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Clinical Trial Results:
A 24-week study to evaluate the effect of fluticasone furoate (GW685698)/vilanterol (GW642444) 100/25 µg Inhalation Powder delivered once-daily via a Novel Dry Powder Inhaler on arterial stiffness compared with placebo and vilanterol in subjects with Chronic Obstructive Pulmonary Disease (COPD).

Summary
EudraCT number	2010-023091-10
Trial protocol	DE NO
Global end of trial date	04 Nov 2014

Results information
Results version number	v1(current)
This version publication date	27 Apr 2016
First version publication date	01 Jul 2015
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

HZC113108

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

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

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

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

29 Jan 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Nov 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate the effect of FF/VI Inhalation Powder 100/25 µg administered once daily compared with placebo on arterial stiffness measured as Aortic Pulse Wave Velocity (aPWV) in subjects with COPD and aPWV ≥ 11.0 m/s at baseline.

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Mar 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 551

Country: Number of subjects enrolled

Norway: 41

Country: Number of subjects enrolled

Korea, Republic of: 211

Country: Number of subjects enrolled

Philippines: 542

Country: Number of subjects enrolled

Thailand: 253

Country: Number of subjects enrolled

United States: 1413

Worldwide total number of subjects

3011

EEA total number of subjects

592

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)

1685

From 65 to 84 years

1307

85 years and over

Subject disposition

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Recruitment details

3011 par. were screened, 559 entered Run-in Period (RIP), of whom 444 randomized and received at >=1 dose of study medication; 430 included in the Intent-to-Treat (ITT) Population. Par. were considered to have completed the TP if they attended Wk 24 and completed the study if also attended the 1-wk follow-up contact and no early withdrawal.

Screening details

Eligible participants (par.) at screening entered a 2-week, single-blind placebo RIP to obtain albuterol (salbutamol) use at Baseline, and to ensure that par.'s COPD was stable at randomization. At the end of the RIP, par. meeting the randomization criteria entered the double-blind treatment period (TP) of 24 weeks (Wk).

Period 1 title

2-week, Single-blind Run-In Period

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Placebo-Run-in

Arm description

Participants received placebo once daily (QD) in the morning for 2 weeks. In addition, participants were provided an inhaled short-acting beta2-receptor agonist (SABA), albuterol (salbutamol) (metered dose inhaler [MDI] or nebules), to be used as a rescue medication for relief of chronic obstructive pulmonary disease (COPD) symptoms during the Run-in and Treatment Periods.

Arm type

Placebo

Investigational medicinal product name

Placebo QD

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

QD in the morning via DPI

Number of subjects in period 1	Placebo-Run-in
Started	559
Completed	444
Not completed	115
Did Not Meet Continuation Criteria	102
Consent withdrawn by subject	9
Physician decision	1
Adverse event, non-fatal	1
Lost to follow-up	2

Period 2 title

24-week, Double-blind Treatment Period

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Placebo QD

Arm description

Participants received placebo QD in the morning via a dry powder inhaler (DPI) for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol), to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Arm type

Placebo

Investigational medicinal product name

Placebo QD

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

QD in the morning via DPI

VI 25 µg QD

Arm description

Participants received vilanterol (VI) 25 micrograms (µg) inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol), to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Arm type

Experimental

Investigational medicinal product name

Vilanterol 25 µg QD

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

QD in the morning via DPI

FF/VI 100/25 µg QD

Arm description

Participants received fluticasone furoate (FF)/VI 100/25 µg inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol), to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Arm type

Experimental

Investigational medicinal product name

Fluticasone Furoate/Vilanterol 100/25 µg QD

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

QD in the morning via DPI

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Eligible par. at screening entered a 2-week, single-blind placebo RIP to obtain albuterol (salbutamol) use at Baseline, and to ensure that par.'s COPD was stable at randomization. At the end of the RIP, par. meeting the randomization criteria entered the double-blind treatment period (TP) of 24 weeks (Wk).

Number of subjects in period 2 ^[2] ^[3]	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Started	141	154	135
Completed the Treatment Period	96 ^[4]	124	110 ^[5]
Completed	97	124	111
Not completed	44	30	24
Physician decision	3	1	1
Consent withdrawn by subject	7	4	1
Adverse event, non-fatal	8	6	7
Lack of Efficacy-Sub-Reason Exacerbation	13	13	6
Protocol-defined Stopping Criteria	4	3	6
Lack of Efficacy-No Sub-Reason	2	-	-
Lost to follow-up	3	-	-
Protocol deviation	4	3	3

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A total of 3011 participants (par.) were screened, 559 entered the Run-in Period (RIP), of whom 444 were randomized and received at least one dose of study medication; 430 of these were included in the Intent-to-Treat (ITT) Population.
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 3011 participants (par.) were screened, 559 entered the Run-in Period (RIP), of whom 444 were randomized and received at least one dose of study medication; 430 of these were included in the Intent-to-Treat (ITT) Population.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This milestone reflects the number of participants completing the Treatment Period. Par. were considered to have completed the TP if they attended Wk 24 and completed the study if also attended the 1-wk follow-up contact and no early withdrawal.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This milestone reflects the number of participants completing the Treatment Period. Par. were considered to have completed the TP if they attended Wk 24 and completed the study if also attended the 1-wk follow-up contact and no early withdrawal.

Baseline characteristics

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Reporting group title

Placebo QD

Reporting group description

Reporting group title

VI 25 µg QD

Reporting group description

Reporting group title

FF/VI 100/25 µg QD

Reporting group description

Reporting group values	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD	Total
Number of subjects	141	154	135	430
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	68.2 ( 8.1 )	68.7 ( 7.69 )	68.5 ( 8.01 )	-
Gender categorical
Units: Subjects
Female	22	36	31	89
Male	119	118	104	341
Race
Units: Subjects
African American/African Heritage	7	4	6	17
Asian - Central/South Asian Heritage	1	0	0	1
Asian - East Asian Heritage	21	23	18	62
Asian - South East Asian Heritage	45	51	47	143
Asian - Mixed Race	1	0	0	1
White - Arabic/North African Heritage	1	1	0	2
White - White/Caucasian/European Heritage	64	75	64	203
Mixed Race	1	0	0	1

End points

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Reporting group title

Placebo-Run-in

Reporting group description

Reporting group title

Placebo QD

Reporting group description

Reporting group title

VI 25 µg QD

Reporting group description

Reporting group title

FF/VI 100/25 µg QD

Reporting group description

Primary: Mean change from Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the end of the 24-week Treatment Period (Day 168)

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End point title

Mean change from Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the end of the 24-week Treatment Period (Day 168)

End point description

PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of (Eh/2ρR), where E is Young’s modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and ρ is the blood density. Change from BL was calculated as the Day 168 value minus the BL value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking history, history of exacerbation strata, geographical region, BL aPWV and interaction terms of BL by visit and treatment by visit. ITT Population: all randomized par. who received at least one dose of study medication.

End point type

Primary

End point timeframe

BL to Day 168 Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT Population without missing covariate information and with at least one post BL measurement are included.

End point values	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Number of subjects analysed	85	117	103
Units: meters per second (m/sec)
least squares mean (standard error)	-1.97 ( 0.279 )	-1.95 ( 0.241 )	-1.75 ( 0.256 )

Analysis 1

Comparison groups

Placebo QD v VI 25 µg QD

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.969 ^[1]

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.71

upper limit

0.74

Notes
[1] - Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)

Analysis 2

Comparison groups

Placebo QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.568 ^[2]

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.96

Notes
[2] - Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)

Analysis 3

Comparison groups

VI 25 µg QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.566 ^[3]

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.89

Notes
[3] - Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)

Secondary: Change from BL in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Day 168

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End point title

Change from BL in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Day 168

End point description

Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry at Screening, Days 1, 28, 84, 126, and 168. BL FEV1 was defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 was defined as the mean of the FEV1 values obtained 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was preformed using a repeated measures model with covariates of visit, treatment, history of exacerbation strata, geographical region, BL FEV1 and interaction terms of BL by visit and treatment by visit.

End point type

Secondary

End point timeframe

End point values	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Number of subjects analysed	96	123	111
Units: Liters (L)
least squares mean (standard error)	-0.049 ( 0.0221 )	0.033 ( 0.0202 )	0.106 ( 0.021 )

Analysis 1

Comparison groups

Placebo QD v VI 25 µg QD

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[4]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.082

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.141

Notes
[4] - Nominal p-value; Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).

Analysis 2

Comparison groups

Placebo QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.155

Confidence interval

level

95%

sides

2-sided

lower limit

0.095

upper limit

0.215

Notes
[5] - Nominal p-value; Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).

Analysis 3

Comparison groups

VI 25 µg QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

234

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012 ^[6]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.074

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.131

Notes
[6] - Nominal p-value; Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).

Secondary: Mean number of occasions rescue medication [albuterol (salbutamol)] used during a 24-hour period averaged over the entire 24-week Treatment Period

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End point title

Mean number of occasions rescue medication [albuterol (salbutamol)] used during a 24-hour period averaged over the entire 24-week Treatment Period

End point description

Participants were given daily record cards for daily completion from BL (Week -1) through Week 24 (Visit 6) each morning and prior to taking study medication (i.e., single-blind and double-blind study medication) supplemental medication (albuterol [salbutamol] if received) and ipratropium bromide (if received). Participants recorded number of occasions supplemental albuterol/salbutamol (MDI and/or nebules) used over the previous 24 hours and any medical problems that they had experienced and any medication used to treat these medical problems over the previous 24 hours. Analysis was performed using an analysis of covarience (ANCOVA) model with covariates of treatment, BL mean of occasions of rescue medication use (Week -1), history of exacerbation, and geographical region. ITT Population: all randomized participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

BL (Week -1), Week 1 to Week 24 Only those participants with at least 1 on treatment rescue medication measurement during the treatment period and without missing covariate information were analyzed.

End point values	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Number of subjects analysed	139	152	135
Units: Occasions per 24 hours
least squares mean (standard error)	1.97 ( 0.093 )	1.5 ( 0.089 )	1.47 ( 0.095 )

Analysis 1

Comparison groups

Placebo QD v VI 25 µg QD

Number of subjects included in analysis

291

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[7]

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

-0.22

Notes
[7] - Nominal p-value

Analysis 2

Comparison groups

Placebo QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[8]

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

-0.24

Notes
[8] - Nominal p-value

Analysis 3

Comparison groups

VI 25 µg QD v FF/VI 100/25 µg QD

Number of subjects included in analysis

287

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.803

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.22

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAE) and non-serious AEs were collected from the start of the double-blind (DB) treatment period (Visit 2) through the follow-up contact (7 days after Visit 6 [Week 25]).

Adverse event reporting additional description

SAEs and non-serious AEs reported for par. of the Safety Population (Pop) comprised of ITT Pop plus par. from the excluded site who qualified for the ITT Pop. On-treatment AE or SAE is defined as an AE with an onset date on or after the start date of DB study medication, but not later than one day after the last dose of DB study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Placebo QD

Reporting group description

Participants received placebo QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol) , to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Reporting group title

VI 25 µg QD

Reporting group description

Participants received VI 25 µg inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol), to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Reporting group title

FF/VI 100/25 µg QD

Reporting group description

Participants received FF/VI 100/25 µg inhalation QD in the morning via a DPI for 24 weeks. In addition, participants were provided an inhaled SABA, albuterol (salbutamol) to be used as a rescue medication for relief of COPD symptoms during the Run-in and Treatment Periods.

Serious adverse events	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 145 (3.45%)	12 / 158 (7.59%)	9 / 141 (6.38%)
number of deaths (all causes)	0	1	1
number of deaths resulting from adverse events
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Colorectal cancer
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	1 / 145 (0.69%)	0 / 158 (0.00%)	0 / 141 (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 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Injury, poisoning and procedural complications
Facial bones fracture
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 145 (0.69%)	0 / 158 (0.00%)	0 / 141 (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
Angina unstable
subjects affected / exposed	1 / 145 (0.69%)	0 / 158 (0.00%)	0 / 141 (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
Cardio-respiratory arrest
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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 disorders
Faecaloma
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 145 (0.69%)	0 / 158 (0.00%)	0 / 141 (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
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 145 (0.69%)	5 / 158 (3.16%)	2 / 141 (1.42%)
occurrences causally related to treatment / all	1 / 1	0 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Infections and infestations
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Pneumonia
subjects affected / exposed	2 / 145 (1.38%)	1 / 158 (0.63%)	2 / 141 (1.42%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Pyelonephritis
subjects affected / exposed	0 / 145 (0.00%)	0 / 158 (0.00%)	1 / 141 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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
Type 2 diabetes mellitus
subjects affected / exposed	0 / 145 (0.00%)	1 / 158 (0.63%)	0 / 141 (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

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Placebo QD	VI 25 µg QD	FF/VI 100/25 µg QD
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 145 (16.55%)	27 / 158 (17.09%)	34 / 141 (24.11%)
Nervous system disorders
Headache
subjects affected / exposed	5 / 145 (3.45%)	9 / 158 (5.70%)	8 / 141 (5.67%)
occurrences all number	6	11	13
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 145 (0.69%)	2 / 158 (1.27%)	6 / 141 (4.26%)
occurrences all number	1	2	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 145 (2.76%)	1 / 158 (0.63%)	5 / 141 (3.55%)
occurrences all number	4	1	7
Back pain
subjects affected / exposed	5 / 145 (3.45%)	5 / 158 (3.16%)	4 / 141 (2.84%)
occurrences all number	5	8	8
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 145 (3.45%)	12 / 158 (7.59%)	9 / 141 (6.38%)
occurrences all number	5	14	11
Oral candidiasis
subjects affected / exposed	1 / 145 (0.69%)	2 / 158 (1.27%)	9 / 141 (6.38%)
occurrences all number	1	2	12
Upper respiratory tract infection
subjects affected / exposed	6 / 145 (4.14%)	4 / 158 (2.53%)	2 / 141 (1.42%)
occurrences all number	9	4	3

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Were there any global substantial amendments to the protocol? Yes

19 Aug 2011

To revise Inclusion Criterion #8: Baseline aortic pulse wave velocity

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: Mean change from Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the end of the 24-week Treatment Period (Day 168)

Primary: Mean change from Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the end of the 24-week Treatment Period (Day 168)

Secondary: Change from BL in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Day 168

Secondary: Change from BL in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Day 168

Secondary: Mean number of occasions rescue medication [albuterol (salbutamol)] used during a 24-hour period averaged over the entire 24-week Treatment Period

Secondary: Mean number of occasions rescue medication [albuterol (salbutamol)] used during a 24-hour period averaged over the entire 24-week Treatment Period

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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