Clinical Trial Results:
A Randomized, Double blind, Placebo controlled, TwoWay Crossover 7day study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Repeat Dose Inhaled GW642444 25μg in Children aged 511 years with Persistent Asthma
Summary


EudraCT number 
201200074112 
Trial protocol 
Outside EU/EEA 
Global end of trial date 
12 Apr 2011

Results information


Results version number 
v1(current) 
This version publication date 
15 Mar 2016

First version publication date 
14 May 2015

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 
HZA112776


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01453296  
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, +1 8664357343,


Scientific contact 
GSK Response Center, GlaxoSmithKline, +1 8664357343,


Paediatric regulatory details


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


EMA paediatric investigation plan number(s) 
EMEA000431PIP0108  
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 
27 May 2011


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
12 Apr 2011


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To determine the safety and tolerability following administration of GW642444 25
μg, via a novel dry powder inhaler, oncedaily for 7 days in subjects aged 5–11
years.


Protection of trial subjects 
A parent was required to stay with the subjects for the long days in the clinic. As much as possible children in the same age group were scheduled for visits on the same day. Games and movies were provided for diversion during the long clinic days. Effort was made to have the same staff members work with the children to help reduce anxiety. Topical anesthetics were used at injection site to reduce discomfort from blood collections. An indwelling cannula was inserted for serial blood draws, to prevent the pain and distress associated with repeated needle sticks.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
09 Mar 2010


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: 28


Worldwide total number of subjects 
28


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) 
28


Adolescents (1217 years) 
0


Adults (1864 years) 
0


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
Participants were enrolled into one of two cohorts based upon age; the younger cohort was enrolled after a review of the safety/pharmacokinetic data of at least six participants from the older cohort. Each participant was assigned to treatment randomly; assignment was not to be influenced by whether participants were in Cohort 1 or Cohort 2.  
Preassignment


Screening details 
A Baseline assessment was carried out on Day 1 of the first treatment period. Participants were then randomized to one of the two possible treatment sequences (Vilanterol [VI] 25 micrograms [µg] followed by matching Placebo; matching placebo followed by VI 25 µg) in a 1:1 ratio in an AB or BA sequence.  
Period 1


Period 1 title 
Treatment Period 1 (Overall)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst, Carer, Assessor  
Arms


Are arms mutually exclusive 
Yes


Arm title

Sequence 1: VI 25 µg followed by Placebo  
Arm description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day wash out (w/o); crossover


Arm title

Sequence 2: Placebo followed by VI 25 µg  
Arm description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental; placebo  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover




Period 2


Period 2 title 
Washout Period


Is this the baseline period? 
No  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst, Carer, Assessor  
Arms


Are arms mutually exclusive 
Yes


Arm title

Sequence 1: VI 25 µg followed by Placebo  
Arm description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental: placebo  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover


Arm title

Sequence 2: Placebo followed by VI 25 µg  
Arm description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental: placebo  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover




Period 3


Period 3 title 
Treatment Period 2


Is this the baseline period? 
No  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator, Monitor, Data analyst, Carer, Assessor  
Arms


Are arms mutually exclusive 
Yes


Arm title

Sequence 1: VI 25 µg followed by Placebo  
Arm description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental: placebo  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover


Arm title

Sequence 2: Placebo followed by VI 25 µg  
Arm description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Arm type 
Experimental: placebo  
Investigational medicinal product name 
Vilanterol; placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Inhalation powder


Routes of administration 
Oral use


Dosage and administration details 
Vilanterol 25mg or Placebo once daily x 14 days; 7 day w/o; crossover





Baseline characteristics reporting groups


Reporting group title 
Treatment Period 1 (Overall)


Reporting group description 
Participants received either vilanterol (VI) 25 micrograms (µg) or matching placebo in the first of two 14day treatment periods, followed by a repeat dose of the other therapy (the therapy not received in the first treatment period) in the second 14day treatment period. Inhaled VI 25 µg or matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.  



End points reporting groups


Reporting group title 
Sequence 1: VI 25 µg followed by Placebo


Reporting group description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Reporting group title 
Sequence 2: Placebo followed by VI 25 µg


Reporting group description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Reporting group title 
Sequence 1: VI 25 µg followed by Placebo


Reporting group description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Reporting group title 
Sequence 2: Placebo followed by VI 25 µg


Reporting group description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Reporting group title 
Sequence 1: VI 25 µg followed by Placebo


Reporting group description 
Participants received vilanterol (VI) 25 micrograms (µg) and matching placebo in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Reporting group title 
Sequence 2: Placebo followed by VI 25 µg


Reporting group description 
Participants received placebo and VI 25 µg in Treatment Periods 1 and 2, respectively. Inhaled VI 25 µg and matching placebo were administered once daily in the morning (Day 1 to Day 14) via a Dry Powder Inhaler. The washout period between the 14day treatment periods was at least 7 days.  
Subject analysis set title 
Placebo


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All participants who received matching placebo in one or both of the two 14day treatment periods. Matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.


Subject analysis set title 
VI 25 µg


Subject analysis set type 
Safety analysis  
Subject analysis set description 
All participants who received VI 25 µg in one or both of the 14day treatment periods. Inhaled VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.


Subject analysis set title 
VI 25 µg


Subject analysis set type 
Subgroup analysis  
Subject analysis set description 
All participants who received VI 25 µg in one or both of the 14day treatment periods. Inhaled VI 25 µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.



End point title 
Number of participants with any adverse event (AE) or any serious adverse event (SAE) during the Treatment Period ^{[1]}  
End point description 
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General AE/SAE module for a complete list of AEs and SAEs.


End point type 
Primary


End point timeframe 
From the start of study medication until Week 11 (Visit 8)/Early Withdrawal


Notes [1]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [2]  All Subjects Population: all participants who received at least one dose of study medication [3]  All Subjects Population: all participants who received at least one dose of study medication 

No statistical analyses for this end point 


End point title 
Basophil, eosinophil, lymphocyte, monocyte, total neutrophil, platelet, and white blood cell count values at Day 14 of the respective treatment period ^{[4]}  
End point description 
Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelets, and white blood cell (WBC) count at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [4]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [5]  All Subjects Population,Only those participants available at the specified time points were analyzed [6]  All Subjects Population,Only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Hemoglobin and mean corpuscle hemoglobin concentration (MCHC) values at Day 14 of the respective treatment period ^{[7]}  
End point description 
Blood samples were collected for the measurement of hemoglobin and MCHC at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [7]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [8]  All Subjects Population, only those participants available at the specified time points were analyed [9]  All Subjects Population, only those participants available at the specified time points were analyed 

No statistical analyses for this end point 


End point title 
Reticulocyte and Red Blood Cell (RBC) values at Day 14 of the respective treatment period ^{[10]}  
End point description 
Blood samples were collected for the measurement of reticulocytes and RBCs at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [10]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [11]  All Subjects Population,only those participants available at the specified time points were analyzed [12]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Hematocrit value at Day 14 of the respective treatment period ^{[13]}  
End point description 
Blood samples were collected for the measurement of hematocrit at Day 14 of the respective treatment period. Hematocrit is a measure of the percentage of the volume of the whole blood that is composed of red blood cells, as determined by separation of red blood cells from the plasma (usually by centrifugation). Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [13]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [14]  All Subjects Population,only those participants available at the specified time points were analyzed [15]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Mean Corpuscle Volume (MCV) value at Day 14 of the respective treatment period ^{[16]}  
End point description 
Blood samples were collected for the measurement of MCV at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [16]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [17]  All Subjects Population,only those participants available at the specified time points were analyzed [18]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Mean Corpuscle Hemoglobin (MCH) value at Day 14 of the respective treatment period ^{[19]}  
End point description 
Blood samples were collected for the measurement of MCH at Day 14 of the respective treatment period . Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [19]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [20]  All Subjects Population,only those participants available at the specified time points were analyzed [21]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Alanine amino transferase (ALT), alkaline phosphatase (ALP), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) values at Day 14 of the respective treatment period ^{[22]}  
End point description 
Blood samples were collected for the measurement of ALT, ALP, AST, and GGT at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [22]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [23]  All Subjects Population,only those participants available at the specified time points were analyzed [24]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Albumin and total protein values at Day 14 of the respective treatment period ^{[25]}  
End point description 
Blood samples were collected for the measurement of albumin and total protein at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [25]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [26]  All Subjects Population,only those participants available at the specified time points were analyzed [27]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) values at Day 14 of the respective treatment period ^{[28]}  
End point description 
Blood samples were collected for the measurement of calcium, chloride, carbon dioxide content/bicarbonate (CO2/BI), glucose, potassium, sodium, and urea/BUN at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [28]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [29]  All Subjects Population,only those participants available at the specified time points were analyzed [30]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Total bilirubin, direct bilirubin, creatinine, and uric acid values at Day 14 of the respective treatment period ^{[31]}  
End point description 
Blood samples were collected for the measurement of total bilirubin, direct bilirubin, creatinine, and uric acid at Day 14 of the respective treatment period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Primary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)


Notes [31]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [32]  All Subjects Population,only those participants available at the specified time points were analyzed [33]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Peak expiratory flow on Day 1, Day 8, and Day 14 of the respective treatment period ^{[34]}  
End point description 
Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF is calculated as the maximum of three readings taken at each timepoint for each participant. Baseline is defined as the predose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)


Notes [34]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [35]  All Subjects Population,only those participants available at the specified time points were analyzed [36]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1, Day 8, and Day 14 of the respective treatment period ^{[37]}  
End point description 
SBP and DBP were measured at Day 1, Day 8, and Day 14 of the respective treatment period. PD=postdose. Baseline is defined as the predose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)


Notes [37]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this primary endpoint; thus, no data are available. 



Notes [38]  All Subjects Population,only those participants available at the specified time points were analyzed [39]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Maximum heart rate at Day 1 and Day 14 of the respective treatment period  
End point description 
Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. For 08 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 02 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [40]  All Subjects Population,only those participants available at the specified time points were analyzed [41]  All Subjects Population,only those participants available at the specified time points were analyzed 

Statistical analysis title 
Analysis 1  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[42]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8  
upper limit 
5.7  
Notes [42]  Estimation based analysis. Day 1 maximum HR (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 2  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[43]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.4  
upper limit 
3.7  
Notes [43]  Estimation based analysis. Day 14 maximum HR (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 3  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[44]}  
Method 

Parameter type 
Median difference (final values)  
Point estimate 
0.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.6  
upper limit 
3.6  
Notes [44]  Estimation based analysis. Day 14 maximum HR (08 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 


End point title 
Weighted mean heart rate at Day 1 and Day 14 of the respective treatment period  
End point description 
Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. For 08 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 02 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [45]  All Subjects Population,only those participants available at the specified time points were analyzed [46]  All Subjects Population,only those participants available at the specified time points were analyzed 

Statistical analysis title 
Analysis 1  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[47]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.8  
upper limit 
5.7  
Notes [47]  Estimation based analysis. Day 1 weighted HR (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 2  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[48]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.4  
upper limit 
3.7  
Notes [48]  Estimation based analysis. Day 14 weighted HR (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 3  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[49]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.5


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.6  
upper limit 
3.6  
Notes [49]  Estimation based analysis. Day 14 weighted HR (08 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 


End point title 
Maximum QTcF at Day 1 and Day 14 of the respective treatment period  
End point description 
The electrocardiographic (ECG) parameter QT duration corrected using Fridericia’s formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. For 08 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 02 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [50]  All Subjects Population,only those participants available at the specified time points were analyzed [51]  All Subjects Population,only those participants available at the specified time points were analyzed 

Statistical analysis title 
Analysis 1  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[52]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.5  
upper limit 
6.6  
Notes [52]  Estimation based analysis. Day 1 maximum QTcF (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 2  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[53]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.6


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.2  
upper limit 
6.3  
Notes [53]  Estimation based analysis. Day 14 maximum QTcF (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 3  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[54]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3  
upper limit 
5.7  
Notes [54]  Estimation based analysis. Day 14 maximum QTcF (08 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 


End point title 
Weighted mean QTcF at Day 1 and Day 14 of the respective treatment period  
End point description 
The electrocardiographic (ECG) parameter QT duration corrected using Fridericia’s formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. For 08 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 02 hr parameters, treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).


End point type 
Primary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [55]  All Subjects Population,only those participants available at the specified time points were analyzed [56]  All Subjects Population,only those participants available at the specified time points were analyzed 

Statistical analysis title 
Analysis 1  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[57]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.01


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.59  
upper limit 
6.61  
Notes [57]  Estimation based analysis. Day 1 weighted QTcF (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 2  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[58]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.93  
upper limit 
7.81  
Notes [58]  Estimation based analysis. Day 14 weighted QTcF (02 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 

Statistical analysis title 
Analysis 3  
Comparison groups 
Placebo v VI 25 µg


Number of subjects included in analysis 
54


Analysis specification 
Prespecified


Analysis type 
other ^{[59]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
3.19


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.7  
upper limit 
7.08  
Notes [59]  Estimation based analysis. Day 14 weighted QTcF (08 hr). The estimated value represents the treatment difference: VI 25 µg minus placebo. 


End point title 
AUC(0t) and AUC(08) on Day 14 of the respective treatment period  
End point description 
Area under the concentrationtime (AUC) curve from time zero (predose) to the last time AUC(0t) and from time zero to 8 hours AUC(08) of quantifiable concentration of VI on Day 14 of the respective treatment period was measured. Samples were collected at the following times: predose; 10 minutes (min) and 30 min postdose; and 1, 2, 4, 6, and 8 hours postdose for participants who were >=20 kilograms and predose; 10 min and 30 min postdose; and 1, 2, and 4 hours postdose for participants who were <=20 kilograms on Day 14 of the respective treatment period. Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Population. Pharmacokinetic (PK) Population: all participants in the All Subjects Population for whom a PK sample was obtained and analyzee. Only those participants available at the specified time points were analyzed (represented by n=X,X in the category titles).


End point type 
Secondary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)




Notes [60]  PK Population:all participants in All Subjects Population for whom a PK sample was obtained/analyzed 

No statistical analyses for this end point 


End point title 
Cmax on Day 14 of the respective treatment period  
End point description 
Cmax is defined as the maximum observed concentration on Day 14 of the respective treatment period. Samples were collected at the following times: predose; 10 minutes (min) and 30 min postdose; and 1, 2, 4, 6, and 8 hours postdose for participants who were >=20 kilograms and predose; 10 min and 30 min postdose; and 1, 2, and 4 hours postdose for participants who were <=20 kilograms on Day 14 of the respective treatment period.


End point type 
Secondary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)




Notes [61]  PK Population 

No statistical analyses for this end point 


End point title 
tmax, t1/2, and t at Day 14 of the respective treatment period  
End point description 
tmax is defined as the time to reach the observed maximum concentration, t1/2 is defined as the time required to reduce the plasma concentration to one half its initial value, and t is defined as the time of the last observed quantifiable concentration on Day 14 of the respective treatment period. Samples were collected at the following times: predose; 10 minutes (min) and 30 min postdose; and 1, 2, 4, 6, and 8 hours postdose for participants who were >=20 kilograms and predose; 10 min and 30 min postdose; and 1, 2, and 4 hours postdose for participants who were <=20 kilograms on Day 14 of the respective treatment period. PK Population. Only those participants available at the specified time points were analyzed (represented by n=X, 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 PK Population.


End point type 
Secondary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)




Notes [62]  PK Population. Only those participants available at the specified time points were analyzed (n=X). 

No statistical analyses for this end point 


End point title 
Blood glucose and potassium on Day 14 of the respective treatment period  
End point description 
Blood glucose and potassium values were measured on Day 14 of the respective treatment period. Samples were collected at the following times: predose; 10 minutes (min) and 30 min postdose; and 1, 2, 4, 6, and 8 hours postdose for participants who were >=20 kilograms and predose; 10 min and 30 min postdose; and 1, 2, and 4 hours postdose for participants who were <=20 kilograms on Day 14 of the respective treatment period. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg. Treatment and period were fitted as fixed effects and participant was fitted as a random effect.


End point type 
Secondary


End point timeframe 
Day 14 of the respective treatment period (up to Study Day 49)




Notes [63]  All Subjects Population,only those participants available at the specified time points were analyzed [64]  All Subjects Population,only those participants available at the specified time points were analyzed 

No statistical analyses for this end point 


End point title 
Average oropharyngeal crosssectional area on Day 1 and Day 14 of the respective treatment period  
End point description 
During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for the study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Pharyngometry data were recorded for each day (Day 1 and Day 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal crosssectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, 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 All Subjects Population.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [65]  All Subjects Population. Only those participants available at the specified time point were analyzed [66]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Distance of assessment on Day 1 and Day 14 of the respective treatment period  
End point description 
During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Distance of assessment is defined as the distance (length measured in centimeters [cm]) estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal crosssectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, 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 All Subjects Population.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [67]  All Subjects Population. Only those participants available at the specified time point were analyzed [68]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Oropharyngeal volume on Day 1 and Day 14 of the respective treatment period  
End point description 
During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Oropharyngeal volume is defined as the volume (centimeters cubed [cm^3]) of the mouth and throat estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal crosssectional area was calculated. All Subjects Population. Only those participants available at the specified time point were analyzed (represented by n=X, 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 All Subjects Population.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [69]  All Subjects Population. Only those participants available at the specified time point were analyzed [70]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Average flow rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the respective treatment period  
End point description 
During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Average flow rate is defined as the average inspiratory flow rate (Liters [L]/min) across the inhalation profile when inhaling across the resistance of the inhaler. PIFR is defined as the Peak Inspiratory Flow Rate (L/min) of the inhalation profile when inhaling across the resistance of the inhaler.The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the average flow rate and PIFR were determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [71]  All Subjects Population. Only those participants available at the specified time point were analyzed [72]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Inhalation time on Day 1 and Day 14 of the respective treatment period  
End point description 
During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhalation time is defined as the duration of the inhalation(s) when inhaling across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalation time was determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [73]  All Subjects Population. Only those participants available at the specified time point were analyzed [74]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Inhaled volume on Day 1 and Day 14 of the respective treatment period  
End point description 
During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhaled volume is defined as the volume of air (Liters) inhaled during the inhalation across the resistance of the inhaler.
The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalaled volume was determined. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [75]  All Subjects Population. Only those participants available at the specified time point were analyzed [76]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Peak pressure drop on Day 1 and Day 14 of the respective treatment period  
End point description 
During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Peak pressure drop is defined as the maximum pressure drop (kilopascal [kPa]) achieved during inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was calculated for each day (Days 1 and 14 of the respective treatment period), and used for subsequent modeling and prediction of dose emission attributes. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [77]  All Subjects Population. Only those participants available at the specified time point were analyzed [78]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Total emitted dose (TED) on Day 1 and Day 14 of the respective treatment period  
End point description 
The total emitted dose (TED) is defined as the mass (micrograms) of the nominal dose that passes beyond the throat. The recorded inhalation profiles of the participants and the mouththroat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted total emitted dose. All Subjects Population. Only those participants available at the specified time point were analyzed. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [79]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


End point title 
Exthroat dose (ETD) and ETD <2 microns on Day 1 and Day 14 of the respective treatment period  
End point description 
The exthroat dose (ETD) and the “nominal ETD” is the mass (micrograms) of active investigational material that passes beyond the throat, nominal being the mean.The recorded inhalation profiles of the participants and the mouththroat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted ETD and ETD <2 microns.


End point type 
Secondary


End point timeframe 
Day 1 and Day 14 of the respective treatment period (up to Study Day 49)




Notes [80]  All Subjects Population. Only those participants available at the specified time point were analyzed 

No statistical analyses for this end point 


Adverse events information


Timeframe for reporting adverse events 
Ontreatment adverse events were reported.


Adverse event reporting additional description 
Serious adverse events (SAEs) and nonserious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
14.0


Reporting groups


Reporting group title 
Placebo


Reporting group description 
All participants who received matching placebo in one or both of the two 14day treatment periods. Matching placebo was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.  
Reporting group title 
VI 25 µg


Reporting group description 
All participants who received VI 25µg in one or both of the two 14day treatment periods. Inhaled VI 25µg was administered once daily in the morning (Day 1 to Day 14) via the Dry Powder Inhaler. The washout period between the treatment periods was at least 7 days.  


Frequency threshold for reporting nonserious adverse events: 3%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? No  
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 