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Clinical Trial Results:
A Randomized Double-Blind, Double Dummy, Placebo-Controlled, Parallel-Group, Multicenter Dose Ranging Study to Evaluate the Efficacy and Safety of GW685698X Inhalation Powder Once Daily and Fluticasone Propionate Inhalation Powder 500mcg Twice Daily compared with Placebo for 8 Weeks in Adolescent and Adult Subjects with Persistent Asthma Symptomatic on Moderate-Dose ICS Therapy.

Summary
EudraCT number	2007-004458-98
Trial protocol	FR NL PL EE CZ BG DE
Global end of trial date	20 Sep 2008

Results information
Results version number	v1(current)
This version publication date	13 Apr 2016
First version publication date	19 Mar 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

FFA109684

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?

Yes

Analysis stage

Final

Date of interim/final analysis

17 Oct 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Sep 2008

Was the trial ended prematurely?

Main objective of the trial

The objective of this 8-week study is to evaluate the dose response, efficacy and safety of four dosage regimens of GW685698X (200mcg, 400mcg, 600mcg and 800mcg) administered once daily in the evening in adolescent and adult subjects 12 years of age and older with persistent uncontrolled asthma to effectively select the appropriate dose of GW685698X to be evaluated in further clinical studies.

Protection of trial subjects

On initial entry into the trial, subjects were assessed for their fitness for the study by a physical exam, chemistry/hematology/urinalysis laboratory tests, and serum pregnancy (females of child-bearing potential). Medical, asthma and previous treatment histories were obtained along with pulmonary function testing. Reversibility was also established. Stability limits of 80% of the subject’s FEV1 and peak expiratory flow (PEF) rate were established at the randomization visit to assist the investigators in monitoring subjects’ asthma status throughout the study. Twice each day (morning and evening), subjects rated their asthma symptoms and measured their PEF. Subjects were instructed to contact the investigator if the PEF fell below the established limit. Albuterol inhalation was provided for rescue use and use was monitored each morning and evening when the other assessments were performed. Pulmonary function was assessed at each visit via spirometry. Vital signs were also taken at each visit and the subjects were questioned in regard to their health and adverse events/serious adverse events that may have occurred. Two medics supported the study and were available for consultation with the investigators as needed.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Dec 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 41

Country: Number of subjects enrolled

Poland: 56

Country: Number of subjects enrolled

Bulgaria: 68

Country: Number of subjects enrolled

Czech Republic: 4

Country: Number of subjects enrolled

Estonia: 12

Country: Number of subjects enrolled

France: 20

Country: Number of subjects enrolled

Germany: 64

Country: Number of subjects enrolled

Australia: 26

Country: Number of subjects enrolled

Canada: 61

Country: Number of subjects enrolled

Chile: 132

Country: Number of subjects enrolled

Mexico: 80

Country: Number of subjects enrolled

Peru: 75

Country: Number of subjects enrolled

Russian Federation: 93

Country: Number of subjects enrolled

South Africa: 55

Country: Number of subjects enrolled

Thailand: 41

Country: Number of subjects enrolled

United States: 347

Worldwide total number of subjects

1175

EEA total number of subjects

265

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)

1000

From 65 to 84 years

113

85 years and over

Subject disposition

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Recruitment details

Screening details

Participants (par.) meeting eligibility criteria at the Screening visit completed a 28-day Run-in Period for Baseline safety evaluations and measures of asthma status. Par. were then randomized to an 8-week Treatment Period. 1175 par. were screened, and 627 par. were randomized, out of which 622 par. received at least one dose of study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo once daily (OD) in the evening from the dry powder inhaler (DPI) and placebo twice daily (BID) from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

Twice daily

GW685698X 200 µg OD

Arm description

Participants received GW685698X 200 micrograms (µg) OD in the evening from the DPI and placebo BID from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

200 μg once daily

GW685698X 400 µg OD

Arm description

Participants received GW685698X 400 µg OD in the evening from the DPI and placebo BID from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

400 μg once daily

GW685698X 600 µg OD

Arm description

Participants received GW685698X 600 µg OD in the evening from the DPI and placebo BID from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

600 μg once daily

GW685698X 800 µg OD

Arm description

Participants received GW685698X 800 µg OD in the evening from the DPI and placebo BID from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

800 μg once daily

FP 500 µg BID

Arm description

Participants received fluticasone propionate (FP) 500 µg BID from the DISKUS/ACCUHALER (one inhalation in the morning and one inhalation in the evening) plus placebo OD in the evening from the DPI for 8 weeks. Albuterol/salbutamol inhalation aerosol was provided to be used as needed for symptomatic relief of asthma symptoms during the Treatment Period.

Arm type

Active comparator

Investigational medicinal product name

Fluticasone propionate

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

500 μg twice daily

Number of subjects in period 1 ^[1]	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Started	103	99	101	107	102	110
Completed	65	81	93	94	85	97
Not completed	38	18	8	13	17	13
Physician decision	1	-	-	-	1	-
Consent withdrawn by subject	1	-	-	1	3	1
Adverse event, non-fatal	2	3	-	1	-	4
Lost to follow-up	-	1	1	-	-	-
Lack of efficacy	34	11	6	11	12	8
Protocol deviation	-	3	1	-	1	-

Notes
[1] - 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: 1175 par. were screened, and 627 par. were randomized, out of which 622 par. received at least one dose of study treatment. Subject disposition is presented for the 622 participants that received at least one dose of study treatment.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

GW685698X 400 µg OD

Reporting group description

Reporting group title

GW685698X 600 µg OD

Reporting group description

Reporting group title

GW685698X 800 µg OD

Reporting group description

Reporting group title

FP 500 µg BID

Reporting group description

Reporting group values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID	Total
Number of subjects	103	99	101	107	102	110	622
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	47.2 ( 14.03 )	45.7 ( 15.02 )	47.2 ( 14.39 )	45.7 ( 14.38 )	46.6 ( 14.09 )	46.1 ( 13.86 )	-
Gender categorical
Units: Subjects
Female	64	63	62	67	63	68	387
Male	39	36	39	40	39	42	235
Race
Units: Subjects
African American/African Heritage (HER)	2	3	3	4	4	4	20
American Indian or Alaska Native	6	7	5	8	5	7	38
Central/South Asian HER	2	3	1	4	1	1	12
Japanese/East Asian HER/South East Asian HER	4	6	6	7	6	6	35
White	83	74	80	77	80	83	477
American Indian or Alaska Native & Asian & White	0	1	0	0	0	0	1
American Indian or Alaska Native & White	6	5	6	7	6	8	38
Missing	0	0	0	0	0	1	1

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

GW685698X 400 µg OD

Reporting group description

Reporting group title

GW685698X 600 µg OD

Reporting group description

Reporting group title

GW685698X 800 µg OD

Reporting group description

Reporting group title

FP 500 µg BID

Reporting group description

Primary: Mean change from Baseline in trough (evening pre-dose and pre- rescue bronchodilator) FEV1 at Week 8

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End point title

Mean change from Baseline in trough (evening pre-dose and pre- rescue bronchodilator) FEV1 at Week 8

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 forcibly exhaled from the lungs in one second. Pre-dose and pre-rescue bronchodilator (albuterol/salbutamol) trough FEV1 (the measurement of FEV1 performed at the end of the dosing interval) was measured electronically by spirometry in the evening at BL through Week 8 clinic visits. The highest of 3 technically acceptable measurements was recorded. The Visit 3 FEV1 assessment was used as the BL value. Change from BL in trough FEV1 was calculated as the value at WK 8 minus the value at BL. The analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of BL trough FEV1, country, sex, age, and treatment group. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-BL on-treatment measurement (scheduled and unscheduled visits) was used to impute missing measurements.

End point type

Primary

End point timeframe

Baseline (BL) and Week (WK) 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[1]	99 ^[2]	101 ^[3]	107 ^[4]	102 ^[5]	110 ^[6]
Units: Liters
least squares mean (standard error)	-0.043 ( 0.0338 )	0.232 ( 0.0347 )	0.229 ( 0.0342 )	0.221 ( 0.0332 )	0.182 ( 0.0342 )	0.155 ( 0.0332 )

Notes
[1] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication
[2] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication
[3] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication
[4] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication
[5] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication
[6] - Intent-to-Treat (ITT) Population: randomized participants who received >= 1 dose of study medication

Analysis 1

Comparison groups

GW685698X 200 µg OD v Placebo

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.275

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

0.37

Analysis 2

Comparison groups

Placebo v GW685698X 400 µg OD

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.272

Confidence interval

level

95%

sides

2-sided

lower limit

0.178

upper limit

0.367

Analysis 3

Comparison groups

Placebo v GW685698X 600 µg OD

Number of subjects included in analysis

210

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.264

Confidence interval

level

95%

sides

2-sided

lower limit

0.171

upper limit

0.357

Analysis 4

Comparison groups

Placebo v GW685698X 800 µg OD

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.225

Confidence interval

level

95%

sides

2-sided

lower limit

0.131

upper limit

0.32

Analysis 5

Comparison groups

Placebo v FP 500 µg BID

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.198

Confidence interval

level

95%

sides

2-sided

lower limit

0.105

upper limit

0.291

Secondary: Mean change from Baseline in daily trough (pre-dose and pre-rescue bronchodilator) evening peak expiratory flow (PEF) averaged over the 8-week Treatment Period

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End point title

Mean change from Baseline in daily trough (pre-dose and pre-rescue bronchodilator) evening peak expiratory flow (PEF) averaged over the 8-week Treatment Period

End point description

PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Trough PEF is defined as the maximal rate (speed) that a person can exhale during a short maximal expiratory effort after a full inspiration. PEF was measured by the participants using a hand-held electronic peak flow meter each evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three attempts was recorded by the participants in a daily diary. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the value of the averaged daily evening PEF over the 8-week treatment period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline trough evening PEF, country, sex, age, and treatment group.

End point type

Secondary

End point timeframe

From Baseline up to Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	100 ^[7]	99 ^[8]	101 ^[9]	107 ^[10]	101 ^[11]	109 ^[12]
Units: Liters per minute
least squares mean (standard error)	-5.1 ( 3.32 )	11.9 ( 3.32 )	14.5 ( 3.29 )	11.7 ( 3.2 )	16.3 ( 3.3 )	11.1 ( 3.17 )

Notes
[7] - ITT Population. Only those participants available at the specified time points were analyzed.
[8] - ITT Population. Only those participants available at the specified time points were analyzed.
[9] - ITT Population. Only those participants available at the specified time points were analyzed.
[10] - ITT Population. Only those participants available at the specified time points were analyzed.
[11] - ITT Population. Only those participants available at the specified time points were analyzed.
[12] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Mean change from Baseline in daily morning PEF averaged over the 8-week Treatment Period

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End point title

Mean change from Baseline in daily morning PEF averaged over the 8-week Treatment Period

End point description

PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Trough PEF is defined as the maximal rate (speed) that a person can exhale during a short maximal expiratory effort after a full inspiration. PEF was measured by the participants using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three attempts was recorded by the participants in a daily diary. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the value of the averaged daily morning PEF over the 8-week treatment period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline trough morning PEF, country, sex, age, and treatment group.

End point type

Secondary

End point timeframe

From Baseline up to Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	101 ^[13]	99 ^[14]	101 ^[15]	107 ^[16]	101 ^[17]	109 ^[18]
Units: Liters per minute
least squares mean (standard error)	-7.3 ( 3.32 )	19.6 ( 3.34 )	20.9 ( 3.31 )	16.7 ( 3.22 )	20.7 ( 3.32 )	16.5 ( 3.19 )

Notes
[13] - ITT Population. Only those participants available at the specified time points were analyzed.
[14] - ITT Population. Only those participants available at the specified time points were analyzed.
[15] - ITT Population. Only those participants available at the specified time points were analyzed.
[16] - ITT Population. Only those participants available at the specified time points were analyzed.
[17] - ITT Population. Only those participants available at the specified time points were analyzed.
[18] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Mean change from Baseline in the percentage of symptom-free 24-hour (hr) periods during the 8-week Treatment Period

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End point title

Mean change from Baseline in the percentage of symptom-free 24-hour (hr) periods during the 8-week Treatment Period

End point description

Asthma symptoms were recorded in a daily diary by the participants every day in the morning and evening before taking any rescue or study medication and before PEF measurement. A 24-hour period in which a participant’s responses to both the morning and evening assessments indicated no symptoms was considered as symptom-free. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 8-week Treatment Period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline, country, sex, age, and treatment group.

End point type

Secondary

End point timeframe

From Baseline up to Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	101 ^[19]	99 ^[20]	101 ^[21]	107 ^[22]	101 ^[23]	110 ^[24]
Units: Percentage of symptom-free 24-hr periods
least squares mean (standard error)	6.4 ( 2.71 )	20.1 ( 2.74 )	19.6 ( 2.71 )	15.1 ( 2.63 )	18.5 ( 2.71 )	15.4 ( 2.61 )

Notes
[19] - ITT Population. Only those participants available at the specified time points were analyzed.
[20] - ITT Population. Only those participants available at the specified time points were analyzed.
[21] - ITT Population. Only those participants available at the specified time points were analyzed.
[22] - ITT Population. Only those participants available at the specified time points were analyzed.
[23] - ITT Population. Only those participants available at the specified time points were analyzed.
[24] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Mean change from Baseline in the percentage of rescue-free 24-hour (hr) periods during the 8-week Treatment Period

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End point title

Mean change from Baseline in the percentage of rescue-free 24-hour (hr) periods during the 8-week Treatment Period

End point description

The number of inhalations of rescue albuterol/salbutamol inhalation aerosol used during the day and night was recorded by the participants in a daily diary. A 24-hour period in which a participant’s responses to both the morning and evening assessments indicated no use of rescue medication was considered as rescue-free. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 8-week Treatment Period minus the value at Baseline. The analysis was performed using an ANCOVA model with covariates of Baseline, country, sex, age, and treatment group.

End point type

Secondary

End point timeframe

From Baseline up to Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	101 ^[25]	99 ^[26]	101 ^[27]	107 ^[28]	101 ^[29]	110 ^[30]
Units: Percentage of rescue-free 24-hr periods
least squares mean (standard error)	3.6 ( 2.75 )	17.9 ( 2.78 )	21.2 ( 2.75 )	17.4 ( 2.67 )	22.3 ( 2.75 )	16.7 ( 2.63 )

Notes
[25] - ITT Population. Only those participants available at the specified time points were analyzed.
[26] - ITT Population. Only those participants available at the specified time points were analyzed.
[27] - ITT Population. Only those participants available at the specified time points were analyzed.
[28] - ITT Population. Only those participants available at the specified time points were analyzed.
[29] - ITT Population. Only those participants available at the specified time points were analyzed.
[30] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Number participants who withdrew due to lack of efficacy during the 8-week Treatment Period

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End point title

Number participants who withdrew due to lack of efficacy during the 8-week Treatment Period

End point description

The number of participants whose primary reason for withdrawal was lack of efficacy was analyzed.

End point type

Secondary

End point timeframe

From the first dose of the study medication up to Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[31]	99 ^[32]	101 ^[33]	107 ^[34]	102 ^[35]	110 ^[36]
Units: Participants	34	11	6	11	12	8

Notes
[31] - ITT Population
[32] - ITT Population
[33] - ITT Population
[34] - ITT Population
[35] - ITT Population
[36] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with any on-treatment adverse event or serious adverse event throughout the 8-week Treatment Period

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End point title

Number of participants with any on-treatment adverse event or serious adverse event throughout the 8-week Treatment Period

End point description

An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general AE/SAE module for a list of AEs (occurring at a frequency threshold >=3%) and SAEs.

End point type

Secondary

End point timeframe

From the first dose of the study medication up to Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[37]	99 ^[38]	101 ^[39]	107 ^[40]	102 ^[41]	110 ^[42]
Units: Participants
Any AE	23	31	34	37	36	39
Any SAE	1	2	0	1	0	2

Notes
[37] - ITT Population
[38] - ITT Population
[39] - ITT Population
[40] - ITT Population
[41] - ITT Population
[42] - ITT Population

No statistical analyses for this end point

Secondary: Number of participants with clinical/visual evidence of oropharyngeal candidiasis

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End point title

Number of participants with clinical/visual evidence of oropharyngeal candidiasis

End point description

A detailed oropharyngeal examination for visual evidence of oral candidiasis was performed.

End point type

Secondary

End point timeframe

From Baseline up to Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[43]	99 ^[44]	101 ^[45]	107 ^[46]	102 ^[47]	110 ^[48]
Units: Participants
Clinical evidence	0	0	0	0	0	0
No clinical evidence	103	99	101	107	102	110

Notes
[43] - ITT Population
[44] - ITT Population
[45] - ITT Population
[46] - ITT Population
[47] - ITT Population
[48] - ITT Population

No statistical analyses for this end point

Secondary: Percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in the blood at Baseline and Week 8

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End point title

Percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in the blood at Baseline and Week 8

End point description

Blood samples were collected for the measurement of the percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in the blood at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[49]	99 ^[50]	101 ^[51]	107 ^[52]	102 ^[53]	110 ^[54]
Units: Percentage in the blood
arithmetic mean (standard deviation)
Basophils, BL, n=96, 98, 96, 101, 96, 104	0.31 ( 0.211 )	0.38 ( 0.315 )	0.35 ( 0.252 )	0.34 ( 0.306 )	0.36 ( 0.22 )	0.34 ( 0.181 )
Basophils, W8, n=64, 78, 86, 88, 80, 93	0.38 ( 0.191 )	0.35 ( 0.199 )	0.28 ( 0.172 )	0.26 ( 0.164 )	0.31 ( 0.175 )	0.3 ( 0.159 )
Eosinophils, BL, n=96, 98, 96, 101, 96, 104	4.21 ( 3.241 )	4.11 ( 3.024 )	3.7 ( 2.942 )	4.34 ( 3.148 )	3.74 ( 2.543 )	3.5 ( 2.675 )
Eosinophils, W 8, n=64, 78, 86, 88, 80, 93	3.92 ( 2.835 )	3.54 ( 2.784 )	2.76 ( 1.943 )	2.94 ( 3.395 )	2.14 ( 2.076 )	3.31 ( 2.815 )
Lymphocytes, BL, n=96, 98, 96, 101, 96, 104	32.23 ( 7.231 )	32.31 ( 8.344 )	33.48 ( 9.299 )	32.03 ( 7.813 )	33.33 ( 7.99 )	30.13 ( 8.938 )
Lymphocytes, W 8, n=64, 78, 86, 88, 80, 93	30.87 ( 8.332 )	30.64 ( 7.046 )	30.28 ( 8.734 )	27.64 ( 9.216 )	29.5 ( 9.763 )	29.23 ( 8.205 )
Monocytes, BL, n=96, 98, 96, 101, 96, 104	5.03 ( 2.337 )	4.75 ( 1.765 )	5.23 ( 2.58 )	4.89 ( 1.896 )	5.19 ( 2.384 )	5.06 ( 1.989 )
Monocytes, W 8, n=64, 78, 86, 88, 80, 93	5.07 ( 1.885 )	4.53 ( 2.025 )	4.82 ( 2.087 )	4.5 ( 2.188 )	4.64 ( 2.224 )	4.97 ( 2.15 )
Total neutrophils, BL, n=96, 98, 96, 101, 96, 104	58.22 ( 8.02 )	58.45 ( 9.166 )	57.08 ( 10.168 )	58.41 ( 8.589 )	57.33 ( 8.627 )	60.96 ( 10.096 )
Total neutrophils, W8, n=64, 78, 86, 88, 80, 93	59.78 ( 9.101 )	60.95 ( 7.819 )	61.87 ( 9.175 )	64.67 ( 10.031 )	63.41 ( 10.926 )	62.19 ( 9.128 )

Notes
[49] - ITT Population. Only those participants available at the specified time points were analyzed.
[50] - ITT Population. Only those participants available at the specified time points were analyzed.
[51] - ITT Population. Only those participants available at the specified time points were analyzed.
[52] - ITT Population. Only those participants available at the specified time points were analyzed.
[53] - ITT Population. Only those participants available at the specified time points were analyzed.
[54] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Hematocrit at Baseline and Week 8

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End point title

Hematocrit at Baseline and Week 8

End point description

Blood samples were collected for the measurement of hematocrit at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[55]	99 ^[56]	101 ^[57]	107 ^[58]	102 ^[59]	110 ^[60]
Units: Proportion of 1
arithmetic mean (standard deviation)
BL, n=95, 98, 96, 100, 94, 104	0.43 ( 0.039 )	0.43 ( 0.034 )	0.42 ( 0.035 )	0.42 ( 0.042 )	0.43 ( 0.038 )	0.42 ( 0.043 )
W8, n=64, 78, 86, 89, 80, 93	0.43 ( 0.04 )	0.42 ( 0.036 )	0.42 ( 0.035 )	0.42 ( 0.042 )	0.43 ( 0.037 )	0.42 ( 0.043 )

Notes
[55] - ITT Population. Only those participants available at the specified time points were analyzed.
[56] - ITT Population. Only those participants available at the specified time points were analyzed.
[57] - ITT Population. Only those participants available at the specified time points were analyzed.
[58] - ITT Population. Only those participants available at the specified time points were analyzed.
[59] - ITT Population. Only those participants available at the specified time points were analyzed.
[60] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Hemoglobin at Baseline and Week 8

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End point title

Hemoglobin at Baseline and Week 8

End point description

Blood samples were collected for the measurement of hemoglobin at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[61]	99 ^[62]	101 ^[63]	107 ^[64]	102 ^[65]	110 ^[66]
Units: Grams per liter (G/L)
arithmetic mean (standard deviation)
BL, n=95, 98, 96, 100, 94, 104	139.99 ( 13.23 )	140.2 ( 11.183 )	139.35 ( 11.577 )	138.5 ( 14.987 )	140.91 ( 13.023 )	138.53 ( 14.77 )
W8, n=64, 78, 86, 89, 80, 93	139.63 ( 12.359 )	137.42 ( 11.461 )	137.56 ( 11.747 )	135.81 ( 13.847 )	140.64 ( 12.679 )	137.31 ( 14.65 )

Notes
[61] - ITT Population. Only those participants available at the specified time points were analyzed.
[62] - ITT Population. Only those participants available at the specified time points were analyzed.
[63] - ITT Population. Only those participants available at the specified time points were analyzed.
[64] - ITT Population. Only those participants available at the specified time points were analyzed.
[65] - ITT Population. Only those participants available at the specified time points were analyzed.
[66] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Platelet count and white blood cell count at Baseline and Week 8

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End point title

Platelet count and white blood cell count at Baseline and Week 8

End point description

Blood samples were collected for determining the platelet count and white blood cell (WBC) count at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[67]	99 ^[68]	101 ^[69]	107 ^[70]	102 ^[71]	110 ^[72]
Units: 10^9 cells per liter (GI/L)
arithmetic mean (standard deviation)
Platelet count, BL, n=95, 98, 96, 99, 94, 104	275.76 ( 58.949 )	281.46 ( 74.55 )	270.32 ( 50.756 )	275.62 ( 56.811 )	269.09 ( 61.89 )	269.8 ( 65.376 )
Platelet count, W8, n=64, 78, 86, 89, 79, 93	265.86 ( 55.155 )	285.62 ( 66.487 )	270.77 ( 50.491 )	291.36 ( 63.65 )	280.78 ( 65.044 )	275.48 ( 65.011 )
WBC count, BL, n=95, 98, 96, 99, 94, 104	8.16 ( 2.182 )	7.77 ( 2.016 )	8.01 ( 2.199 )	8.18 ( 1.807 )	7.91 ( 1.853 )	8.25 ( 2.4 )
WBC count, W8, n=64, 78, 86, 88, 80, 93	7.84 ( 1.944 )	7.97 ( 1.671 )	8.38 ( 2.416 )	9.1 ( 2.134 )	8.9 ( 1.964 )	8.21 ( 1.973 )

Notes
[67] - ITT Population. Only those participants available at the specified time points were analyzed.
[68] - ITT Population. Only those participants available at the specified time points were analyzed.
[69] - ITT Population. Only those participants available at the specified time points were analyzed.
[70] - ITT Population. Only those participants available at the specified time points were analyzed.
[71] - ITT Population. Only those participants available at the specified time points were analyzed.
[72] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Red blood cell count at Baseline and Week 8

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End point title

Red blood cell count at Baseline and Week 8

End point description

Blood samples were collected for determining the red blood cell count at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[73]	99 ^[74]	101 ^[75]	107 ^[76]	102 ^[77]	110 ^[78]
Units: 10^12 cells per liter (TI/L)
arithmetic mean (standard deviation)
BL, n=95, 98, 96, 100, 94, 104	4.67 ( 0.413 )	4.69 ( 0.438 )	4.64 ( 0.413 )	4.6 ( 0.428 )	4.66 ( 0.416 )	4.64 ( 0.421 )
W8, n=64, 78, 86, 89, 80, 93	4.61 ( 0.423 )	4.64 ( 0.472 )	4.57 ( 0.383 )	4.52 ( 0.442 )	4.65 ( 0.425 )	4.61 ( 0.43 )

Notes
[73] - ITT Population. Only those participants available at the specified time points were analyzed.
[74] - ITT Population. Only those participants available at the specified time points were analyzed.
[75] - ITT Population. Only those participants available at the specified time points were analyzed.
[76] - ITT Population. Only those participants available at the specified time points were analyzed.
[77] - ITT Population. Only those participants available at the specified time points were analyzed.
[78] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) at Baseline and Week 8

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End point title

Clinical chemistry parameters of alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) at Baseline and Week 8

End point description

Blood samples were collected for the measurement of ALT, ALP, AST, GGT, and LDH at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[79]	99 ^[80]	101 ^[81]	107 ^[82]	102 ^[83]	110 ^[84]
Units: International units per liter (IU/L)
arithmetic mean (standard deviation)
ALT, BL, n=101, 97, 101, 107, 101, 109	22.4 ( 12.52 )	21 ( 10.02 )	23.9 ( 15.07 )	23.5 ( 18.89 )	23.1 ( 14.71 )	20.5 ( 13.26 )
ALT, W8, n=66, 79, 91, 90, 86, 96	23.7 ( 19.99 )	20.2 ( 11.31 )	21.6 ( 14.43 )	20.4 ( 12.33 )	22 ( 12.14 )	20.7 ( 14.56 )
ALP, BL, n=101, 97, 101, 107, 100, 109	74.7 ( 21.34 )	80.2 ( 41.24 )	90.9 ( 54.98 )	77.1 ( 38.35 )	73.9 ( 31.02 )	76.7 ( 32.97 )
ALP, W8, n=66, 78, 91, 89, 86, 96	75.1 ( 21.38 )	80.4 ( 54.47 )	86.6 ( 42.66 )	74.5 ( 26.54 )	70.6 ( 26.33 )	77.2 ( 28.25 )
AST, BL, n=101, 97, 100, 106, 101, 108	21.6 ( 6.45 )	21.6 ( 7.11 )	23.7 ( 10.46 )	23.3 ( 20.15 )	22.7 ( 8.42 )	21.9 ( 11.34 )
AST, W8, n=66, 78, 91, 89, 85, 96	24.1 ( 20.87 )	21.6 ( 8.39 )	22 ( 11.41 )	22.1 ( 17.12 )	22 ( 9.25 )	21.4 ( 8.61 )
GGT, BL, n=101, 97, 101, 107, 101, 109	33 ( 26.34 )	36.8 ( 39.79 )	40.4 ( 44.86 )	42.3 ( 109.34 )	31.2 ( 22.88 )	28.2 ( 20.5 )
GGT, W8, n=66, 79, 91, 90, 86, 96	36.4 ( 37.07 )	32.7 ( 22.5 )	40.6 ( 70.55 )	47.4 ( 167.46 )	34.1 ( 28.31 )	29.2 ( 20.01 )
LDH, BL, n=101, 97, 100, 106, 101, 108	158.2 ( 26.1 )	162 ( 27.64 )	163.5 ( 35.16 )	158.7 ( 30.24 )	161.6 ( 31.49 )	160.6 ( 24.97 )
LDH, W8, n=66, 78, 91, 89, 85, 96	160.4 ( 43.44 )	159 ( 27.52 )	163.6 ( 37 )	164.6 ( 35.8 )	170.6 ( 33.92 )	164 ( 27.59 )

Notes
[79] - ITT Population. Only those participants available at the specified time points were analyzed.
[80] - ITT Population. Only those participants available at the specified time points were analyzed.
[81] - ITT Population. Only those participants available at the specified time points were analyzed.
[82] - ITT Population. Only those participants available at the specified time points were analyzed.
[83] - ITT Population. Only those participants available at the specified time points were analyzed.
[84] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of albumin and total protein at Baseline and Week 8

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End point title

Clinical chemistry parameters of albumin and total protein at Baseline and Week 8

End point description

Blood samples were collected for the measurement of albumin and total protein at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[85]	99 ^[86]	101 ^[87]	107 ^[88]	102 ^[89]	110 ^[90]
Units: Grams per liter (g/L)
arithmetic mean (standard deviation)
Albumin, BL, n=101, 97, 101, 107, 101, 109	44.6 ( 2.36 )	44.9 ( 3.11 )	45.1 ( 2.91 )	44.3 ( 3.27 )	44.8 ( 3.49 )	44.9 ( 2.96 )
Albumin, W8, n=66, 79, 91, 90, 86, 96	44.5 ( 2.66 )	44.8 ( 3.27 )	44.6 ( 3.32 )	44 ( 3.28 )	44.1 ( 3.38 )	44.6 ( 3.07 )
Total protein, BL, n=101, 97, 101, 107, 101, 109	72.7 ( 3.82 )	73.4 ( 3.9 )	73.2 ( 4.15 )	73.3 ( 4.22 )	73.1 ( 4.8 )	72.5 ( 3.85 )
Total protein, W8, n=66, 79, 91, 90, 86, 96	72 ( 4.21 )	72.6 ( 3.67 )	72.7 ( 4.54 )	72.2 ( 4.2 )	72 ( 4.39 )	71.9 ( 4.34 )

Notes
[85] - ITT Population. Only those participants available at the specified time points were analyzed.
[86] - ITT Population. Only those participants available at the specified time points were analyzed.
[87] - ITT Population. Only those participants available at the specified time points were analyzed.
[88] - ITT Population. Only those participants available at the specified time points were analyzed.
[89] - ITT Population. Only those participants available at the specified time points were analyzed.
[90] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of calcium, carbon dioxide content/bicarbonate, chloride, cholesterol, glucose, phosphorus inorganic, potassium, sodium, and urea at Baseline and Week 8

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End point title

Clinical chemistry parameters of calcium, carbon dioxide content/bicarbonate, chloride, cholesterol, glucose, phosphorus inorganic, potassium, sodium, and urea at Baseline and Week 8

End point description

Blood samples were collected for the measurement of calcium, carbon dioxide content/bicarbonate (CO2/BI), chloride, cholesterol, glucose, phosphorus inorganic (PI), potassium, sodium, and urea at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[91]	99 ^[92]	101 ^[93]	107 ^[94]	102 ^[95]	110 ^[96]
Units: Millimoles per liter (mmol/L)
arithmetic mean (standard deviation)
Calcium, BL, n=101, 97, 100, 106, 101, 108	2.3 ( 0.07 )	2.3 ( 0.1 )	2.4 ( 0.09 )	2.3 ( 0.09 )	2.3 ( 0.09 )	2.3 ( 0.09 )
Calcium, W8, n=66, 78, 91, 89, 85, 96	2.3 ( 0.09 )	2.3 ( 0.11 )	2.4 ( 0.1 )	2.3 ( 0.11 )	2.3 ( 0.1 )	2.3 ( 0.09 )
CO2/BI, BL, n=101, 97, 100, 106, 101, 108	23.2 ( 2.45 )	22.9 ( 2.75 )	23.3 ( 2.39 )	22.6 ( 2.87 )	23.1 ( 2.56 )	23.2 ( 2.33 )
CO2/BI, W8, n=66, 78, 91, 89, 85, 96	22.7 ( 3.01 )	22.7 ( 2.68 )	23.5 ( 2.71 )	22.6 ( 2.56 )	23.3 ( 2.11 )	22.9 ( 2.73 )
Chloride, BL, n=101, 97, 101, 107, 101, 109	104.8 ( 2.45 )	104.4 ( 2.24 )	104.1 ( 2.84 )	104.3 ( 2.24 )	104.4 ( 2.25 )	105 ( 2.8 )
Chloride, W8, n=66, 79, 91, 90, 86, 96	105 ( 2.52 )	104.4 ( 2.46 )	103.9 ( 2.84 )	104.3 ( 2.46 )	104.1 ( 2.68 )	104.9 ( 2.79 )
Cholesterol, BL, n=101, 97, 101, 107, 101, 109	5.4 ( 1.04 )	5.3 ( 1.11 )	5.3 ( 1.13 )	5.3 ( 1.21 )	5.5 ( 1.15 )	5.1 ( 1.08 )
Cholesterol, W8, n=66, 79, 91, 90, 86, 96	5.3 ( 1 )	5.2 ( 1.09 )	5.2 ( 1.07 )	5.4 ( 1.24 )	5.5 ( 1.03 )	5.2 ( 1.17 )
Glucose, BL, n=101, 97, 101, 107, 101, 109	5.3 ( 0.81 )	5.5 ( 2.36 )	5.2 ( 1.27 )	5.2 ( 1.14 )	5.4 ( 1.73 )	5.3 ( 0.91 )
Glucose, W8, n=66, 78, 91, 90, 86, 96	5.2 ( 1.38 )	5.3 ( 1.81 )	5.5 ( 3.24 )	5.2 ( 1.19 )	5.4 ( 1.91 )	5.3 ( 1.16 )
PI, BL, n=101, 97, 101, 107, 101, 109	1.1 ( 0.18 )	1.1 ( 0.18 )	1.2 ( 0.22 )	1.2 ( 0.19 )	1.2 ( 0.19 )	1.1 ( 0.18 )
PI, W8, n=66, 79, 91, 90, 86, 96	1.2 ( 0.16 )	1.2 ( 0.17 )	1.2 ( 0.15 )	1.2 ( 0.16 )	1.2 ( 0.17 )	1.2 ( 0.16 )
Potassium, BL, n=101, 97, 100, 106, 101, 108	4.2 ( 0.38 )	4.3 ( 0.47 )	4.2 ( 0.51 )	4.2 ( 0.41 )	4.2 ( 0.3 )	4.2 ( 0.41 )
Potassium, W8, n=66, 78, 91, 89, 85, 96	4.2 ( 0.36 )	4.2 ( 0.6 )	4.2 ( 0.41 )	4.2 ( 0.38 )	4.2 ( 0.32 )	4.2 ( 0.36 )
Sodium, BL, n=101, 97, 101, 107, 101, 109	140.8 ( 1.93 )	140.4 ( 1.92 )	140.4 ( 2.06 )	140.1 ( 1.93 )	140.1 ( 1.64 )	140.8 ( 1.95 )
Sodium, W8, n=66, 79, 91, 90, 86, 96	140.5 ( 2.15 )	140.3 ( 2.17 )	140.3 ( 2.09 )	140.1 ( 1.99 )	140.4 ( 2.21 )	140.6 ( 2.08 )
Urea, BL, n=101, 97, 101, 107, 101, 109	5.7 ( 1.68 )	5.4 ( 1.49 )	5.8 ( 1.72 )	5 ( 1.34 )	5.5 ( 1.52 )	5.4 ( 1.63 )
Urea, W8, n=66, 79, 91, 90, 86, 96	5.5 ( 1.57 )	5.4 ( 1.5 )	5.7 ( 1.37 )	5.4 ( 1.45 )	5.6 ( 1.35 )	5.6 ( 1.55 )

Notes
[91] - ITT Population. Only those participants available at the specified time points were analyzed.
[92] - ITT Population. Only those participants available at the specified time points were analyzed.
[93] - ITT Population. Only those participants available at the specified time points were analyzed.
[94] - ITT Population. Only those participants available at the specified time points were analyzed.
[95] - ITT Population. Only those participants available at the specified time points were analyzed.
[96] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of creatinine, direct bilirubin, total bilirubin, and uric acid at Baseline and Week 8

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End point title

Clinical chemistry parameters of creatinine, direct bilirubin, total bilirubin, and uric acid at Baseline and Week 8

End point description

Blood samples were collected for the measurement of creatinine, direct bilirubin (DBIL), total bilirubin (TBIL), and uric acid at Baseline and Week 8. The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[97]	99 ^[98]	101 ^[99]	107 ^[100]	102 ^[101]	110 ^[102]
Units: Micromoles per liter (µmol/L)
arithmetic mean (standard deviation)
Creatinine, BL, n=101, 97, 101, 107, 101, 109	84.4 ( 14.89 )	79.8 ( 14.17 )	79.4 ( 15.86 )	78.8 ( 14.12 )	81.4 ( 13.9 )	82 ( 18.12 )
Creatinine, W8, n=66, 79, 91, 90, 86, 96	83.2 ( 15.84 )	79.9 ( 12.4 )	78.6 ( 15.25 )	78.7 ( 13.95 )	81.7 ( 13.87 )	83.1 ( 18.02 )
DBIL, BL, n=101, 97, 101, 107, 101, 109	2 ( 0.92 )	2 ( 1.08 )	2.1 ( 1.15 )	2 ( 1.05 )	1.7 ( 0.94 )	2.1 ( 1.38 )
DBIL, W8, n=65, 78, 91, 90, 86, 96	1.7 ( 0.75 )	1.8 ( 0.91 )	2.1 ( 1.19 )	1.9 ( 1.22 )	1.7 ( 0.82 )	2 ( 1.2 )
TBIL, BL, n=101, 97, 101, 107, 101, 109	9.4 ( 4.67 )	9.9 ( 4.87 )	9.8 ( 5.19 )	9.7 ( 5 )	8.2 ( 3.31 )	10.3 ( 5.86 )
TBIL, W8, n=66, 79, 91, 90, 86, 96	8.3 ( 3.68 )	9 ( 4.44 )	9.8 ( 5.1 )	9.4 ( 5.65 )	8.6 ( 3.33 )	9.6 ( 4.76 )
Uric acid, BL, n=101, 97, 101, 107, 101, 109	323.3 ( 102.51 )	326.1 ( 75.18 )	330.4 ( 81.69 )	322.1 ( 87.22 )	330.8 ( 90.07 )	310.6 ( 83.25 )
Uric acid, W8, n=66, 79, 91, 90, 86, 96	326.2 ( 104.11 )	318.5 ( 75.93 )	319.2 ( 89.12 )	305.8 ( 91.04 )	316.5 ( 92.8 )	322.7 ( 88.44 )

Notes
[97] - ITT Population. Only those participants available at the specified time points were analyzed.
[98] - ITT Population. Only those participants available at the specified time points were analyzed.
[99] - ITT Population. Only those participants available at the specified time points were analyzed.
[100] - ITT Population. Only those participants available at the specified time points were analyzed.
[101] - ITT Population. Only those participants available at the specified time points were analyzed.
[102] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated result for the indicated urinalysis parameters tested by dipstick at Baseline and Week 8/Withdrawal

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End point title

Number of participants with the indicated result for the indicated urinalysis parameters tested by dipstick at Baseline and Week 8/Withdrawal

End point description

Urinalysis parameters included: Urine Occult Blood (UOB), Urine Glucose (UG), Urine Ketones (UK), Urine Protein (UP), and Urine Leukocyte Esterase test for detecting White Blood Cells (UWBC). The dipstick was a strip used to detect the presence or absence of these parameters in the urine sample. The dipstick test gives results in a semi-quantitative manner; results for urinalysis parameters can be read as 1+, 2+, 3+, Large, Moderate, Negative (Neg), Small, and Trace. For UG, the result can be read as Neg, Trace, Trace or 1/10 grams per deciliter (G/dL), 1+ or 1/4 G/dL, 2+ or 1/2 G/dL, 3+ or 1 G/dL, 4+ or 2 or more G/dL, indicating proportional concentrations in the urine sample. Data are reported as the number of participants who had 1+, 2+, 3+, Large, Moderate, Neg, Small, or Trace levels at Baseline (BL) and Week 8 (W8)/Early Withdrawal (EW). The Baseline value was the measurement taken at screening (Visit 1).

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[103]	99 ^[104]	101 ^[105]	107 ^[106]	102 ^[107]	110 ^[108]
Units: Participants
UOB, 1+, BL, n=97, 98, 96, 102, 95, 103	0	3	3	0	1	4
UOB, 2+, BL, n=97, 98, 96, 102, 95, 103	3	1	2	1	3	0
UOB, 3+, BL, n=97, 98, 96, 102, 95, 103	0	0	4	2	1	1
UOB, Large, BL, n=97, 98, 96, 102, 95, 103	0	1	0	1	0	0
UOB, Moderate, BL, n=97, 98, 96, 102, 95, 103	1	0	1	0	0	0
UOB, Neg, BL, n=97, 98, 96, 102, 95, 103	87	87	81	93	83	95
UOB, Small, BL, n=97, 98, 96, 102, 95, 103	0	2	0	0	0	0
UOB, Trace, BL, n=97, 98, 96, 102, 95, 103	6	4	5	5	7	3
UOB, 1+, W8, n=65, 79, 88, 90, 80, 92	1	0	0	4	1	1
UOB, 2+, W8, n=65, 79, 88, 90, 80, 92	0	1	2	3	0	1
UOB, 3+, W8, n=65, 79, 88, 90, 80, 92	1	2	3	2	0	2
UOB, Large, W8, n=65, 79, 88, 90, 80, 92	0	0	0	1	0	0
UOB, Moderate, W8, n=65, 79, 88, 90, 80, 92	0	0	1	1	0	0
UOB, Neg, W8, n=65, 79, 88, 90, 80, 92	57	71	75	71	72	79
UOB, Small, W8, n=65, 79, 88, 90, 80, 92	0	0	0	1	0	0
UOB, Trace, W8, n=65, 79, 88, 90, 80, 92	6	5	7	7	7	9
UOB, Neg, EW, n=7, 0, 1, 4, 5, 4	7	0	1	4	5	4
UG, 1+ or 1/4 G/DL, BL, n=97, 98, 96, 102, 95, 103	0	0	1	0	0	1
UG, 2+ or 1/2 G/DL, BL, n=97, 98, 96, 102, 95, 103	0	0	0	1	0	0
UG, 3+ or 1 G/DL, BL, n=97, 98, 96, 102, 95, 103	0	2	0	1	1	0
UG, Neg, BL, n=97, 98, 96, 102, 95, 103	97	95	93	99	94	101
UG, Trace, BL, n=97, 98, 96, 102, 95, 103	0	0	0	0	0	1
UG, Trace or 1/10 G/DL,BL,n=97, 98, 96, 102,95,103	0	1	2	1	0	0
UG, 1+ or 1/4 G/DL, W8, n=65, 79, 88, 90, 80, 92	0	1	2	1	1	0
UG, 3+ or 1 G/DL, W8, n=65, 79, 88, 90, 80, 92	1	0	1	0	1	0
UG, 4+ or 2 or more G/DL,W8,n=65,79, 88, 90, 80,92	0	1	1	0	0	0
UG, Neg, W8, n=65, 79, 88, 90, 80, 92	63	77	83	88	78	90
UG, Trace, W8, n=65, 79, 88, 90, 80, 92	0	0	0	1	0	1
UG, Trace or 1/10 G/DL,W8,n=65, 79, 88, 90, 80, 92	1	0	1	0	0	1
UG, Neg, EW, n=7, 0, 1, 4, 5, 4	7	0	1	4	5	4
UK, 1+, BL, n=97, 98, 96, 102, 95, 103	1	0	0	0	1	0
UK, Neg, BL, n=97, 98, 96, 102, 95, 103	93	97	93	101	91	99
UK, Trace, BL, n=97, 98, 96, 102, 95, 103	3	1	3	1	3	4
UK, Neg, W8, n=65, 79, 88, 90, 80, 92	63	78	86	86	78	87
UK, Trace, W8, n=65, 79, 88, 90, 80, 92	2	1	2	4	2	5
UK, Neg, EW, n=7, 0, 1, 4, 5, 4	7	0	1	4	5	4
UP, 1+, BL, n=97, 98, 96, 102, 95, 103	3	3	5	7	3	3
UP, 2+, BL, n=97, 98, 96, 102, 95, 103	0	0	3	0	0	0
UP, 3+, BL, n=97, 98, 96, 102, 95, 103	0	0	0	1	0	1
UP, Neg, BL, n=97, 98, 96, 102, 95, 103	90	84	80	88	85	82
UP, Trace, BL, n=97, 98, 96, 102, 95, 103	4	11	8	6	7	17
UP, 1+, W8, n=65, 79, 88, 90, 80, 92	1	1	5	5	2	3
UP, 2+, W8, n=65, 79, 88, 90, 80, 92	2	0	0	1	0	0
UP, 3+, W8, n=65, 79, 88, 90, 80, 92	0	0	0	0	0	1
UP, Neg, W8, n=65, 79, 88, 90, 80, 92	56	69	77	77	71	81
UP, Trace, W8, n=65, 79, 88, 90, 80, 92	6	9	6	7	7	7
UP, Neg, EW, n=7, 0, 1, 4, 5, 4	6	0	0	4	5	4
UP, Trace, EW, n=7, 0, 1, 4, 5, 4	1	0	1	0	0	0
UWBC, 1+, BL, n=97, 98, 96, 102, 95, 103	3	9	4	9	6	3
UWBC, 2+, BL, n=97, 98, 96, 102, 95, 103	1	1	3	1	3	2
UWBC, 3+, BL, n=97, 98, 96, 102, 95, 103	0	2	1	0	1	4
UWBC, Moderate, BL, n=97, 98, 96, 102, 95, 103	1	1	0	1	0	0
UWBC, Neg, BL, n=97, 98, 96, 102, 95, 103	88	78	83	85	83	81
UWBC, Small, BL, n=97, 98, 96, 102, 95, 103	0	2	3	0	0	2
UWBC, Trace, BL, n=97, 98, 96, 102, 95, 103	4	5	2	6	2	11
UWBC, 1+, W8, n=65, 79, 88, 90, 80, 92	3	5	5	8	4	8
UWBC, 2+, W8, n=65, 79, 88, 90, 80, 92	0	1	0	2	5	5
UWBC, 3+, W8, n=65, 79, 88, 90, 80, 92	0	1	1	1	2	1
UWBC, Large, W8, n=65, 79, 88, 90, 80, 92	0	0	0	0	0	1
UWBC, Moderate, W8, n=65, 79, 88, 90, 80, 92	1	1	1	1	0	0
UWBC, Neg, W8, n=65, 79, 88, 90, 80, 92	58	69	75	72	65	71
UWBC, Small, W8, n=65, 79, 88, 90, 80, 92	1	0	0	0	0	1
UWBC, Trace, W8, n=65, 79, 88, 90, 80, 92	2	2	6	6	4	5
UWBC, 1+, EW, n=7, 0, 1, 4, 5, 4	2	0	0	0	0	0
UWBC, Neg, EW, n=7, 0, 1, 4, 5, 4	4	0	1	4	5	4
UWBC, Small, EW, n=7, 0, 1, 4, 5, 4	1	0	0	0	0	0

Notes
[103] - ITT Population. Only those participants available at the specified time points were analyzed.
[104] - ITT Population. Only those participants available at the specified time points were analyzed.
[105] - ITT Population. Only those participants available at the specified time points were analyzed.
[106] - ITT Population. Only those participants available at the specified time points were analyzed.
[107] - ITT Population. Only those participants available at the specified time points were analyzed.
[108] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Urine specific gravity at Baseline and Week 8/Early Withdrawal

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End point title

Urine specific gravity at Baseline and Week 8/Early Withdrawal

End point description

Urine samples were collected for the measurement of urine specific gravity by dipstick method at Baseline and at Week 8/Early Withdrawal. The Baseline value was the measurement taken at screening (Visit 1). Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020. Please note that for the GW685698X 200 µg OD treatment no participants were analyzed; therefore, the value of 99999 was entered which represents NA. Also for the GW685698X 400 µg OD treatment the standard deviation could not be calculated for a single participant; therefore the value of 99999 was entered which represents NA.

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[109]	99 ^[110]	101 ^[111]	107 ^[112]	102 ^[113]	110 ^[114]
Units: ratio
arithmetic mean (standard deviation)
Baseline, n=97, 98, 96, 102, 95, 103	1.0221 ( 0.00721 )	1.0232 ( 0.00762 )	1.0217 ( 0.00786 )	1.0223 ( 0.00653 )	1.021 ( 0.00692 )	1.0218 ( 0.00774 )
Week 8, n=65, 79, 88, 90, 80, 92	1.0223 ( 0.00633 )	1.0214 ( 0.0069 )	1.0223 ( 0.0073 )	1.023 ( 0.0068 )	1.0214 ( 0.00702 )	1.0228 ( 0.00813 )
EW, n=7, 0, 1, 4, 5, 4	1.0203 ( 0.00685 )	99999 ( 99999 )	1.038 ( 99999 )	1.0255 ( 0.00311 )	1.02 ( 0.00863 )	1.0233 ( 0.00506 )

Notes
[109] - ITT Population. Only those participants available at the specified time points were analyzed.
[110] - ITT Population. Only those participants available at the specified time points were analyzed.
[111] - ITT Population. Only those participants available at the specified time points were analyzed.
[112] - ITT Population. Only those participants available at the specified time points were analyzed.
[113] - ITT Population. Only those participants available at the specified time points were analyzed.
[114] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Urine pH at Baseline and Week 8/Early Withdrawal

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End point title

Urine pH at Baseline and Week 8/Early Withdrawal

End point description

Urine samples were collected for the measurement of urine pH by dipstick method at Baseline and at Week 8/Early Withdrawal. The Baseline value was the measurement taken at screening (Visit 1). Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Please note that for the GW685698X 200 µg OD treatment no participants were analyzed; therefore, the value of 99999 which represents NA. Also for the GW685698X 400 µg OD treatment the standard deviation could not be calculated for a single participant; therefore the value of 99999 was entered which represents NA.

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	103 ^[115]	99 ^[116]	101 ^[117]	107 ^[118]	102 ^[119]	110 ^[120]
Units: scores on a scale
arithmetic mean (standard deviation)
Baseline, n=97, 98, 96, 102, 95, 103	6.01 ( 0.405 )	5.93 ( 0.429 )	6.01 ( 0.441 )	6 ( 0.482 )	5.92 ( 0.486 )	5.88 ( 0.415 )
Week 8, n=65, 79, 88, 90, 80, 92	6.11 ( 0.534 )	6 ( 0.416 )	5.91 ( 0.469 )	5.97 ( 0.494 )	5.98 ( 0.493 )	6.04 ( 0.464 )
EW, n=7, 0, 1, 4, 5, 4	5.71 ( 0.267 )	99999 ( 99999 )	6 ( 99999 )	5.88 ( 0.479 )	5.6 ( 0.418 )	5.88 ( 0.25 )

Notes
[115] - ITT Population. Only those participants available at the specified time points were analyzed.
[116] - ITT Population. Only those participants available at the specified time points were analyzed.
[117] - ITT Population. Only those participants available at the specified time points were analyzed.
[118] - ITT Population. Only those participants available at the specified time points were analyzed.
[119] - ITT Population. Only those participants available at the specified time points were analyzed.
[120] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: 24-hour urinary cortisol excretion at Baseline and Week 8

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End point title

24-hour urinary cortisol excretion at Baseline and Week 8

End point description

A 24-hour urine sample was collected for the measurement of 24-hour urinary cortisol excretion at the following scheduled time points: within 7 days prior to Study Visit 3 (Baseline; Week 0) and Study Visit 8 (Week 8). The Baseline value for 24-hour urinary cortisol was taken from Visit 3. Urine Cortisol (UC) Population: all participants whose urine samples did not have confounding factors that could affect the interpretation of results.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	52 ^[121]	71 ^[122]	74 ^[123]	71 ^[124]	66 ^[125]	80 ^[126]
Units: Nanomoles per 24 hours (nmol/24 hours)
median (full range (min-max))
Baseline	52.55 (5.2 to 273.8)	66 (3.6 to 362)	54.65 (6.3 to 662.4)	67.5 (12.2 to 694.8)	51.3 (9.7 to 182.4)	70.12 (7.4 to 282)
Week 8	51.79 (2.8 to 253.2)	69.4 (4.2 to 244.8)	55.19 (3 to 374.5)	49.8 (4 to 345.4)	22.99 (2.7 to 252)	62.35 (7.2 to 1441.3)

Notes
[121] - UC Population
[122] - UC Population
[123] - UC Population
[124] - UC Population
[125] - UC Population
[126] - UC Population

No statistical analyses for this end point

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 8

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End point title

Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 8

End point description

Change from Baseline was calculated as the Week 8 value minus the Baseline value.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	66 ^[127]	82 ^[128]	93 ^[129]	95 ^[130]	86 ^[131]	97 ^[132]
Units: Millimeters of mercury (mmHg)
arithmetic mean (standard deviation)
SBP	-0.4 ( 11.17 )	-1.2 ( 9.96 )	-1.9 ( 9.56 )	-0.8 ( 11.07 )	0 ( 11.57 )	-2.8 ( 11.32 )
DBP	1 ( 8.28 )	-1 ( 8.36 )	-0.9 ( 8.37 )	1.7 ( 7.74 )	1.8 ( 8.72 )	-1.5 ( 9.48 )

Notes
[127] - ITT Population. Only those participants available at the specified time points were analyzed.
[128] - ITT Population. Only those participants available at the specified time points were analyzed.
[129] - ITT Population. Only those participants available at the specified time points were analyzed.
[130] - ITT Population. Only those participants available at the specified time points were analyzed.
[131] - ITT Population. Only those participants available at the specified time points were analyzed.
[132] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate at Week 8

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End point title

Change from Baseline in heart rate at Week 8

End point description

Change from Baseline was calculated as the Week 8 value minus the Baseline value.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Number of subjects analysed	66 ^[133]	82 ^[134]	93 ^[135]	95 ^[136]	86 ^[137]	97 ^[138]
Units: Beats per minute
arithmetic mean (standard deviation)	0.7 ( 8.07 )	-0.8 ( 9.4 )	0.2 ( 8.89 )	-0.1 ( 8.7 )	-0.4 ( 8.24 )	0 ( 8.6 )

Notes
[133] - ITT Population. Only those participants available at the specified time points were analyzed.
[134] - ITT Population. Only those participants available at the specified time points were analyzed.
[135] - ITT Population. Only those participants available at the specified time points were analyzed.
[136] - ITT Population. Only those participants available at the specified time points were analyzed.
[137] - ITT Population. Only those participants available at the specified time points were analyzed.
[138] - ITT Population. Only those participants available at the specified time points were analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the the treatment period (up to Week 8).

Adverse event reporting additional description

SAEs and non-serious AEs were reported for members of the Intent-to-Treat (ITT) Population, comprised of all participants randomized to treatment who received at least one dose of trial medication during the treatment period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

GW685698X 400 µg OD

Reporting group description

Reporting group title

GW685698X 600 µg OD

Reporting group description

Reporting group title

GW685698X 800 µg OD

Reporting group description

Reporting group title

FP 500 µg BID

Reporting group description

Serious adverse events	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 103 (0.97%)	2 / 99 (2.02%)	0 / 101 (0.00%)	1 / 107 (0.93%)	0 / 102 (0.00%)	2 / 110 (1.82%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	0 / 103 (0.00%)	0 / 99 (0.00%)	0 / 101 (0.00%)	0 / 107 (0.00%)	0 / 102 (0.00%)	1 / 110 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 103 (0.00%)	0 / 99 (0.00%)	0 / 101 (0.00%)	1 / 107 (0.93%)	0 / 102 (0.00%)	0 / 110 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 103 (0.97%)	0 / 99 (0.00%)	0 / 101 (0.00%)	0 / 107 (0.00%)	0 / 102 (0.00%)	1 / 110 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 103 (0.00%)	0 / 99 (0.00%)	0 / 101 (0.00%)	0 / 107 (0.00%)	0 / 102 (0.00%)	1 / 110 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastrointestinal infection
subjects affected / exposed	0 / 103 (0.00%)	1 / 99 (1.01%)	0 / 101 (0.00%)	0 / 107 (0.00%)	0 / 102 (0.00%)	0 / 110 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 103 (0.00%)	1 / 99 (1.01%)	0 / 101 (0.00%)	0 / 107 (0.00%)	0 / 102 (0.00%)	0 / 110 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	GW685698X 200 µg OD	GW685698X 400 µg OD	GW685698X 600 µg OD	GW685698X 800 µg OD	FP 500 µg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 103 (14.56%)	18 / 99 (18.18%)	21 / 101 (20.79%)	21 / 107 (19.63%)	26 / 102 (25.49%)	21 / 110 (19.09%)
Nervous system disorders
Headache
subjects affected / exposed	10 / 103 (9.71%)	3 / 99 (3.03%)	10 / 101 (9.90%)	12 / 107 (11.21%)	10 / 102 (9.80%)	10 / 110 (9.09%)
occurrences all number	15	3	13	25	19	12
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain
subjects affected / exposed	1 / 103 (0.97%)	2 / 99 (2.02%)	0 / 101 (0.00%)	3 / 107 (2.80%)	1 / 102 (0.98%)	4 / 110 (3.64%)
occurrences all number	1	2	0	6	2	4
Dysphonia
subjects affected / exposed	1 / 103 (0.97%)	4 / 99 (4.04%)	5 / 101 (4.95%)	1 / 107 (0.93%)	4 / 102 (3.92%)	2 / 110 (1.82%)
occurrences all number	1	4	5	1	4	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 103 (0.97%)	1 / 99 (1.01%)	1 / 101 (0.99%)	4 / 107 (3.74%)	2 / 102 (1.96%)	0 / 110 (0.00%)
occurrences all number	1	1	1	4	3	0
Infections and infestations
Oral candidiasis
subjects affected / exposed	0 / 103 (0.00%)	2 / 99 (2.02%)	2 / 101 (1.98%)	1 / 107 (0.93%)	7 / 102 (6.86%)	0 / 110 (0.00%)
occurrences all number	0	2	3	1	7	0
Oropharyngeal candidiasis
subjects affected / exposed	1 / 103 (0.97%)	4 / 99 (4.04%)	4 / 101 (3.96%)	1 / 107 (0.93%)	4 / 102 (3.92%)	4 / 110 (3.64%)
occurrences all number	1	5	5	1	6	4
Nasopharyngitis
subjects affected / exposed	4 / 103 (3.88%)	3 / 99 (3.03%)	5 / 101 (4.95%)	2 / 107 (1.87%)	7 / 102 (6.86%)	4 / 110 (3.64%)
occurrences all number	5	3	6	2	8	4

More information

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Were there any global substantial amendments to the protocol? Yes

17 Sep 2007

To correct a typographical error in the document number on the Sponsor Signatory Page; to provide additional details on PGx blood sampling (Protocol Summary, Pharmacogenetics Sampling, Section 6.5, Table 1); to correct typographical error concerning pregnancy tests (Section 4.2); to remove statement on subjects who are screen failures (Section 4.5); to add statement to study treatments footnote number 1 (Section 5.1); to clarify non asthma medications (Section 5.6.1.); to clarify the fasting laboratory assessment (footnote number 7) is only for clinical chemistry (Table 1); to clarify that PK sampling is at Visits 5 and 8 only and not at the Early Withdrawal Visit (Table 1); to clarify that the FEV1 to be performed at Visits 1 and 3 through 8 (Section 6.2.1); to clarify the visits for oropharynx exam and vital signs (Protocol Summary, Section 6.3.1.); to clarify that AE collection starts at Visit 3 (Section 6.3.4); to clarify the Visits for the physical exam (Section 6.3.8.1); to clarify the IP collection at Visit 6, 8 or Early Withdrawal (Table 1); corrected typographical error for SAE (Section 6.3.7.); corrected typographical error on visit number for baseline values (Section 8.3.5.); to change the reference from “electronic” Daily Diary (or eDiary) to Daily Diary (Protocol Summary - Study Design, Section 3.1., Section 4.2., Section 4.3.2., Section 4.4.1., Section 6.2.2., Section 6.2.2.1. and Section 6.3.4.); to clarify the list of abbreviations; to remove the sentence in Appendix 1: Pharmacogenetic Research (PGx) (Section 11); to clarify inclusion and exclusion criteria for randomization to treatment (Section 4.3.1 and Section 4.3.2. number 6); to remove statement on medical dictionary use (Section 7); to correct typographical errors throughout the document.

24 Oct 2007

To change once daily GW685698X administration from morning to evening and to amend timing of measures that are impacted by this change (i.e. FEV1, PK,) To amend entry criterion % predicted normal FEV1 range. To up-date NIH reference from 2002 to 2007. To include reference to IB Supplement. To clarify when vital sign assessments will occur

06 Dec 2007

To amend Inclusion Criterion number 7, anti-asthma therapy. To amend IP compliance at Visit 6. To clarify the Lung Function reversibility procedure. To clarify the Urinary Coritsol Population.

21 Mar 2008

To adjust the FEV1 entry criteria depending on the time of day the screening period is conducted. To allow subjects to re-screen for Visit 1 if they fail to meet lung function criteria. To clarify the exclusion of subjects with upper and lower respiratory tract infections at Visit 1 and Visit 3 (Randomization to Treatment). To allow the use of long acting anti-histamines

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 in trough (evening pre-dose and pre- rescue bronchodilator) FEV1 at Week 8

Primary: Mean change from Baseline in trough (evening pre-dose and pre- rescue bronchodilator) FEV1 at Week 8

Secondary: Mean change from Baseline in daily trough (pre-dose and pre-rescue bronchodilator) evening peak expiratory flow (PEF) averaged over the 8-week Treatment Period

Secondary: Mean change from Baseline in daily trough (pre-dose and pre-rescue bronchodilator) evening peak expiratory flow (PEF) averaged over the 8-week Treatment Period

Secondary: Mean change from Baseline in daily morning PEF averaged over the 8-week Treatment Period

Secondary: Mean change from Baseline in daily morning PEF averaged over the 8-week Treatment Period

Secondary: Mean change from Baseline in the percentage of symptom-free 24-hour (hr) periods during the 8-week Treatment Period

Secondary: Mean change from Baseline in the percentage of symptom-free 24-hour (hr) periods during the 8-week Treatment Period

Secondary: Mean change from Baseline in the percentage of rescue-free 24-hour (hr) periods during the 8-week Treatment Period

Secondary: Mean change from Baseline in the percentage of rescue-free 24-hour (hr) periods during the 8-week Treatment Period

Secondary: Number participants who withdrew due to lack of efficacy during the 8-week Treatment Period

Secondary: Number participants who withdrew due to lack of efficacy during the 8-week Treatment Period

Secondary: Number of participants with any on-treatment adverse event or serious adverse event throughout the 8-week Treatment Period

Secondary: Number of participants with any on-treatment adverse event or serious adverse event throughout the 8-week Treatment Period

Secondary: Number of participants with clinical/visual evidence of oropharyngeal candidiasis

Secondary: Number of participants with clinical/visual evidence of oropharyngeal candidiasis

Secondary: Percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in the blood at Baseline and Week 8

Secondary: Percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in the blood at Baseline and Week 8

Secondary: Hematocrit at Baseline and Week 8

Secondary: Hematocrit at Baseline and Week 8

Secondary: Hemoglobin at Baseline and Week 8

Secondary: Hemoglobin at Baseline and Week 8

Secondary: Platelet count and white blood cell count at Baseline and Week 8

Secondary: Platelet count and white blood cell count at Baseline and Week 8

Secondary: Red blood cell count at Baseline and Week 8

Secondary: Red blood cell count at Baseline and Week 8

Secondary: Clinical chemistry parameters of alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) at Baseline and Week 8

Secondary: Clinical chemistry parameters of alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) at Baseline and Week 8

Secondary: Clinical chemistry parameters of albumin and total protein at Baseline and Week 8

Secondary: Clinical chemistry parameters of albumin and total protein at Baseline and Week 8

Secondary: Clinical chemistry parameters of calcium, carbon dioxide content/bicarbonate, chloride, cholesterol, glucose, phosphorus inorganic, potassium, sodium, and urea at Baseline and Week 8

Secondary: Clinical chemistry parameters of calcium, carbon dioxide content/bicarbonate, chloride, cholesterol, glucose, phosphorus inorganic, potassium, sodium, and urea at Baseline and Week 8

Secondary: Clinical chemistry parameters of creatinine, direct bilirubin, total bilirubin, and uric acid at Baseline and Week 8

Secondary: Clinical chemistry parameters of creatinine, direct bilirubin, total bilirubin, and uric acid at Baseline and Week 8

Secondary: Number of participants with the indicated result for the indicated urinalysis parameters tested by dipstick at Baseline and Week 8/Withdrawal

Secondary: Number of participants with the indicated result for the indicated urinalysis parameters tested by dipstick at Baseline and Week 8/Withdrawal

Secondary: Urine specific gravity at Baseline and Week 8/Early Withdrawal

Secondary: Urine specific gravity at Baseline and Week 8/Early Withdrawal

Secondary: Urine pH at Baseline and Week 8/Early Withdrawal

Secondary: Urine pH at Baseline and Week 8/Early Withdrawal

Secondary: 24-hour urinary cortisol excretion at Baseline and Week 8

Secondary: 24-hour urinary cortisol excretion at Baseline and Week 8

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 8

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 8

Secondary: Change from Baseline in heart rate at Week 8

Secondary: Change from Baseline in heart rate at Week 8

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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