviation)
Week 26, pre-dose	0.69 ( 7.8 )	0.24 ( 8.14 )	0.51 ( 7.26 )
Week 26, 10 min post-dose	0.88 ( 7.18 )	0.16 ( 7.49 )	0.91 ( 7.55 )
Week 52, pre-dose	0.74 ( 8.14 )	0.79 ( 8.57 )	0.78 ( 8.67 )
Week 52, 10 min post-dose	1.07 ( 8.46 )	0.63 ( 8.8 )	0.8 ( 8.17 )

Notes
[167] - Safety population W 26 pre n=1015 W 26 post n=983 W 52 pre n=963 W 52 post n=958
[168] - Safety population actual N=1076 W 26 pre n=978 W 26 post n=911 W 52 pre n=902 W 52 post n=879
[169] - Safety population W 26 pre n=504 W 26 post n=491 W 52 pre n=486 W 52 post n=485

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from the time of patient informed consent signature to study completion or discontinuation.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Treatment A: fixed combination CHF 5993 pMDI (400/24/50μg/d)

Reporting group description

Reporting group title

Treatment B: Tiotropium (18µg/d)

Reporting group description

Reporting group title

Treatment C: CHF 1535 pMDI (400/24µg/d) + Tiotropium (18µg/d)

Reporting group description

Serious adverse events	Treatment A: fixed combination CHF 5993 pMDI (400/24/50μg/d)	Treatment B: Tiotropium (18µg/d)	Treatment C: CHF 1535 pMDI (400/24µg/d) + Tiotropium (18µg/d)
Total subjects affected by serious adverse events
subjects affected / exposed	140 / 1077 (13.00%)	164 / 1076 (15.24%)	68 / 537 (12.66%)
number of deaths (all causes)	20	29	8
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 1077 (0.00%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	1 / 1077 (0.09%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniopharyngioma
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder neoplasm
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal carcinoma
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Laryngeal squamous cell carcinoma
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	2 / 1077 (0.19%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic gastric cancer
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nasal sinus cancer
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer stage IV
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	2 / 1077 (0.19%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 1077 (0.00%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the tongue
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arterial thrombosis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	2 / 1077 (0.19%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	2 / 1077 (0.19%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Facial pain
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	2 / 1077 (0.19%)	2 / 1076 (0.19%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 2
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	76 / 1077 (7.06%)	100 / 1076 (9.29%)	35 / 537 (6.52%)
occurrences causally related to treatment / all	0 / 90	0 / 124	0 / 40
deaths causally related to treatment / all	0 / 5	0 / 4	0 / 1
Epistaxis
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mediastinal disorder
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	3 / 1077 (0.28%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal injury
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest injury
subjects affected / exposed	0 / 1077 (0.00%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial rupture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tongue injury
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 1077 (0.19%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 1077 (0.09%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 1077 (0.19%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	3 / 1077 (0.28%)	3 / 1076 (0.28%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 1077 (0.00%)	4 / 1076 (0.37%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1
Cardiopulmonary failure
subjects affected / exposed	1 / 1077 (0.09%)	2 / 1076 (0.19%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	1 / 1077 (0.09%)	3 / 1076 (0.28%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Cor pulmonale chronic
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 1077 (0.19%)	4 / 1076 (0.37%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Left ventricular hypertrophy
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 1077 (0.19%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	3 / 1077 (0.28%)	1 / 1076 (0.09%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar ischaemia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolic cerebral infarction
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	5 / 1077 (0.46%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Radial nerve palsy
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radicular syndrome
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombotic cerebral infarction
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polycythaemia
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecal incontinence
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal polyp haemorrhage
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophagitis haemorrhagic
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary tract disorder
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 1077 (0.00%)	0 / 1076 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	2 / 1077 (0.19%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mycobacterial infection
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	19 / 1077 (1.76%)	13 / 1076 (1.21%)	9 / 537 (1.68%)
occurrences causally related to treatment / all	0 / 19	0 / 14	0 / 10
deaths causally related to treatment / all	0 / 1	0 / 4	0 / 1
Pulmonary tuberculosis
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Scrotal abscess
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 1077 (0.09%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 1077 (0.00%)	1 / 1076 (0.09%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Metabolism and nutrition disorders
Electrolyte imbalance
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 1077 (0.09%)	0 / 1076 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Treatment A: fixed combination CHF 5993 pMDI (400/24/50μg/d)	Treatment B: Tiotropium (18µg/d)	Treatment C: CHF 1535 pMDI (400/24µg/d) + Tiotropium (18µg/d)
Total subjects affected by non serious adverse events
subjects affected / exposed	556 / 1077 (51.62%)	565 / 1076 (52.51%)	297 / 537 (55.31%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	296 / 1077 (27.48%)	315 / 1076 (29.28%)	146 / 537 (27.19%)
occurrences all number	411	464	218
Infections and infestations
Nasopharyngitis
subjects affected / exposed	57 / 1077 (5.29%)	66 / 1076 (6.13%)	20 / 537 (3.72%)
occurrences all number	64	85	22

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Moderate and severe COPD exacerbation rate over 52 weeks of treatment, CHF 5993 vs Tiotropium

Primary: 1_Moderate and severe COPD exacerbation rate over 52 weeks of treatment, CHF 5993 vs Tiotropium

Secondary: 2_Change from baseline in pre-dose morning FEV1 at week 52

Secondary: 2_Change from baseline in pre-dose morning FEV1 at week 52

Secondary: 3_Time to first moderate or severe COPD exacerbation

Secondary: 3_Time to first moderate or severe COPD exacerbation

Secondary: 4_Rate of severe COPD exacerbations over 52 weeks of treatment

Secondary: 4_Rate of severe COPD exacerbations over 52 weeks of treatment

Secondary: 5_Time to first severe COPD exacerbation

Secondary: 5_Time to first severe COPD exacerbation

Secondary: 6_Rate of moderate COPD exacerbations over 52 weeks of treatment

Secondary: 6_Rate of moderate COPD exacerbations over 52 weeks of treatment

Secondary: 7_Change from baseline in pre-dose morning FEV1 at all other clinic visits

Secondary: 7_Change from baseline in pre-dose morning FEV1 at all other clinic visits

Secondary: 8_Change from baseline to the average over the treatment period in pre-dose morning FEV1

Secondary: 8_Change from baseline to the average over the treatment period in pre-dose morning FEV1

Secondary: 9_FEV1 response (change from baseline in pre-dose morning FEV1 ≥ 100 mL) at Week 26 and Week 52

Secondary: 9_FEV1 response (change from baseline in pre-dose morning FEV1 ≥ 100 mL) at Week 26 and Week 52

Secondary: 10_Change from baseline in pre-dose morning inspiratory capacity (IC) at all clinic visits

Secondary: 10_Change from baseline in pre-dose morning inspiratory capacity (IC) at all clinic visits

Secondary: 11_Change from baseline in SGRQ at all study visits: Total Score

Secondary: 11_Change from baseline in SGRQ at all study visits: Total Score

Secondary: 12_Change from baseline in SGRQ at all study visits: Symptoms Score

Secondary: 12_Change from baseline in SGRQ at all study visits: Symptoms Score

Secondary: 13_Change from baseline in SGRQ at all study visits: Activity Score

Secondary: 13_Change from baseline in SGRQ at all study visits: Activity Score

Secondary: 14_Change from baseline in SGRQ at all study visits: Impact on daily life Score

Secondary: 14_Change from baseline in SGRQ at all study visits: Impact on daily life Score

Secondary: 15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52

Secondary: 15_SGRQ response (change from baseline in Total score ≤-4) at Week 26 and Week 52

Secondary: 16_Change from baseline for percentage of days without intake of rescue medication

Secondary: 16_Change from baseline for percentage of days without intake of rescue medication

Secondary: 17_Change from baseline for the average use of rescue medication

Secondary: 17_Change from baseline for the average use of rescue medication

Secondary: 18_Vital signs: Systolic blood pressure

Secondary: 18_Vital signs: Systolic blood pressure

Secondary: 19_Vital signs: Diastolic blood pressure

Secondary: 19_Vital signs: Diastolic blood pressure

Secondary: 20_Vital signs: Body mass index

Secondary: 20_Vital signs: Body mass index

Secondary: 21_Electrocardiogram parameters: Heart rate

Secondary: 21_Electrocardiogram parameters: Heart rate

Secondary: 22_Electrocardiogram parameters: QTcF interval

Secondary: 22_Electrocardiogram parameters: QTcF interval

Secondary: 23_Electrocardiogram parameters: PR interval

Secondary: 23_Electrocardiogram parameters: PR interval

Secondary: 24_Electrocardiogram parameters: QRS interval

Secondary: 24_Electrocardiogram parameters: QRS interval

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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