Clinical Trial Results:
A repeatdose, openlabel, randomized, incomplete block design in pediatric subjects with asthma, ages 4  11 years, to compare systemic exposure and pharmacodynamics of fluticasone propionate and salmeterol following Advair® HFA 45/21 mcg (2 inhalations), Advair HFA 45/21 mcg (2 inhalations) with Aerochamber Plus Spacer and Advair Diskus 100/50 twice daily.
Summary


EudraCT number 
201500486627 
Trial protocol 
Outside EU/EEA 
Global end of trial date 
02 Feb 2007

Results information


Results version number 
v1(current) 
This version publication date 
19 Dec 2016

First version publication date 
19 Dec 2016

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


Trial identification


Sponsor protocol code 
SAS105519


Additional study identifiers


ISRCTN number 
  
US NCT number 
  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
GlaxoSmithKline


Sponsor organisation address 
980 Great West Road, Brentford, Middlesex, United Kingdom,


Public contact 
GSK Response Center, GlaxoSmithKline, 1866 4357343, GSKClinicalSupportHD@gsk.com


Scientific contact 
GSK Response Center, GlaxoSmithKline, 1866 4357343, GSKClinicalSupportHD@gsk.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


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


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


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
11 Jul 2007


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
02 Feb 2007


Global end of trial reached? 
Yes


Global end of trial date 
02 Feb 2007


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
The purpose of this study was to compare the systemic exposure and pharmacodynamics of therapeutic
doses of Advair HFA


Protection of trial subjects 
Not applicable


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
30 Oct 2006


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
United States: 31


Worldwide total number of subjects 
31


EEA total number of subjects 
0


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
31


Adolescents (1217 years) 
0


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
This was a repeatdose, openlabel randomized, incomplete block design study in pediatric participants with asthma, aged 411 years to compare systemic exposure and pharmacodynamics of Advair HFA (A), Advair DISKUS (B), and Advair HFA with Aerochamber Plus Spacer (C) in two treatment periods, with a followup period within 24 hours post last dose.  
Preassignment


Screening details 
Following Baseline assessments, participants received Advair HFA 45/21 microgram (µg) (two inhalations), Advair DISKUS 100/50 µg (one inhlation), or Advair HFA with Aerochamber Plus Spacer 45/21 µg (two inhalations) twice daily for 21 days, in accordance with the treatment sequence to which they were randomized (AB,BA,AC,CA,BC,or CB).  
Period 1


Period 1 title 
Overall study (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Not blinded  
Arms


Arm title

All study treatments  
Arm description 
Participants were randomized to one of the 6 possible treatment arms (AB, BC, AC, CA, BC, or CB): Treatment regimen A: two inhalations of ADVAIR HFA 45/21 µg, which was a combination of 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol administered via a metered dose inhaler (MDI), treatment regimen B: Advair HFA 42/21 µg with Aerochamber Plus Spacer, or treatment regimen C: Adavir DISKUS 100/50 µg twice daily (BID) for 21 days (on outpatient basis except on Day 21) in both treatment periods without any washout period.  
Arm type 
Experimental  
Investigational medicinal product name 
ADVAIR HFA


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
Advair HFA 45/21 µg was supplied as an HFApropelled 120actuation MDI desgined to deliver approximately 21 µg salmeterol and 42 µg FP per actuation. Two inhalations from this device twice daily (BID) for 21 days.


Investigational medicinal product name 
ADVAIR HFA with Aerochamber Plus Spacer


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
Advair HFA 45/21 µg was supplied as supplied as a 6 mutlidose powder inhaler (MDPI) to deliver 45 µg of salmeterol and 21 µg of fluticasone propionate (FP). Two inhalations from the DISKUS device twice daily (BID) for 21 days


Investigational medicinal product name 
ADVAIR DISKUS


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Inhalation use


Dosage and administration details 
One inhalation of ADVAIR DISKUS 100/50mcg (Fluticasone, Salmeterol) will be administered twice daily for 21 days





Baseline characteristics reporting groups


Reporting group title 
Overall study


Reporting group description 
  



End points reporting groups


Reporting group title 
All study treatments


Reporting group description 
Participants were randomized to one of the 6 possible treatment arms (AB, BC, AC, CA, BC, or CB): Treatment regimen A: two inhalations of ADVAIR HFA 45/21 µg, which was a combination of 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol administered via a metered dose inhaler (MDI), treatment regimen B: Advair HFA 42/21 µg with Aerochamber Plus Spacer, or treatment regimen C: Adavir DISKUS 100/50 µg twice daily (BID) for 21 days (on outpatient basis except on Day 21) in both treatment periods without any washout period.  
Subject analysis set title 
Advair HFA


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg , which was supplied as a HFApropelled 120actuation metered dose inhaler (MDI) desgined to deliver 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.


Subject analysis set title 
Advair HFA with Spacer


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg with Aerochamber Plus Spacer, which was supplied as a metered dose inhaler (MDI) designed to deliver 45 µg of FP and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.


Subject analysis set title 
Advair DISKUS


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC or CB): one inhalation of ADVAIR DISKUS 100/50 µg, which was supplied as a 60dose multidose powder inhaler (MPDI) designed to deliver 100 µg of FP and 50 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir HFA. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.



End point title 
Weighted mean serum cortisol (SC) over 0 to 12 hours (h; 012 h) postdose for fluticasone propionate (FP)  
End point description 
Participants' blood samples were collected and analyzed for SC levels. The serum cortisol weighted mean, calculated by dividing the area under the concentration curve (AUC) over the 012 h period by the sample collection time interval, was determined at Baseline and at the end of each treatment period. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title. Pharmacodynamic (PD) parameter population was defined as all participants who received treatment during both periods and for whom PD parameters were derived for both periods.


End point type 
Primary


End point timeframe 
Baseline and 0, 2, 4, 8, and 12 h postdose on Day 21 of each treatment period




Notes [1]  Pharmacodynamic (PD) Parameter Population [2]  Pharmacodynamic (PD) Parameter Population [3]  Pharmacodynamic (PD) Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair DISKUS v Advair HFA


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other ^{[4]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.98


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.87  
upper limit 
1.12  
Variability estimate 
Standard error of the mean


Dispersion value 
0.062


Notes [4]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 

Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other ^{[5]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.89


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.78  
upper limit 
1.01  
Variability estimate 
Standard error of the mean


Dispersion value 
0.061


Notes [5]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 

Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other ^{[6]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.79  
upper limit 
1.03  
Variability estimate 
Standard error of the mean


Dispersion value 
0.064


Notes [6]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 


End point title 
Serum cortisol minimum (Cmin) over 012 h postdose for FP  
End point description 
Blood samples of participants were collected for the evaluation of Cmin. Any differences in systemic exposure as a result of the absorbed steroid component of the three differing inhaled treatments should also result in differences in serum cortisol concentrations. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Primary


End point timeframe 
At Baseline and 0, 2, 4, 8, and 12 h postdose on Day 21 of each treatment period




Notes [7]  Pharmacodynamic (PD) Parameter Population [8]  Pharmacodynamic (PD) Parameter Population [9]  Pharmacodynamic (PD) Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other ^{[10]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.83


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.57  
upper limit 
1.2  
Variability estimate 
Standard error of the mean


Dispersion value 
0.185


Notes [10]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 

Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other ^{[11]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.62


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.43  
upper limit 
0.89  
Variability estimate 
Standard error of the mean


Dispersion value 
0.183


Notes [11]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 

Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other ^{[12]}  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.75


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.51  
upper limit 
1.09  
Variability estimate 
Standard error of the mean


Dispersion value 
0.189


Notes [12]  If the twosided CI for the ratio of geometric means for the two formulations is contained within the range of 0.7 to 1.43, the two formulations were deemed comparable. 


End point title 
Maximum mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours postdose  
End point description 
Twelvelead electrocardiogram was performed to measure QTcB at Baseline, predose and at 15 min, 45 min, 1.5 h, 3h, 6 h and 9 h postdose on Day 21 of each treatment period and maximum value for QTcB was derived during the 09 h period. Baseline was defined as the derived parameter from the Baseline assessment. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title). Pharmacodynamic (PD) parameter population was defined as all participants who received treatment during both periods and for whom PD parameters were derived for both periods.


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [13]  Pharmacodynamic (PD) Parameter Population [14]  Pharmacodynamic (PD) Parameter Population [15]  Pharmacodynamic (PD) Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
3.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
8.8  
Variability estimate 
Standard error of the mean


Dispersion value 
2.73


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
2.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
8  
upper limit 
2.9  
Variability estimate 
Standard error of the mean


Dispersion value 
2.69


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
5.8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
11.5  
upper limit 
0.1  
Variability estimate 
Standard error of the mean


Dispersion value 
2.82



End point title 
Weighted mean change from Baseline of the QT Interval Corrected According to Bazett’s Formula (QTcB) at 9 hours postdose  
End point description 
Twelvelead electrocardiograms were performed to measure QTcB at Baseline, predose and 15 min, 45 min, 1.5 h, 3h, 6 h and 9 h postdose on Day 21 of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Weighted mean (WM) was derived by calculating the area under curve (AUC), and then dividing by the relevant time interval. The data are presented as the adjusted means of WM. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [16]  PD Parameter Population [17]  PD Parameter Population [18]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.2  
upper limit 
7.9  
Variability estimate 
Standard error of the mean


Dispersion value 
1.9


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
0.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.8  
upper limit 
3  
Variability estimate 
Standard error of the mean


Dispersion value 
1.9


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
4.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
9.1  
upper limit 
0.8  
Variability estimate 
Standard error of the mean


Dispersion value 
2.03



End point title 
Maximum mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours postdose  
End point description 
Twelvelead electrocardiograms (ECGs) were performed to measure QT interval corrected according to Fridericia's formula (QTcF) at Baseline, predose and 15 minutes (min), 45 min, 1.5 hours (h), 3h, 6 h and 9 h postdose on Day 21 of each treatment period and the maximum values for QTcF were derived during the 09 h period. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted means of the maximum QTcF. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [19]  PD Parameter Population [20]  PD Parameter Population [21]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
3.4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.2  
upper limit 
8  
Variability estimate 
Standard error of the mean


Dispersion value 
2.26


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
0.4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.1  
upper limit 
5  
Variability estimate 
Standard error of the mean


Dispersion value 
2.24


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.8  
upper limit 
1.8  
Variability estimate 
Standard error of the mean


Dispersion value 
2.35



End point title 
Weighted mean change from Baseline of the QT Interval Corrected According to Fridericia's Formula (QTcF) at 9 hours postdose  
End point description 
Twelvelead ECGs (electrocardiograms) were performed to measure QTcF at Baseline, predose and 15 minutes (min), 45 min, 1.5 h, 3h, 6 h and 9 h postdose on Day 21 of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Data are presented as the adjusted means of WM. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [22]  PD Parameter Population [23]  PD Parameter Population [24]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
5.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.2  
upper limit 
8.9  
Variability estimate 
Standard error of the mean


Dispersion value 
1.65


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
0.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3  
upper limit 
3.7  
Variability estimate 
Standard error of the mean


Dispersion value 
1.65


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
36


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
5.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
8.7  
upper limit 
1.7  
Variability estimate 
Standard error of the mean


Dispersion value 
1.74



End point title 
Maximum mean change from Baseline of the supine heart rate at 9 hours postdose  
End point description 
Heart rate was recorded at Screening, prior to dosing, and at 15 minutes, 45 minutes, 1.5, 3, 6 and 9 h postdose on Day 21of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Heart rate measurement was taken in a supine position having rested in this position for at least 10 min before each reading. The maximum observed value of heart rate was measured and data are presented as adjusted mean of maximum heart rate. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [25]  PD Parameter Population [26]  PD Parameter Population [27]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
1.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.8  
upper limit 
4.6  
Variability estimate 
Standard error of the mean


Dispersion value 
2.82


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
10.6  
upper limit 
0.7  
Variability estimate 
Standard error of the mean


Dispersion value 
2.79


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of adjusted means  
Point estimate 
3.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
9.8  
upper limit 
2.1  
Variability estimate 
Standard error of the mean


Dispersion value 
2.92



End point title 
Weighted Mean change from Baseline of supine heart rate at 9 hours postdose  
End point description 
Heart rate was recorded at Screening, prior to dosing, and at 15 min, 45 min, 1.5, 3, 6 and 9 h postdose on Day 21of each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. Heart rate measurement was taken in a supine position having rested in this position for at least 10 min before each reading. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [28]  PD Parameter Population [29]  PD Parameter Population [30]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
1.7


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.8  
upper limit 
2.4  
Variability estimate 
Standard error of the mean


Dispersion value 
2.03


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
2.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.7  
upper limit 
1.5  
Variability estimate 
Standard error of the mean


Dispersion value 
2.03


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
36


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.2  
upper limit 
3.4  
Variability estimate 
Standard error of the mean


Dispersion value 
2.13



End point title 
Maximum change from Baseline for supine systolic blood pressure (SBP) at 9 hours postdose  
End point description 
Blood pressure (BP) measurement included supine SBP and diastolic BP (DBP). SBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h postdose on Day 21 of the each treatment period. The maximum observed values for SBP from the time of the morning dose on Day 21 to 9 h postdose were measured and the data are presented as adjusted mean of maximum SBP. Baseline was defined as the derived parameter from the Baseline assessment. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [31]  PD Parameter Population [32]  PD Parameter Population [33]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
1.8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.7  
upper limit 
5.3  
Variability estimate 
Standard error of the mean


Dispersion value 
1.72


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair HFA with Spacer v Advair DISKUS


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
2.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.3  
upper limit 
5.7  
Variability estimate 
Standard error of the mean


Dispersion value 
1.71


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0.4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.3  
upper limit 
4  
Variability estimate 
Standard error of the mean


Dispersion value 
1.79



End point title 
Minimum change from Baseline of the supine diastolic BP (DBP) at 9 hours postdose  
End point description 
Blood pressure (BP) measurement included supine SBP and DBP. DBP were recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h postdose on Day 21 of the each treatment period. Baseline was defined as the derived parameter from the Baseline assessment. The minimum observed values from the time of the morning dose on Day 21 to 9 hours post dose were measured and the data are presented as adjusted mean of minimum DBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [34]  PD Parameter Population [35]  PD Parameter Population [36]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair DISKUS v Advair HFA


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.7  
upper limit 
0.7  
Variability estimate 
Standard error of the mean


Dispersion value 
1.33


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
2.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.4  
upper limit 
4.9  
Variability estimate 
Standard error of the mean


Dispersion value 
1.31


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA v Advair HFA with Spacer


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
4.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
7  
Variability estimate 
Standard error of the mean


Dispersion value 
1.37



End point title 
Weighted mean change from Baseline for supine SBP at 9 hours postdose  
End point description 
Blood pressure (BP) measurement included supine SBP and DBP. SBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h postdose on Day 21 of the each treatment period. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted mean of WM SBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [37]  PD Parameter Population [38]  PD Parameter Population [39]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
2.8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7  
upper limit 
6.2  
Variability estimate 
Standard error of the mean


Dispersion value 
1.7


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
3.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.1  
upper limit 
6.8  
Variability estimate 
Standard error of the mean


Dispersion value 
1.68


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3  
upper limit 
4.1  
Variability estimate 
Standard error of the mean


Dispersion value 
1.76



End point title 
Weighted mean change from Baseline for supine DBP at 9 hours postdose  
End point description 
Blood pressure (BP) measurement included SBP and DBP. DBP was recorded at screening, prior to dosing, and at 15 min, 45 min, 1.5,2, 4, 6 and 9 h postdose on Day 21 of the each treatment period. Weighted mean (WM) was derived by calculating the AUC, and then dividing by the relevant time interval. Baseline was defined as the derived parameter from the Baseline assessment. The data are presented as adjusted mean of WM DBP. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).


End point type 
Secondary


End point timeframe 
At Baseline, and predose, 15 min, 45 min, 1.5 h, 3 h, 6 h, and 9 h on Day 21 of each treatment period




Notes [40]  PD Parameter Population [41]  PD Parameter Population [42]  PD Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
2.2  
Variability estimate 
Standard error of the mean


Dispersion value 
1.09


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair DISKUS v Advair HFA with Spacer


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0.8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
3.1  
Variability estimate 
Standard error of the mean


Dispersion value 
1.09


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair HFA


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Difference of treatment ratios  
Point estimate 
0.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
3.2  
Variability estimate 
Standard error of the mean


Dispersion value 
1.14



End point title 
Area under the concentrationtime curve from time 0 to the last quantifiable concentration (AUC[last]) for FP  
End point description 
Blood samples were collected to determine the plasma concentrations of FP from predose up to 12 hour postdose of each treatment period to derive the AUC(0t). Blood samples for PK analysis of FP were obtained on Day 21 at predose and 30 minutes (min), 1 hour (h), 2,4,8, and12 h post FP dose administration. For 8 and 12 h post dose, two 4 mL blood samples were collected. Pharmacokinetic (PK) Parameter Population was defined as all participants who received treatment during both treatment periods and for whom PK parameters were derived for both periods.


End point type 
Secondary


End point timeframe 
At premorning dose, 30 min, 1, 2, 4, 8, and 12 h postdose on Day 21 of Treatments periods 1 and 2




Notes [43]  PK Parameter Population [44]  PK Parameter Population [45]  PK Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.16


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.07  
upper limit 
0.37  
Variability estimate 
Standard error of the mean


Dispersion value 
0.512


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair HFA v Advair HFA with Spacer


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
4.17


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.7  
upper limit 
10.2  
Variability estimate 
Standard error of the mean


Dispersion value 
0.529


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair DISKUS


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.65


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.28  
upper limit 
1.54  
Variability estimate 
Standard error of the mean


Dispersion value 
0.507



End point title 
AUC(last) for Salmeterol  
End point description 
Blood samples were collected to determine the plasma concentrations of Salmeterol from predose up to 4 hour postdose of each treatment period to derive the AUC(0t). Blood samples for PK analysis of salmeterol were obtained on Day 21 at predose and 30 minutes (min), 1 hour (h), 2 h, and 4 h post salmeterol dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21.


End point type 
Secondary


End point timeframe 
At premorning dose, 10 minutes (min), 30 min, 1, 2, and 4 h postdose on Day 21 of Treatments periods 1 and 2




Notes [46]  PK Parameter Population [47]  PK Parameter Population [48]  PK Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
1.11


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.53  
upper limit 
2.32  
Variability estimate 
Standard error of the mean


Dispersion value 
0.437


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair HFA v Advair HFA with Spacer


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.83


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.39  
upper limit 
1.75  
Variability estimate 
Standard error of the mean


Dispersion value 
0.448


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair DISKUS


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.92


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.44  
upper limit 
1.9  
Variability estimate 
Standard error of the mean


Dispersion value 
0.431



End point title 
Maximum observed plasma concentration (Cmax) at steady state for FP  
End point description 
Blood samples were collected to determine the plasma concentrations of FP from predose up to 12 hour postdose of each treatment period to derive the Cmax. Blood samples for PK analysis of FP were obtained on Day 21 at predose and 30 minutes (min), 1 hour (h), 2 h, 4 h, 8 h, 12 h post FP dose administration. For 8 and 12 h post dose, two 4 mL blood samples were collected.


End point type 
Secondary


End point timeframe 
At premorning dose, 30 min, 1, 2, 4, 8, and 12 h postdose on Day 21 of Treatments periods 1 and 2




Notes [49]  PK Parameter Population [50]  PK Parameter Population [51]  PK Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.27


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.15  
upper limit 
0.47  
Variability estimate 
Standard error of the mean


Dispersion value 
0.33


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair HFA v Advair HFA with Spacer


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
2.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.18  
upper limit 
3.74  
Variability estimate 
Standard error of the mean


Dispersion value 
0.342


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair DISKUS


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.56


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.32  
upper limit 
0.98  
Variability estimate 
Standard error of the mean


Dispersion value 
0.327



End point title 
Cmax at steady state for salmeterol  
End point description 
Blood samples were collected to determine the plasma concentrations of Salmeterol from predose up to 4 hour postdose of each treatment period to derive the Cmax. Blood samples for PK analysis of salmeterol were obtained on Day 21 at predose and 30 minutes (min), 1 hour (h), 2 h, and 4 h post salmeterol dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21.


End point type 
Secondary


End point timeframe 
At premorning dose, 10 minutes (min), 30 min, 1, 2, and 4 h postdose on Day 21 of Treatments periods 1 and 2




Notes [52]  PK Parameter Population [53]  PK Parameter Population [54]  PK Parameter Population 

Statistical analysis title 
Statistical analysis 1  
Comparison groups 
Advair HFA v Advair DISKUS


Number of subjects included in analysis 
38


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
0.77


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.47  
upper limit 
1.25  
Variability estimate 
Standard error of the mean


Dispersion value 
0.291


Statistical analysis title 
Statistical analysis 2  
Comparison groups 
Advair HFA v Advair HFA with Spacer


Number of subjects included in analysis 
37


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
1.62


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.98  
upper limit 
2.67  
Variability estimate 
Standard error of the mean


Dispersion value 
0.298


Statistical analysis title 
Statistical analysis 3  
Comparison groups 
Advair HFA with Spacer v Advair DISKUS


Number of subjects included in analysis 
39


Analysis specification 
Prespecified


Analysis type 
other  
Method 

Parameter type 
Ratio of adjusted geometric means  
Point estimate 
1.24


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.76  
upper limit 
2.01  
Variability estimate 
Standard error of the mean


Dispersion value 
0.287



End point title 
Time to occurrence of Cmax (Tmax) at steady state for FP and salmeterol  
End point description 
Blood samples were collected to determine the plasma concentrations of FP and salmeterol from predose up to 12 h postdose of each treatment period to derive tmax. Blood samples of participants were collected for evaluating Tmax. Tmax is a measure of the time required to reach the maximum concentration of the drug. Blood samples for PK analysis were obtained on Day 21 at predose and 30 minutes (min), 1 hour (h), 2 h, 4 h, 8 h, 12 h post FP dose administration. One 4 mL sample was also collected at 10 min post dose on Day 21. For 8 and 12 h post dose, two 4 mL blood samples were collected.


End point type 
Secondary


End point timeframe 
At premorning dose, 10 minutes (min), 30 min, 1, 2, 4, 8, and 12 h postdose on Day 21 of Treatments periods 1 and 2




Notes [55]  PK Parameter Population [56]  PK Parameter Population [57]  PK Parameter Population 

No statistical analyses for this end point 


End point title 
Number of paritcipants with any adverse event (AE) or serious adverse event (SAE)  
End point description 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any AE with onset after the start dose of the study medication and on or before the followup phone call were collected. All Subjects Population was defined as all participants who received at least one study treatment.


End point type 
Secondary


End point timeframe 
From the first dose of the study medication until followup period (Up to 7 weeks)




Notes [58]  All Subjects Population [59]  All Subjects Population [60]  All Subjects Population 

No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
Ontreatment serious adverse events (SAEs) and nonserious adverse events (AEs) were collected from start of IP (Session 1) until Week 7 including the followup period.


Adverse event reporting additional description 
Ontreatment SAEs and nonserious AEs are reported for all Subjects Population, comprised of all participants who received at least one dose of study treatment.


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
18.0


Reporting groups


Reporting group title 
Advair HFA


Reporting group description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg , which was supplied as a HFApropelled 120actuation metered dose inhaler (MDI) desgined to deliver 45 µg of fluticasone propionate (FP) and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.  
Reporting group title 
Advair HFA with Spacer


Reporting group description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC, or CB): two inhalations of ADVAIR HFA 45/21 µg with Aerochamber Plus Spacer, which was supplied as a metered dose inhaler (MDI) designed to deliver 45 µg of FP and 21 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA or Adavir DISKUS. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.  
Reporting group title 
Advair DISKUS


Reporting group description 
Participants were randomized to one of the 6 possible treatment arms (AB, BA, AC, CA, BC or CB): one inhalation of ADVAIR DISKUS 100/50 µg, which was supplied as a 60dose multidose powder inhaler (MPDI) desgined to deliver 100 µg of FP and 50 µg of salmeterol twice daily (BID) for 21 days (on outpatient basis except on Day 21) along with either Advair HFA with Aerochamber Plus Spacer or Adavir HFA. After this treatment period 1, participants received a repeat dosing of the same sequence for 21 days without any washout period.  


Frequency threshold for reporting nonserious adverse events: 1%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

12 Sep 2006 
The purpose of this amendment was to change the study design to include a third arm to evaluate the systemic exposure and pharmacodynamics of ADVAIR HFA following administration using the Aerochamber plus Spacer. GlaxoSmithKline plans to use the Aerochamber Plus Spacer in a 12week safety study (SFA 106484). Since systemic exposure of an inhaled drug product can vary gently depending on the mechanism of administration, the FDA recommended an assessment of the difference of systemic exposure with and without a spacer to be included in this clinical pharmacology protocol. This protocol has also been modified to remove inconsistencies in study procedures and to make clarification to the inclusion/exclusion criteria. 

09 Nov 2006 
Based on feedback at a recent investigators meeting, the inclusion criteria regarding minimum weight for eligibility in this study will be amended to facilitate in the 4 to 7 years age range. The protocol states that 1/3 of the subjects must be ≤7 years of age. However, the current weight restriction would make it difficult to reach this enrollment target. Furthermore, this amendment will clarify exclusion criteria regarding inhaled corticosteroid use. 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported 