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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 100mcg Twice Daily compared with Placebo for 8 Weeks in Adolescent and Adult Subjects with Persistent Asthma Symptomatic on Non Steroidal Asthma Therapy

Summary
EudraCT number	2007-004442-32
Trial protocol	FR SE EE PL SK BG DE
Global end of trial date	02 Oct 2008

Results information
Results version number	v1(current)
This version publication date	13 Apr 2016
First version publication date	23 May 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

FFA109687

ISRCTN number

US NCT number

NCT00603382

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-000431-PIP01-08

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

02 Dec 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Oct 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 (25mcg, 50mcg, 100mcg and 200mcg) 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

The following steps were taken to protect trial subjects: 1). Only subjects meeting all of the inclusion criteria and none of the exclusion criteria were randomized to investigational medication. 2). All subjects enrolled into the study were provided rescue medication for use as necessary. 3). Subject lung function, as measured by morning and evening peak expiratory flow (PEF), use of rescue medication and symptoms were monitored through the use of a daily electronic diary. 4) Both safety and efficacy parameters were also assessed by the investigator regularly in the clinic to minimise any potential risks to the patients. 5). The investigator or treating physician may unblind a subject’s treatment assignment in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Dec 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 74

Country: Number of subjects enrolled

Korea, Republic of: 37

Country: Number of subjects enrolled

Mexico: 69

Country: Number of subjects enrolled

Peru: 67

Country: Number of subjects enrolled

Philippines: 177

Country: Number of subjects enrolled

Russian Federation: 25

Country: Number of subjects enrolled

United States: 659

Country: Number of subjects enrolled

Poland: 100

Country: Number of subjects enrolled

Slovakia: 24

Country: Number of subjects enrolled

Sweden: 35

Country: Number of subjects enrolled

Bulgaria: 75

Country: Number of subjects enrolled

Estonia: 12

Country: Number of subjects enrolled

France: 86

Country: Number of subjects enrolled

Germany: 19

Worldwide total number of subjects

1459

EEA total number of subjects

351

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)

177

Adults (18-64 years)

1230

From 65 to 84 years

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. Total 1459 par. were screened, 601 were randomized of which 598 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, Carer, Assessor

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. In addition, participants were provided supplemental albuterol/salbutamol inhalation aerosol to be used as needed throughout the study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

twice daily via dry powder inhaler

GW685698X 25 µg OD

Arm description

Participants received GW685698X 25 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. In addition, participants were provided supplemental albuterol/salbutamol aerosol to be used as needed throughout the study.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

25 mcg once daily via dry powder inhaler

GW685698X 50 µg OD

Arm description

Participants received GW685698X 50 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. In addition, participants were provided supplemental albuterol/salbutamol aerosol to be used as needed throughout the study.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

50 mcg once daily via dry powder inhaler

GW685698X 100 µg OD

Arm description

Participants received GW685698X 100 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. In addition, participants were provided supplemental albuterol/salbutamol aerosol to be used as needed throughout the study.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

100 mcg once daily via dry powder inhaler

GW685698X 200 µg OD

Arm description

Participants received GW685698X 200 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. In addition, participants were provided supplemental albuterol/salbutamol aerosol to be used as needed throughout the study.

Arm type

Experimental

Investigational medicinal product name

GW685698X

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

200 mcg once daily via dry powder inhaler

FP 100 µg BID

Arm description

Participants received fluticasone propionate (FP) 100 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. In addition, participants were provided supplemental albuterol/salbutamol aerosol to be used as needed throughout the study.

Arm type

Active comparator

Investigational medicinal product name

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Inhalation use

Dosage and administration details

100 mcg twice daily via dry powder inhaler

Number of subjects in period 1 ^[1]	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Started	94	97	100	110	95	102
Completed	76	83	91	98	86	84
Not completed	18	14	9	12	9	18
Consent withdrawn by subject	3	3	1	1	-	1
Physician decision	-	-	2	-	1	3
Adverse event, non-fatal	-	1	1	2	1	2
Lost to follow-up	-	1	1	1	-	1
Lack of efficacy	14	9	3	6	6	11
Protocol deviation	1	-	1	2	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: Only those enrolled participants who received >=1 dose of study treatment are reported to be in the baseline period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 25 µg OD

Reporting group description

Reporting group title

GW685698X 50 µg OD

Reporting group description

Reporting group title

GW685698X 100 µg OD

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

FP 100 µg BID

Reporting group description

Reporting group values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID	Total
Number of subjects	94	97	100	110	95	102	598
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	39.2 ± 15.82	37.7 ± 15.4	38.3 ± 14.49	36.8 ± 15.56	40.7 ± 15.96	39.9 ± 15.03	-
Gender categorical
Units: Subjects
Female	47	57	59	60	60	56	339
Male	47	40	41	50	35	46	259
Race, Customized
Units: Subjects
African American/African Heritage (AA/AHER)	5	4	4	8	6	5	32
American Indian or Alaska Native	5	7	5	6	6	5	34
Asian	7	13	9	10	10	10	59
White	69	64	72	76	64	74	419
AA/AHER & American Indian or Alaska Native	0	0	0	0	1	0	1
American Indian or Alaska Native & White	8	8	9	10	8	8	51
Native Hawaiian or other Pacific Islander & White	0	1	1	0	0	0	2

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 25 µg OD

Reporting group description

Reporting group title

GW685698X 50 µg OD

Reporting group description

Reporting group title

GW685698X 100 µg OD

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

FP 100 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 forcefully 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 the Baseline through Week 8 clinic visits. Trough FEV1 is the FEV1 measured approximately 24 hours after the last administration of study drug. The highest of 3 technically acceptable measurements was recorded. The Visit 3 FEV1 assessment was used as the Baseline value. Change from Baseline in trough FEV1 was calculated as the value at Week 8 minus the value at Baseline. The analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of Baseline trough FEV1, country, sex, age, and treatment group. ITT=Intent-to-Treat. The Last Observation Carried Forward (LOCF) method was used.

End point type

Primary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	93 ^[1]	94 ^[2]	97 ^[3]	109 ^[4]	94 ^[5]	101 ^[6]
Units: Liters
least squares mean (standard error)	0.137 ± 0.0428	0.239 ± 0.0428	0.266 ± 0.042	0.341 ± 0.0396	0.367 ± 0.0428	0.243 ± 0.0411

Notes
[1] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.
[2] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.
[3] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.
[4] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.
[5] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.
[6] - ITT Population: all participants randomized to treatment who received >=1 dose of study medication.

Statistical Analysis 1

Comparison groups

Placebo v GW685698X 25 µg OD

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.095

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.101

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.221

Statistical Analysis 2

Comparison groups

Placebo v GW685698X 50 µg OD

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.129

Confidence interval

level

95%

sides

2-sided

lower limit

0.011

upper limit

0.247

Statistical Analysis 3

Comparison groups

Placebo v GW685698X 100 µg OD

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

0.204

Confidence interval

level

95%

sides

2-sided

lower limit

0.089

upper limit

0.319

Statistical Analysis 4

Comparison groups

Placebo v GW685698X 200 µg OD

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Median difference (final values)

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.111

upper limit

0.349

Statistical Analysis 5

Comparison groups

Placebo v FP 100 µg BID

Number of subjects included in analysis

194

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.074

Method

ANCOVA

Parameter type

Median difference (final values)

Point estimate

0.106

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.223

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 PEF measurement performed at the end of the dosing interval. 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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[7]	96 ^[8]	98 ^[9]	110 ^[10]	95 ^[11]	102 ^[12]
Units: Liters per minute
least squares mean (standard error)	9.6 ± 4.21	23.6 ± 4.17	30.3 ± 4.12	25.7 ± 3.9	31.3 ± 4.2	24.4 ± 4.04

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 PEF measurement performed at the end of the dosing interval. 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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[13]	96 ^[14]	98 ^[15]	110 ^[16]	95 ^[17]	102 ^[18]
Units: Liters per minute
least squares mean (standard error)	13.6 ± 4.27	27.2 ± 4.23	33.5 ± 4.17	29.5 ± 3.95	35.6 ± 4.26	25.6 ± 4.09

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 dairy 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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[19]	96 ^[20]	98 ^[21]	110 ^[22]	95 ^[23]	102 ^[24]
Units: Percentage of symptom-free 24-hr periods
least squares mean (standard error)	18.4 ± 3.21	25.3 ± 3.17	31.1 ± 3.14	38.7 ± 2.97	31.7 ± 3.2	33.3 ± 3.08

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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[25]	96 ^[26]	98 ^[27]	110 ^[28]	95 ^[29]	102 ^[30]
Units: Percentage of rescue-free 24-hr periods
least squares mean (standard error)	21.9 ± 3.32	29.3 ± 3.28	34.5 ± 3.24	40.8 ± 3.08	32 ± 3.31	35.5 ± 3.18

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

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End point title

Number of 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 study medication up to Week 8/Early Withdrawal

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[31]	97 ^[32]	100 ^[33]	110 ^[34]	95 ^[35]	102 ^[36]
Units: Participants	14	9	3	6	6	11

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 events or serious adverse events throughout the 8-week Treatment Period

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End point title

Number of participants with any on-treatment adverse events or serious adverse events 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 judgement 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 study medication up to Week 8/Early Withdrawal

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[37]	97 ^[38]	100 ^[39]	110 ^[40]	95 ^[41]	102 ^[42]
Units: Particpants
Any AE	24	19	28	35	27	35
Any SAE	0	1	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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[43]	97 ^[44]	100 ^[45]	110 ^[46]	95 ^[47]	102 ^[48]
Units: Participants
Clinical evidence	0	0	4	4	2	2
No clinical evidence	94	97	96	106	93	100

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 basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[49]	97 ^[50]	100 ^[51]	110 ^[52]	95 ^[53]	102 ^[54]
Units: Percentage
arithmetic mean (standard deviation)
Basophils, BL, n=92, 94, 95, 106, 92, 97	0.31 ± 0.199	0.32 ± 0.2	0.31 ± 0.194	0.32 ± 0.19	0.33 ± 0.205	0.33 ± 0.234
Basophils, W8, n=72, 80, 83, 94, 82, 79	0.3 ± 0.186	0.26 ± 0.153	0.31 ± 0.169	0.35 ± 0.236	0.35 ± 0.22	0.34 ± 0.264
Eosinophils, BL, n=92, 94, 95, 106, 92, 97	3.87 ± 3.022	3.38 ± 2.693	3.95 ± 2.503	4.4 ± 3.286	4.75 ± 3.358	3.88 ± 3.073
Eosinophils, W8, n=72, 80, 83, 94, 82, 79	4.31 ± 3.544	3.38 ± 3.3	3.76 ± 2.608	3.77 ± 3.066	3.96 ± 2.867	3.34 ± 2.364
Lymphocytes, BL, n=92, 94, 95, 106, 92, 97	33.96 ± 8.378	31.57 ± 8.821	33.33 ± 7.768	33.69 ± 8.682	34.32 ± 8.806	34.25 ± 8.514
Lymphocytes, W8, n=72, 80, 83, 94, 82, 79	32.88 ± 8.063	29.82 ± 10.12	30.36 ± 8.322	30.39 ± 7.326	31.97 ± 7.44	32.22 ± 7.877
Monocytes, BL, n=92, 94, 95, 106, 92, 97	5.09 ± 2.379	4.41 ± 1.851	4.7 ± 2.056	5.2 ± 2.113	4.78 ± 2.301	4.92 ± 2.093
Monocytes, W8, n=72, 80, 83, 94, 82, 79	5.41 ± 3.042	4.32 ± 2.098	4.6 ± 2.486	4.6 ± 2.178	4.5 ± 2.174	4.87 ± 2.38
Total Neutrophils, BL, n=92, 94, 95, 106, 92, 97	56.74 ± 9.22	60.24 ± 9.62	57.68 ± 8.309	56.34 ± 9.832	55.8 ± 10.281	56.6 ± 9.226
Total Neutrophils, W8, n=72, 80, 83, 94, 82, 79	57.08 ± 9.543	62.19 ± 11.58	60.95 ± 9.008	60.86 ± 8.054	59.2 ± 8.881	59.19 ± 8.672

Notes
[49] - ITT Population
[50] - ITT Population
[51] - ITT Population
[52] - ITT Population
[53] - ITT Population
[54] - ITT Population

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 (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[55]	97 ^[56]	100 ^[57]	110 ^[58]	95 ^[59]	102 ^[60]
Units: Proportion of 1
arithmetic mean (standard deviation)
Hematocrit, BL, n=92, 94, 95, 106, 92, 97	0.43 ± 0.041	0.42 ± 0.039	0.42 ± 0.04	0.43 ± 0.043	0.42 ± 0.039	0.43 ± 0.034
Hematocrit, W8, n=72, 79, 83, 94, 82, 79	0.43 ± 0.038	0.42 ± 0.038	0.42 ± 0.037	0.43 ± 0.04	0.42 ± 0.033	0.43 ± 0.039

Notes
[55] - ITT Population
[56] - ITT Population
[57] - ITT Population
[58] - ITT Popultion
[59] - ITT Population
[60] - ITT Population

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 (BL)and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[61]	97 ^[62]	100 ^[63]	110 ^[64]	95 ^[65]	102 ^[66]
Units: Grams per liter (G/L)
arithmetic mean (standard deviation)
Hemoglobin, BL, n=92, 94, 95, 106, 92, 96	141.54 ± 14.116	138.05 ± 13.178	140.7 ± 13.769	141.14 ± 14.625	139.5 ± 12.978	141.9 ± 11.632
Hemoglobin, W8, n=72, 79, 83, 94, 82, 79	140.81 ± 12.973	137.86 ± 12.862	138.95 ± 12.785	140.16 ± 13.647	136.32 ± 11.594	139.81 ± 13.009

Notes
[61] - ITT Population
[62] - ITT Population
[63] - ITT Population
[64] - ITT Population
[65] - ITT Population
[66] - ITT Population

No statistical analyses for this end point

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

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End point title

Platelet count and white blood cell (WBC) count at Baseline and Week 8

End point description

Blood samples were collected for the measurement of platelet count and WBC count at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[67]	97 ^[68]	100 ^[69]	110 ^[70]	95 ^[71]	102 ^[72]
Units: 10^9 cells per liter (GI/L)
arithmetic mean (standard deviation)
Platelet count, BL, n=91, 91, 95, 106, 92, 95	271.68 ± 62.861	265.75 ± 51.446	279.38 ± 57.658	272.2 ± 61.111	268.37 ± 60.442	281.26 ± 66.492
Platelet count, W8, n=72, 76, 83, 93, 81, 78	265.47 ± 49.978	262.07 ± 45.837	271.03 ± 47.156	278.57 ± 58.302	272.53 ± 68.404	274.46 ± 61.819
WBC, BL, n=92, 94, 95, 106, 92, 97	7.82 ± 2.018	7.96 ± 1.892	8.01 ± 2.095	7.62 ± 1.878	7.79 ± 2.055	7.94 ± 1.982
WBC, W8, n=72, 79, 83, 94, 82, 79	7.56 ± 1.679	8.26 ± 2.169	8.34 ± 2.211	7.94 ± 2.046	7.94 ± 1.769	8 ± 2.292

Notes
[67] - ITT Population
[68] - ITT Population
[69] - ITT Population
[70] - ITT Population
[71] - ITT Population
[72] - ITT Population

No statistical analyses for this end point

Secondary: Red blood cells (RBC) count at Baseline and Week 8

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End point title

Red blood cells (RBC) count at Baseline and Week 8

End point description

Blood samples were collected for the measurement of RBC count at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[73]	97 ^[74]	100 ^[75]	110 ^[76]	95 ^[77]	102 ^[78]
Units: 10^12 cells per liter (TI/L)
arithmetic mean (standard deviation)
RBC, BL, n=92, 94, 95, 106, 92, 97	4.71 ± 0.429	4.65 ± 0.438	4.68 ± 0.425	4.71 ± 0.46	4.68 ± 0.422	4.71 ± 0.416
RBC, W8, n=72, 79, 83, 94, 82, 79	4.65 ± 0.41	4.61 ± 0.445	4.63 ± 0.435	4.67 ± 0.45	4.6 ± 0.369	4.65 ± 0.462

Notes
[73] - ITT Population
[74] - ITT Population
[75] - ITT Population
[76] - ITT Population
[77] - ITT Population
[78] - ITT Population

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LD), and gamma glutamyltransferase (GGT) at Baseline and Week 8

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End point title

Clinical chemistry parameters of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LD), and gamma glutamyltransferase (GGT) at Baseline and Week 8

End point description

Blood samples were collected for the measurement of ALP, ALT, AST, LD and GGT at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at Screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[79]	97 ^[80]	100 ^[81]	110 ^[82]	95 ^[83]	102 ^[84]
Units: International units per liter (IU/L)
arithmetic mean (standard deviation)
ALP, BL, n=94, 97, 99, 106, 94, 101	82.7 ± 36.11	79.7 ± 32.21	83.5 ± 40.07	90.3 ± 56.43	94.4 ± 71.94	84.7 ± 62.31
ALP, W8, n=78, 84, 90, 97, 85, 83	83 ± 40.83	74.8 ± 27.91	82.9 ± 41.61	87 ± 49.65	90.8 ± 76.22	84 ± 59.81
ALT, BL, n=94, 97, 99, 106, 94, 101	21.8 ± 15.91	21.5 ± 14.57	23.6 ± 19.4	22.3 ± 16.61	20.7 ± 11.38	20.1 ± 9.84
ALT, W8, n=78, 84, 90, 97, 86, 83	22.3 ± 22.79	20.3 ± 11.92	20.7 ± 10.39	20.8 ± 14.01	19.5 ± 12.03	19.9 ± 10.04
AST, BL, n=94, 96, 99, 105, 93, 101	21 ± 7.64	22.8 ± 11.39	22.8 ± 13.35	21.9 ± 9.68	21.3 ± 7.2	20.3 ± 5.1
AST, W8, n=78, 83, 90, 97, 86, 82	22.2 ± 10.76	20.8 ± 6.48	21.1 ± 7.52	20.5 ± 8.07	20.2 ± 5.91	20.5 ± 5.38
LD, BL, n=94, 96, 99, 105, 93, 101	157.9 ± 47.78	170.7 ± 59.82	169.3 ± 64.08	165.6 ± 70.56	172.9 ± 62.38	164.2 ± 57.04
LD, W8, n=78, 83, 90, 97, 86, 82	151.8 ± 32.37	159.1 ± 31.46	159.9 ± 32.14	153.8 ± 26.9	161.9 ± 36.79	157.3 ± 27.36
GGT, BL, n=94, 97, 99, 106, 94, 101	27.6 ± 20	33 ± 30.67	33.1 ± 31.42	30.1 ± 22.29	29.9 ± 26.3	28.2 ± 21.4
GGT, W8, n=78, 84, 90, 97, 86, 83	29.7 ± 27.53	31.1 ± 24.61	32.4 ± 30.84	31.9 ± 24.96	29.3 ± 32.75	27.9 ± 21.24

Notes
[79] - ITT Population
[80] - ITT Population
[81] - ITT Population
[82] - ITT Population
[83] - ITT Population
[84] - ITT Population

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 (BL) and Week 8 (W8). The Baseline value was the measurement taken at Screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[85]	97 ^[86]	100 ^[87]	110 ^[88]	95 ^[89]	102 ^[90]
Units: Grams per liter (g/L)
arithmetic mean (standard deviation)
Albumin,BL, n=94, 97, 99, 106, 94, 101	45.2 ± 3.18	45.6 ± 3.08	45.1 ± 2.86	45.9 ± 3	45.3 ± 2.96	45.2 ± 3.01
Albumin, W8, n= 78, 84, 90, 97, 86, 83	44.9 ± 3.12	44.8 ± 3.3	44.9 ± 2.97	45.6 ± 2.91	44.5 ± 3.22	44.9 ± 2.62
Total protein, BL, n=94, 97, 99, 106, 94, 101	73.2 ± 4.04	74 ± 4.46	73.1 ± 4.6	74.1 ± 4.63	73.4 ± 4.5	73.2 ± 4.23
Total protein, W8, n= 78, 84, 90, 97, 86, 83	71.7 ± 3.65	72.6 ± 4.21	72.6 ± 4.62	73.4 ± 4.58	72 ± 4.66	72.5 ± 4.05

Notes
[85] - ITT Population
[86] - ITT Population
[87] - ITT Population
[88] - ITT Population
[89] - ITT Population
[90] - ITT Population

No statistical analyses for this end point

Secondary: Clinical chemistry parameters of chloride, calcium, carbon dioxide content/bicarbonate (CO2/BI), cholesterol, glucose, phosphorus inorganic(PI), potassium, sodium, and urea/blood urea nitrogen (BUN) at Baseline and Week 8

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End point title

Clinical chemistry parameters of chloride, calcium, carbon dioxide content/bicarbonate (CO2/BI), cholesterol, glucose, phosphorus inorganic(PI), potassium, sodium, and urea/blood urea nitrogen (BUN) at Baseline and Week 8

End point description

Blood samples were collected for the measurement of chloride, calcium, CO2/BI, cholesterol, glucose, PI, potassium, sodium, and urea/blood urea nitrogen at Baseline (BL) and Week 8 (W8). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[91]	97 ^[92]	100 ^[93]	110 ^[94]	95 ^[95]	102 ^[96]
Units: Millimoles per liter (mmol/L)
arithmetic mean (standard deviation)
Chloride, BL, n=94, 97, 99, 106, 94, 101	104.4 ± 2.25	104.7 ± 2.38	104.5 ± 2.5	104.4 ± 2.41	104.8 ± 2.17	104.4 ± 2.49
Chloride, W8, n=78, 84, 90, 97, 86, 83	104.8 ± 2.24	104.8 ± 2.36	104.7 ± 2.55	104.2 ± 2.15	104.7 ± 2.11	104.6 ± 2.67
Calcium, BL, n=94, 96, 99, 105, 93, 101	2.4 ± 0.1	2.4 ± 0.1	2.3 ± 0.09	2.4 ± 0.11	2.4 ± 0.13	2.3 ± 0.09
Calcium, W8, n=78, 83, 90, 97, 85, 82	2.4 ± 0.1	2.3 ± 0.1	2.3 ± 0.1	2.4 ± 0.1	2.4 ± 0.11	2.4 ± 0.09
CO2/BI, BL, n=94, 96, 99, 105, 93, 101	23.2 ± 2.58	22.8 ± 2.71	23 ± 2.31	23.4 ± 2.49	23.5 ± 2.45	23.5 ± 2.74
CO2/BI, W8, n=78, 83, 90, 97, 86, 82	23.1 ± 2.57	22.8 ± 2.62	22.7 ± 2.61	23.3 ± 2.55	22.7 ± 2.42	22.8 ± 2.6
Cholesterol, BL, n=94, 97, 99, 106, 94, 101	4.9 ± 1.02	5 ± 1.04	5.2 ± 1.14	5 ± 0.97	5 ± 1.08	5 ± 1.1
Cholesterol, W8, n=78, 84, 90, 97, 86, 83	5 ± 1.24	4.9 ± 1.05	5.1 ± 1.05	5.2 ± 1.16	5 ± 1.03	5 ± 1.07
Glucose, BL, n=94, 97, 99, 106, 94, 101	5.2 ± 0.99	5.5 ± 2.05	5.2 ± 1.18	5.1 ± 0.89	5.1 ± 0.83	5.3 ± 1.54
Glucose, W8, n=78, 84, 90, 97, 86, 83	5.2 ± 1.07	5.4 ± 1.96	5.2 ± 1.2	5 ± 0.88	5.2 ± 1.21	5.1 ± 1.18
PI, BL, n=94, 97, 99, 106, 94, 101	1.2 ± 0.22	1.1 ± 0.2	1.2 ± 0.17	1.2 ± 0.22	1.2 ± 0.21	1.2 ± 0.18
PI, W8, n=78, 84, 90, 97, 86, 83	1.3 ± 0.21	1.2 ± 0.17	1.2 ± 0.18	1.3 ± 0.2	1.2 ± 0.21	1.2 ± 0.2
Potassium, BL, n=94, 96, 99, 105, 93, 101	4.1 ± 0.39	4.2 ± 0.44	4.1 ± 0.38	4.2 ± 0.4	4.2 ± 0.45	4.2 ± 0.4
Potassium, W8, n=78, 83, 90, 97, 85, 82	4.2 ± 0.34	4.2 ± 0.41	4.2 ± 0.32	4.2 ± 0.38	4.2 ± 0.38	4.2 ± 0.36
Sodium, BL, n=94, 97, 99, 106, 94, 101	140.8 ± 1.82	140.5 ± 2.05	140.6 ± 1.92	140.8 ± 2.16	141.1 ± 1.91	140.8 ± 2.04
Sodium, W8, n=78, 84, 90, 97, 86, 83	140.7 ± 2.09	140.5 ± 2.01	140.7 ± 2.02	140.6 ± 1.63	140.9 ± 2.36	140.8 ± 1.97
BUN, BL, n=94, 97, 99, 106, 94, 101	5.4 ± 1.75	5.3 ± 1.66	5.3 ± 1.92	5.7 ± 1.94	5.7 ± 2.09	5.4 ± 1.72
BUN, W8, n=78, 84, 90, 97, 86, 83	5.5 ± 1.68	5.2 ± 1.97	5 ± 1.3	5.5 ± 1.44	5.2 ± 1.54	5 ± 1.43

Notes
[91] - ITT Population
[92] - ITT Population
[93] - ITT Population
[94] - ITT Population
[95] - ITT Population
[96] - ITT Population

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). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[97]	97 ^[98]	100 ^[99]	110 ^[100]	95 ^[101]	102 ^[102]
Units: Micromoles per liter (µmol/L)
arithmetic mean (standard deviation)
DBIL, BL, n=94, 97, 99, 106, 94, 101	2.1 ± 1.26	2.1 ± 1.29	2 ± 1.04	2 ± 1.13	1.8 ± 1.17	2 ± 1.04
DBIL, W8, n=77, 84, 89, 97, 86, 83	2 ± 1.03	2 ± 0.94	1.9 ± 0.98	1.9 ± 1.02	1.7 ± 0.93	1.9 ± 1.05
TBIL, BL, n=94, 97, 99, 106, 94, 101	9.6 ± 6.1	9.7 ± 6.08	9 ± 4.39	9.3 ± 4.35	8.7 ± 4.11	9 ± 3.93
TBIL, W8, n=78, 84, 90, 97, 86, 83	10.3 ± 5.57	9.1 ± 4.14	8.7 ± 3.99	9.1 ± 3.88	8.5 ± 3.46	9.4 ± 4.39
Uric acid, BL, n=94, 97, 99, 105, 94, 101	337.8 ± 88.15	327.2 ± 85.64	325.6 ± 85.82	334.1 ± 90.63	326.6 ± 85.37	324.5 ± 78.64
Uric acid, W8, n=78, 84, 90, 96, 86, 83	353.6 ± 86.64	327.5 ± 84.69	321.9 ± 91.9	340.9 ± 89.48	316.5 ± 81.29	325.4 ± 80.48
Creatinine, BL, n=94, 97, 99, 106, 94, 101	83.2 ± 19.89	79.8 ± 14.72	77.7 ± 14.52	81.9 ± 16.68	78.3 ± 15.21	79.3 ± 15.08
Creatinine, W8, n=78, 84, 90, 97, 86, 83	84.5 ± 19.21	79.7 ± 15.67	79 ± 13.45	81.7 ± 14.9	77.7 ± 14.32	80.4 ± 15.97

Notes
[97] - ITT Population
[98] - ITT Population
[99] - ITT Population
[100] - ITT Population
[101] - ITT Population
[102] - ITT Population

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/Early 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/Early 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 Cell (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, and results for urinalysis parameters can be read as large, moderate (Mod), negative (Neg), small, Trace, 1+, 2+, 3+ and 4+, and for UG the result can be read as Neg, Trace, Trace or 1/10 G/dL, 1+ or 1/4 G/dL, 3+ or 1 G/dL, indicating proportional concentrations in the urine sample. Data are reported as the number of participants who had neg, Trace, 1+, 2+, 3+ and 4+ levels at Baseline (BL) and Week 8 (W8)/Early Withdrawal (EW). The Baseline value was the measurement taken at screening (Visit 1). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[103]	97 ^[104]	100 ^[105]	110 ^[106]	95 ^[107]	102 ^[108]
Units: Participants
UOB, 1+, BL, n=92, 94, 95, 106, 93, 96	2	1	3	4	3	2
UOB, 2+, BL, n=92, 94, 95, 106, 93, 96	3	1	2	0	1	1
UOB, 3+, BL, n=92, 94, 95, 106, 93, 96	2	0	0	2	2	2
UOB, 4+, BL, n=92, 94, 95, 106, 93, 96	0	0	0	1	0	0
UOB, Mod, BL, n=92, 94, 95, 106, 93, 96	1	0	0	0	0	1
UOB, Neg, BL, n=92, 94, 95, 106, 93, 96	79	91	83	97	81	82
UOB, Small, BL, n=92, 94, 95, 106, 93, 96	0	0	3	0	1	0
UOB, Trace, BL, n=92, 94, 95, 106, 93, 96	5	1	4	2	5	8
UOB, 1+, W8, n=71, 81, 82, 93, 82, 77	1	1	1	0	4	3
UOB, 2+, W8, n=71, 81, 82, 93, 82, 77	4	2	2	2	2	3
UOB, 3+, W8, n=71, 81, 82, 93, 82, 77	0	3	0	0	0	1
UOB, Large, W8, n=71, 81, 82, 93, 82, 77	0	0	0	0	1	0
UOB, Mod, W8, n=71, 81, 82, 93, 82, 77	0	0	0	0	1	0
UOB, Neg, W8, n=71, 81, 82, 93, 82, 77	62	71	73	83	69	66
UOB, Trace, W8, n=71, 81, 82, 93, 82, 77	4	4	6	8	5	4
UOB, Neg, EW, n=2, 1, 2, 3, 1, 7	2	1	2	3	1	7
UG, 1+ or 1/4 G/DL, BL, n=92, 94, 95, 106, 93, 96	0	0	0	0	0	1
UG, 3+ or 1 G/DL, BL, n=92, 94, 95, 106, 93, 96	0	2	1	0	0	1
UG, 4+ or 2 more G/DL, n=92, 94, 95, 106, 93, 96	0	1	0	0	0	0
UG, Neg, BL, n=92, 94, 95, 106, 93, 96	90	91	94	105	91	94
UG, Trace, BL, n=92, 94, 95, 106, 93, 96	1	0	0	1	1	0
UG, Trace or 1/10 G/DL, BL, n=92, 94, 95,106,93,96	1	0	0	0	1	0
UG 1+ or 1/4 G/DL, W8, n=71, 81, 82, 93, 82, 77	0	1	1	0	0	0
UG, 3+ or 1 G/DL, W8, n=71, 81, 82, 93, 82, 77	0	3	1	0	0	1
UG, Neg, W8, n=71, 81, 82, 93, 82, 77	71	77	80	92	78	76
UG, Trace, W8, n=71, 81, 82, 93, 82, 77	0	0	0	0	2	0
UG, Trace or 1/10 G/DL, W8, n=71, 81, 82,93,82,77	0	0	0	1	2	0
UG, Neg, EW, n=2, 1, 2, 3, 1, 7	2	1	2	3	1	7
UK, 1+, BL, n=92, 94, 95, 106, 93, 96	0	0	1	1	1	0
UK, 2+, BL, n=92, 94, 95, 106, 93, 96	0	0	0	0	1	0
UK, Neg, BL, n=92, 94, 95, 106, 93, 96	91	89	92	104	90	95
UK, Trace, BL, n=92, 94, 95, 106, 93, 96	1	5	2	1	1	1
UK, 2+, W8, n=71, 81, 82, 93, 82, 77	0	0	0	1	0	0
UK, Neg, W8, n=71, 81, 82, 93, 82, 77	67	77	78	91	79	69
UK, Trace, W8, n=71, 81, 82, 93, 82, 77	4	4	4	1	3	8
UK, Neg, EW, n=2, 1, 2, 3, 1, 7	2	1	2	3	1	7
UP, 1+, BL, n=92, 94, 95, 106, 93, 96	7	7	6	8	5	4
UP, 2+, BL, n=92, 94, 95, 106, 93, 96	0	0	2	1	1	0
UP, 3+, BL, n=92, 94, 95, 106, 93, 96	1	1	0	0	0	0
UP, Neg, BL, n=92, 94, 95, 106, 93, 96	70	76	80	89	80	78
UP, Trace, BL, n=92, 94, 95, 106, 93, 96	14	10	7	8	7	14
UP, 1+, W8, n=71, 81, 82, 93, 82, 77	3	2	5	1	4	2
UP, 2+, W8, n=71, 81, 82, 93, 82, 77	2	1	0	1	1	0
UP, 3+, W8, n=71, 81, 82, 93, 82, 77	0	0	0	0	1	0
UP, Neg, W8,n=71, 81, 82, 93, 82, 77	60	70	68	78	64	71
UP, Trace, W8, n=71, 81, 82, 93, 82, 77	6	8	9	13	12	4
UP, Neg, EW, n=2, 1, 2, 3, 1, 7	2	1	2	3	1	5
UP, Trace, EW, n=2, 1, 2, 3, 1, 7	0	0	0	0	0	2
UWBC, 1+, BL, n=92, 94, 95, 106, 93, 96	1	1	6	1	6	3
UWBC, 2+, BL, n=92, 94, 95, 106, 93, 96	1	3	1	7	2	3
UWBC, 3+, BL, n=92, 94, 95, 106, 93, 96	0	3	2	2	1	2
UWBC, Mod, BL, n=92, 94, 95, 106, 93, 96	0	0	0	0	1	0
UWBC, Neg, BL, n=92, 94, 95, 106, 93, 96	88	84	82	92	81	85
UWBC, Trace, BL, n=92, 94, 95, 106, 93, 96	2	3	4	4	2	3
UWBC, 1+, W8, n=71, 81, 82, 93, 82, 77	1	3	2	3	7	4
UWBC, 2+, W8, n=71, 81, 82, 93, 82, 77	1	1	4	3	2	3
UWBC, 3+, W8, n=71, 81, 82, 93, 82, 77	0	0	2	1	0	1
UWBC, Neg, W8, n=71, 81, 82, 93, 82, 77	66	71	69	81	67	67
UWBC, Small, W8, n=71, 81, 82, 93, 82, 77	1	0	1	0	0	0
UWBC, Trace, W8, n=71, 81, 82, 93, 82, 77	2	6	4	5	6	2
UWBC, 2+, EW, n=2, 1, 2, 3, 1, 7	0	1	0	0	0	1
UWBC, Neg, EW, n=2, 1, 2, 3, 1, 7	2	0	2	3	1	6

Notes
[103] - ITT Population
[104] - ITT Population
[105] - ITT Population
[106] - ITT Population
[107] - ITT Population
[108] - ITT Population

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. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[109]	97 ^[110]	100 ^[111]	110 ^[112]	95 ^[113]	102 ^[114]
Units: ratio
arithmetic mean (standard deviation)
Baseline, n=92, 94, 95, 106, 93, 96	1.023 ± 0.00707	1.024 ± 0.0069	1.0236 ± 0.00682	1.023 ± 0.00687	1.0242 ± 0.0062	1.0227 ± 0.0076
Week 8, n=71, 81, 82, 93, 82, 77	1.0238 ± 0.00731	1.0227 ± 0.00735	1.023 ± 0.00714	1.0223 ± 0.00738	1.0235 ± 0.00727	1.0217 ± 0.00751
EW, n=2, 1, 2, 3, 1, 7	1.0265 ± 0.00071	1.0121 ± 0	1.02 ± 0.00141	1.0233 ± 0.00987	1.019 ± 0	1.024 ± 0.00653

Notes
[109] - ITT Population
[110] - ITT Population
[111] - ITT Population
[112] - ITT Population
[113] - ITT Population
[114] - ITT Population

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). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.

End point type

Secondary

End point timeframe

Baseline and Week 8/Early Withdrawal

End point values	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	94 ^[115]	97 ^[116]	100 ^[117]	110 ^[118]	95 ^[119]	102 ^[120]
Units: scores on a scale
arithmetic mean (standard deviation)
Baseline, n=92, 94, 95, 106, 93, 96	6.04 ± 0.487	6.05 ± 0.418	6.06 ± 0.455	6.13 ± 0.488	6.05 ± 0.489	6.08 ± 0.415
Week 8, n=71, 81, 82, 93, 82, 77	6.03 ± 0.422	6.01 ± 0.418	6.12 ± 0.462	6.06 ± 0.435	6.06 ± 0.523	5.96 ± 0.342
EW, n=2, 1, 2, 3, 1, 7	6 ± 0.707	6 ± 0	5.75 ± 0.354	6.83 ± 0.289	7.5 ± 0	5.86 ± 0.556

Notes
[115] - ITT Population
[116] - ITT Population
[117] - ITT Population
[118] - ITT Population
[119] - ITT Population
[120] - ITT Population

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 hr urinary cortisol excretion at the following scheduled time points: within 7 days prior to Study Visits 3 (Week 0) and Visit 8 (Week 8). The Baseline value for 24 hr 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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	66 ^[121]	72 ^[122]	72 ^[123]	76 ^[124]	69 ^[125]	70 ^[126]
Units: Nanomoles per 24 hours (nmol/24 hours)
median (full range (min-max))
Baseline	70.2 (10.1 to 382.7)	74.45 (6.1 to 645.2)	65.8 (5.9 to 341.1)	65.56 (8.8 to 457.3)	66.8 (4.6 to 396.2)	66.2 (6.4 to 338.6)
Week 8	79.25 (7.5 to 275)	76.74 (5.2 to 306.6)	79.15 (13.9 to 680.9)	81 (10.6 to 506.6)	62.1 (8 to 366.7)	82.14 (4.7 to 231)

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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	78 ^[127]	85 ^[128]	91 ^[129]	98 ^[130]	86 ^[131]	84 ^[132]
Units: Millimeters of mercury (mmHg)
arithmetic mean (standard deviation)
SBP	-2.5 ± 9.29	1.5 ± 10.54	0.9 ± 10.35	-0.4 ± 10.46	1.4 ± 9.53	0.2 ± 10.64
DBP	-1.1 ± 8.16	0.3 ± 7.65	0.2 ± 7.5	-0.3 ± 8.41	0.1 ± 8.5	-0.2 ± 8.55

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 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Number of subjects analysed	78 ^[133]	85 ^[134]	91 ^[135]	98 ^[136]	86 ^[137]	84 ^[138]
Units: Beats per minute
arithmetic mean (standard deviation)	2.9 ± 9.23	0.4 ± 8.26	1.5 ± 8.35	0.8 ± 8.12	-2.3 ± 8.32	0.8 ± 9.14

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

11.1

Reporting group title

Placebo

Reporting group description

Reporting group title

GW685698X 25 µg OD

Reporting group description

Reporting group title

GW685698X 50 µg OD

Reporting group description

Reporting group title

GW685698X 100 µg OD

Reporting group description

Reporting group title

GW685698X 200 µg OD

Reporting group description

Reporting group title

FP 100 µg BID

Reporting group description

Serious adverse events	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 94 (0.00%)	1 / 97 (1.03%)	0 / 100 (0.00%)	1 / 110 (0.91%)	0 / 95 (0.00%)	2 / 102 (1.96%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Snake bite
subjects affected / exposed	0 / 94 (0.00%)	1 / 97 (1.03%)	0 / 100 (0.00%)	0 / 110 (0.00%)	0 / 95 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	0 / 100 (0.00%)	0 / 110 (0.00%)	0 / 95 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	0 / 100 (0.00%)	0 / 110 (0.00%)	0 / 95 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastritis
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	0 / 100 (0.00%)	0 / 110 (0.00%)	0 / 95 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	0 / 100 (0.00%)	0 / 110 (0.00%)	0 / 95 (0.00%)	1 / 102 (0.98%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	0 / 100 (0.00%)	1 / 110 (0.91%)	0 / 95 (0.00%)	0 / 102 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	GW685698X 25 µg OD	GW685698X 50 µg OD	GW685698X 100 µg OD	GW685698X 200 µg OD	FP 100 µg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 94 (11.70%)	6 / 97 (6.19%)	8 / 100 (8.00%)	17 / 110 (15.45%)	9 / 95 (9.47%)	16 / 102 (15.69%)
Nervous system disorders
Headache
subjects affected / exposed	10 / 94 (10.64%)	6 / 97 (6.19%)	6 / 100 (6.00%)	12 / 110 (10.91%)	5 / 95 (5.26%)	12 / 102 (11.76%)
occurrences all number	15	7	14	22	6	18
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 94 (1.06%)	0 / 97 (0.00%)	1 / 100 (1.00%)	4 / 110 (3.64%)	3 / 95 (3.16%)	2 / 102 (1.96%)
occurrences all number	1	0	1	4	3	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 94 (0.00%)	0 / 97 (0.00%)	3 / 100 (3.00%)	0 / 110 (0.00%)	1 / 95 (1.05%)	1 / 102 (0.98%)
occurrences all number	0	0	4	0	1	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 94 (1.06%)	0 / 97 (0.00%)	0 / 100 (0.00%)	4 / 110 (3.64%)	3 / 95 (3.16%)	2 / 102 (1.96%)
occurrences all number	1	0	0	4	4	2

More information

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Were there any global substantial amendments to the protocol? Yes

17 Sep 2007

• To clarify examination of oropharynx and vital signs assessments at Clinic Visit 1 and Clinic Visits 3 through 8 (Summary); • Amended Study Entry Criteria to exclude female subjects who are lactating • Clarified exclusion criteria for randomization to treatment (Protocol Section 4.3.2 number 6) • Clarified the fasting laboratory assessment (footnote number 7) is only for clinical chemistry • Clarified PK sampling at Visits 5 and 8 only and not at the Early Withdrawal Visit • Clarified that Lung Function testing is to be performed at Clinic Visit 1 and Clinic Visits 3 through 8 (Protocol Section 6.2.1) • Amended AE collection to start as Visit 3

24 Oct 2007

• Amended once-daily GW685698X (FF) administration from morning to evening • Amended timing of clinic lung function assessments from morning to evening • Amended fasting requirements for chemistry laboratory assessments • Amended the time of dosing documentation required for pharmacokinetic blood samples • Clarify details of Urinary Cortisol Population • Amended PEF trough analysis from morning to evening

21 Mar 2008

• To amend to allow for a Visit 1 screening period to be performed any time of day and to allow for re-screening if subjects fail lung function assessments at Visit 1. • Clarification of Lung Function reversibility procedure. • Amend respiratory infection exclusion criterion. • To allow use of long-acting anti-histamines. • Amend IP compliance at Visit 6. • To clarify timing of clinical laboratory assessments

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

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

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

Secondary: Number of participants with any on-treatment adverse events or serious adverse events 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 (WBC) count at Baseline and Week 8

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

Secondary: Red blood cells (RBC) count at Baseline and Week 8

Secondary: Red blood cells (RBC) count at Baseline and Week 8

Secondary: Clinical chemistry parameters of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LD), and gamma glutamyltransferase (GGT) at Baseline and Week 8

Secondary: Clinical chemistry parameters of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LD), and gamma glutamyltransferase (GGT) 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 chloride, calcium, carbon dioxide content/bicarbonate (CO2/BI), cholesterol, glucose, phosphorus inorganic(PI), potassium, sodium, and urea/blood urea nitrogen (BUN) at Baseline and Week 8

Secondary: Clinical chemistry parameters of chloride, calcium, carbon dioxide content/bicarbonate (CO2/BI), cholesterol, glucose, phosphorus inorganic(PI), potassium, sodium, and urea/blood urea nitrogen (BUN) 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/Early Withdrawal

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

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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