Trial Outcomes & Findings for Pharmacokinetics and Pharacodynamics of GW642444 in Paedetric Subjects (NCT NCT01453296)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

28 participants

Primary outcome timeframe

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

Results posted on

2017-01-13

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Sequence 1: VI 25 µg Followed by Placebo 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 ae Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.	Sequence 2: Placebo Followed by VI 25 µg 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 14-day treatment periods was at least 7 days.
Treatment Period 1 STARTED	14	14
Treatment Period 1 COMPLETED	13	13
Treatment Period 1 NOT COMPLETED	1	1
Washout Period STARTED	13	13
Washout Period COMPLETED	13	13
Washout Period NOT COMPLETED	0	0
Treatment Period 2 STARTED	13	13
Treatment Period 2 COMPLETED	11	13
Treatment Period 2 NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence 1: VI 25 µg Followed by Placebo 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 ae Dry Powder Inhaler. The washout period between the 14-day treatment periods was at least 7 days.	Sequence 2: Placebo Followed by VI 25 µg 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 14-day treatment periods was at least 7 days.
Treatment Period 1 Adverse Event	0	1
Treatment Period 1 Met Protocol-Defined Stopping Criteria	1	0
Treatment Period 2 Adverse Event	1	0
Treatment Period 2 Withdrawal by Subject	1	0

Baseline Characteristics

Pharmacokinetics and Pharacodynamics of GW642444 in Paedetric Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	VI 25 µg/Placebo or Placebo/VI 25 µg n=28 Participants Participants received either vilanterol (VI) 25 micrograms (µg) or matching placebo in the first of two 14-day treatment periods, followed by a repeat dose of the other therapy (the therapy not received in the first treatment period) in the second 14-day 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.
Age, Continuous	8.0 Years STANDARD_DEVIATION 1.90 • n=5 Participants
Gender Female	10 Participants n=5 Participants
Gender Male	18 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	5 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	22 Participants n=5 Participants
Race/Ethnicity, Customized Mixed Race	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the start of study medication until Week 11 (Visit 8)/Early Withdrawal

Population: All Subjects Population: all participants who received at least one dose of study medication

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period Any AE	6 Participants	9 Participants
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period Any SAE	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Basophils, n=24, 25	0.021 10^9 cells per liter (GI/L) Standard Deviation 0.0145	0.034 10^9 cells per liter (GI/L) Standard Deviation 0.0185
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Eosinophils, n=24, 25	0.276 10^9 cells per liter (GI/L) Standard Deviation 0.3002	0.348 10^9 cells per liter (GI/L) Standard Deviation 0.3458
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Lymphocytes, n=24, 25	2.404 10^9 cells per liter (GI/L) Standard Deviation 0.8652	2.419 10^9 cells per liter (GI/L) Standard Deviation 0.8729
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Monocytes, n=24, 25	0.268 10^9 cells per liter (GI/L) Standard Deviation 0.1310	0.376 10^9 cells per liter (GI/L) Standard Deviation 0.1419
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Total neutrophils, n=24, 25	3.354 10^9 cells per liter (GI/L) Standard Deviation 1.3054	3.127 10^9 cells per liter (GI/L) Standard Deviation 0.9625
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period Platelets, n=23, 25	280.7 10^9 cells per liter (GI/L) Standard Deviation 54.11	279.4 10^9 cells per liter (GI/L) Standard Deviation 54.71
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period WBCs, n=24, 25	6.32 10^9 cells per liter (GI/L) Standard Deviation 1.808	6.30 10^9 cells per liter (GI/L) Standard Deviation 1.640

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period Hemoglobin, n=24, 25	133.0 Grams per liter (g/L) Standard Deviation 11.30	130.7 Grams per liter (g/L) Standard Deviation 11.22
Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period MCHC, n=24, 25	337.1 Grams per liter (g/L) Standard Deviation 5.50	338.3 Grams per liter (g/L) Standard Deviation 11.60

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period Reticulocytes, n=24, 25	0.05010 10^12 cells per liter (TI/L) Standard Deviation 0.020696	0.05275 10^12 cells per liter (TI/L) Standard Deviation 0.024571
Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period RBCs, n=24, 25	4.60 10^12 cells per liter (TI/L) Standard Deviation 0.374	4.47 10^12 cells per liter (TI/L) Standard Deviation 0.339

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Hematocrit Value at Day 14 of the Respective Treatment Period	0.3948 proportion of 1 Standard Deviation 0.03430	0.3863 proportion of 1 Standard Deviation 0.02617

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Mean Corpuscle Volume (MCV) Value at Day 14 of the Respective Treatment Period	86.0 10^15 femtoliters (fL) per cell Standard Deviation 4.08	86.6 10^15 femtoliters (fL) per cell Standard Deviation 3.59

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=24 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Mean Corpuscle Hemoglobin (MCH) Value at Day 14 of the Respective Treatment Period	28.97 10^12 picograms (pg) per cell Standard Deviation 1.337	29.29 10^12 picograms (pg) per cell Standard Deviation 1.464

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
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 ALT, n=22, 25	13.9 International units per liter (IU/L) Standard Deviation 4.21	13.5 International units per liter (IU/L) Standard Deviation 3.56
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 ALP, n=22, 25	260.5 International units per liter (IU/L) Standard Deviation 109.65	273.4 International units per liter (IU/L) Standard Deviation 103.51
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 AST, n=22, 24	27.7 International units per liter (IU/L) Standard Deviation 6.11	25.5 International units per liter (IU/L) Standard Deviation 4.52
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 GGT, n=22, 25	14.1 International units per liter (IU/L) Standard Deviation 4.12	13.6 International units per liter (IU/L) Standard Deviation 3.51

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Albumin and Total Protein Values at Day 14 of the Respective Treatment Period Albumin, n=22, 25	42.8 Grams per liter Standard Deviation 2.95	43.2 Grams per liter Standard Deviation 1.96
Albumin and Total Protein Values at Day 14 of the Respective Treatment Period Total protein, n=22, 25	67.9 Grams per liter Standard Deviation 4.82	68.6 Grams per liter Standard Deviation 3.16

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
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 Calcium, n=22, 24	2.327 Millimoles per liter (mmol/L) Standard Deviation 0.1357	2.359 Millimoles per liter (mmol/L) Standard Deviation 0.0666
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 Chloride, n=22, 25	105.5 Millimoles per liter (mmol/L) Standard Deviation 3.90	105.1 Millimoles per liter (mmol/L) Standard Deviation 2.01
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 CO2 content/bicarbonate, n=22, 24	17.6 Millimoles per liter (mmol/L) Standard Deviation 2.30	18.1 Millimoles per liter (mmol/L) Standard Deviation 1.98
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 Glucose, n=22, 25	4.95 Millimoles per liter (mmol/L) Standard Deviation 0.510	5.04 Millimoles per liter (mmol/L) Standard Deviation 0.513
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 Potassium, n=22, 24	4.30 Millimoles per liter (mmol/L) Standard Deviation 0.408	4.33 Millimoles per liter (mmol/L) Standard Deviation 0.242
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 Sodium, n=22, 25	137.7 Millimoles per liter (mmol/L) Standard Deviation 2.43	137.8 Millimoles per liter (mmol/L) Standard Deviation 2.12
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 Urea/BUN, n=22, 25	4.91 Millimoles per liter (mmol/L) Standard Deviation 1.368	4.48 Millimoles per liter (mmol/L) Standard Deviation 1.150

PRIMARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 All Subjects Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period Total bilirubin, n=22, 25	6.2 Micromoles per liter (µmol/L) Standard Deviation 2.22	5.8 Micromoles per liter (µmol/L) Standard Deviation 1.99
Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period Direct bilirubin, n=22, 25	1.7 Micromoles per liter (µmol/L) Standard Deviation 0.94	1.2 Micromoles per liter (µmol/L) Standard Deviation 1.00
Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period Creatinine, n=22, 25	39.45 Micromoles per liter (µmol/L) Standard Deviation 7.653	39.35 Micromoles per liter (µmol/L) Standard Deviation 6.731
Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period Uric acid, n=22, 25	241.4 Micromoles per liter (µmol/L) Standard Deviation 69.51	245.6 Micromoles per liter (µmol/L) Standard Deviation 47.27

PRIMARY outcome

Timeframe: Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

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 pre-dose 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).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1, Baseline, n=26, 28	230.6 liters/minute Standard Deviation 72.55	233.0 liters/minute Standard Deviation 68.55
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1, 20 minutes post-dose, n=26, 28	237.5 liters/minute Standard Deviation 69.65	245.6 liters/minute Standard Deviation 73.47
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8, Pre-dose, n=26, 28	232.1 liters/minute Standard Deviation 64.76	228.8 liters/minute Standard Deviation 64.42
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8, 20 minutes post-dose, n=25, 28	233.8 liters/minute Standard Deviation 220.0	240.7 liters/minute Standard Deviation 65.66
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14, Pre-dose, n=24, 26	240.3 liters/minute Standard Deviation 75.90	239.0 liters/minute Standard Deviation 72.02
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14, 20 minutes post-dose, n=24, 26	243.3 liters/minute Standard Deviation 75.18	248.1 liters/minute Standard Deviation 76.20

PRIMARY outcome

Timeframe: Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

SBP and DBP were measured at Day 1, Day 8, and Day 14 of the respective treatment period. PD=post-dose. Baseline is defined as the pre-dose 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).

Outcome measures

PRIMARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 1 maximum HR (0-2 hr), n=26, 28	83.6 Beats per minute Standard Error 1.44	86.1 Beats per minute Standard Error 1.40
Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 14 maximum HR (0-2 hr), n=24, 26	84.3 Beats per minute Standard Error 1.38	85.0 Beats per minute Standard Error 1.35
Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 14 maximum HR (0-8 hr), n=24, 26	88.1 Beats per minute Standard Error 1.45	88.6 Beats per minute Standard Error 1.41

PRIMARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

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 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 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).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Weighted Mean Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 1 weighted HR (0-2 hr), n=26, 28	76.39 Beats per minute Standard Error 1.311	79.20 Beats per minute Standard Error 1.285
Weighted Mean Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 14 weighted mean HR (0-2 hr), n=23, 26	76.11 Beats per minute Standard Error 1.309	77.67 Beats per minute Standard Error 1.264
Weighted Mean Heart Rate at Day 1 and Day 14 of the Respective Treatment Period Day 14 weighted mean HR (0-8 hr), n=23, 26	80.54 Beats per minute Standard Error 1.458	80.65 Beats per minute Standard Error 1.404

PRIMARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

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 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 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).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 1 maximum QTcF (0-2 hr), n=26, 28	405.6 milliseconds Standard Error 2.29	406.6 milliseconds Standard Error 2.22
Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 14 maximum QTcF (0-2 hr), n=24, 26	406.1 milliseconds Standard Error 2.06	407.7 milliseconds Standard Error 2.00
Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 14 maximum QTcF (0-8 hr), n=24, 26	407.8 milliseconds Standard Error 1.87	409.2 milliseconds Standard Error 1.82

PRIMARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

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 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 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).

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 1 weighted mean QTcF (0-2 hr), n=26, 28	394.21 milliseconds Standard Error 2.007	396.22 milliseconds Standard Error 1.960
Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 14 weighted mean QTcF (0-2 hr), n=23, 26	395.09 milliseconds Standard Error 2.122	398.03 milliseconds Standard Error 2.024
Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period Day 14 weighted mean QTcF (0-8 hr), n=23, 26	393.43 milliseconds Standard Error 1.867	396.62 milliseconds Standard Error 1.793

SECONDARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

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 in the category titles).

Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 8 hours AUC(0-8) of quantifiable concentration of VI on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were \>=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose 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.

Outcome measures

Outcome measures
Measure	Placebo All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period AUC(0-t), n=25	—	132.8 picogramshour per milliliter (pghr/mL) Interval 96.0 to 183.8
AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period AUC(0-8), n=19	—	181.7 picogramshour per milliliter (pghr/mL) Interval 145.0 to 227.7

SECONDARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: PK Population

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

Outcome measures

Outcome measures
Measure	Placebo All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Cmax on Day 14 of the Respective Treatment Period	—	97.44 picograms per milliliter (pg/mL) Interval 64.83 to 146.45

SECONDARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were \>=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were \<=20 kilograms on Day 14 of the respective treatment period.

Outcome measures

Outcome measures
Measure	Placebo All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Tmax, t1/2, and t at Day 14 of the Respective Treatment Period tmax, n=23	—	0.20 hours Interval 0.0 to 1.0
Tmax, t1/2, and t at Day 14 of the Respective Treatment Period t1/2, n=14	—	3.131 hours Interval 1.06 to 6.32
Tmax, t1/2, and t at Day 14 of the Respective Treatment Period t, n=23	—	6.00 hours Interval 1.0 to 8.13

SECONDARY outcome

Timeframe: Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects 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 at different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood glucose and potassium values were measured on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were \>=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose 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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Maximum Glucose (0-2 hr), n=24, 26	5.55 Millimoles per liter (mmol/L) Standard Error 0.184	5.57 Millimoles per liter (mmol/L) Standard Error 0.182
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Maximum Glucose (0-8 hr), n=24, 26	6.22 Millimoles per liter (mmol/L) Standard Error 0.187	6.03 Millimoles per liter (mmol/L) Standard Error 0.183
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Weighted Mean Glucose (0-2 hr), n=21, 25	5.02 Millimoles per liter (mmol/L) Standard Error 0.114	5.06 Millimoles per liter (mmol/L) Standard Error 0.109
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Weighted Mean Glucose (0-8 hr), n=19, 24	5.26 Millimoles per liter (mmol/L) Standard Error 0.108	5.21 Millimoles per liter (mmol/L) Standard Error 0.100
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Minimum Potassium (0-2 hr), n=23, 26	4.05 Millimoles per liter (mmol/L) Standard Error 0.040	4.00 Millimoles per liter (mmol/L) Standard Error 0.038
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Minimum Potassium (0-8 hr), n=24, 26	3.89 Millimoles per liter (mmol/L) Standard Error 0.060	3.87 Millimoles per liter (mmol/L) Standard Error 0.059
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Weighted Mean Potassium (0-2 hr), n=19, 22	4.21 Millimoles per liter (mmol/L) Standard Error 0.049	4.23 Millimoles per liter (mmol/L) Standard Error 0.046
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period Weighted Mean Potassium (0-8 hr), n=17, 22	4.05 Millimoles per liter (mmol/L) Standard Error 0.052	4.11 Millimoles per liter (mmol/L) Standard Error 0.049

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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 cross-sectional area was calculated.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=15, 13	5.65 centimeters squared (cm^2) Standard Deviation 1.834	4.42 centimeters squared (cm^2) Standard Deviation 2.310
Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=14, 15	5.47 centimeters squared (cm^2) Standard Deviation 1.661	5.16 centimeters squared (cm^2) Standard Deviation 2.139

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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 cross-sectional area was calculated.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=15, 13	18.40 centimeters (cm) Standard Deviation 1.502	18.26 centimeters (cm) Standard Deviation 1.824
Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=14, 15	18.46 centimeters (cm) Standard Deviation 1.395	18.41 centimeters (cm) Standard Deviation 1.276

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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 cross-sectional area was calculated.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=15, 13	102.33 cm^3 Standard Deviation 32.451	78.60 cm^3 Standard Deviation 39.296
Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=14, 15	102.26 cm^3 Standard Deviation 36.322	93.35 cm^3 Standard Deviation 37.190

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period Day 1, Average flow rate, n=23, 25	38.84 Liters per minute (L/min) Standard Deviation 9.440	42.23 Liters per minute (L/min) Standard Deviation 10.952
Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period Day 14, Average flow rate, n=23, 25	40.45 Liters per minute (L/min) Standard Deviation 10.538	42.08 Liters per minute (L/min) Standard Deviation 10.191
Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period Day 1, PIFR, n=23, 25	58.27 Liters per minute (L/min) Standard Deviation 14.258	61.41 Liters per minute (L/min) Standard Deviation 16.513
Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period Day 14, PIFR, n=23, 25	60.93 Liters per minute (L/min) Standard Deviation 14.901	61.79 Liters per minute (L/min) Standard Deviation 15.348

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=23, 25	1.45 Seconds (sec) Standard Deviation 0.604	1.36 Seconds (sec) Standard Deviation 0.551
Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=23, 25	1.35 Seconds (sec) Standard Deviation 0.528	1.34 Seconds (sec) Standard Deviation 0.476

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=23, 25	0.93 Liters Standard Deviation 0.433	0.92 Liters Standard Deviation 0.343
Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=23, 25	0.90 Liters Standard Deviation 0.426	0.95 Liters Standard Deviation 0.417

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period Day 1, n=23, 25	2.97 Kilopascal (kpa) Standard Deviation 1.275	3.33 Kilopascal (kpa) Standard Deviation 1.632
Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period Day 14, n=23, 25	3.23 Kilopascal (kpa) Standard Deviation 1.479	3.33 Kilopascal (kpa) Standard Deviation 1.350

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: 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.

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 mouth-throat (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.

Outcome measures

Outcome measures
Measure	Placebo All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=25 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period Nominal TED	—	20.28 micrograms Standard Deviation 0.177
Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period Minimum TED	—	20.24 micrograms Standard Deviation 0.188
Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period Maximum TED	—	20.31 micrograms Standard Deviation 0.173

SECONDARY outcome

Timeframe: Day 1 and Day 14 of the respective treatment period (up to Study Day 49)

Population: All Subjects Population. Only those participants available at the specified time point were analyzed.

The ex-throat 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 mouth-throat (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.

Outcome measures

Outcome measures
Measure	Placebo All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=15 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period Nominal ETD	—	9.00 micrograms Standard Deviation 0.697
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period Minimum ETD	—	8.94 micrograms Standard Deviation 0.652
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period Maximum ETD	—	9.06 micrograms Standard Deviation 0.747
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period ETD <2 microns	—	4.19 micrograms Standard Deviation 1.079
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period Minimum ETD <2 microns	—	4.10 micrograms Standard Deviation 1.011
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period Maximum ETD <2 microns	—	4.29 micrograms Standard Deviation 1.157

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

VI 25 µg

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=26 Participants All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=28 Participants All participants who received VI 25 µg in one or both of the 14-day 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.
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 30 minutes PD, n=24, 26	62.8 Millimeters of mercury (mmHg) Standard Deviation 3.83	63.7 Millimeters of mercury (mmHg) Standard Deviation 7.88
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, Baseline, n=26, 28	101.8 Millimeters of mercury (mmHg) Standard Deviation 6.59	102.9 Millimeters of mercury (mmHg) Standard Deviation 9.21
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, 10 minutes PD, n=26, 28	100.7 Millimeters of mercury (mmHg) Standard Deviation 7.59	102.4 Millimeters of mercury (mmHg) Standard Deviation 7.69
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, 30 minutes PD, n=26, 28	100.9 Millimeters of mercury (mmHg) Standard Deviation 9.35	103.5 Millimeters of mercury (mmHg) Standard Deviation 6.89
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, 45 minutes PD, n=26, 28	100.9 Millimeters of mercury (mmHg) Standard Deviation 7.41	103.5 Millimeters of mercury (mmHg) Standard Deviation 7.05
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, 74 minutes PD, n=26, 28	102.7 Millimeters of mercury (mmHg) Standard Deviation 7.95	104.4 Millimeters of mercury (mmHg) Standard Deviation 6.81
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 SBP, 2 hours PD, n=26, 28	103.3 Millimeters of mercury (mmHg) Standard Deviation 8.16	104.8 Millimeters of mercury (mmHg) Standard Deviation 7.82
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 SBP, Pre-dose, n=25, 28	99.6 Millimeters of mercury (mmHg) Standard Deviation 6.92	103.7 Millimeters of mercury (mmHg) Standard Deviation 8.64
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 SBP, 30 minutes PD, n=25, 28	101.7 Millimeters of mercury (mmHg) Standard Deviation 7.29	102.9 Millimeters of mercury (mmHg) Standard Deviation 7.31
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 SBP, 1 hour PD, n=25, 28	101.8 Millimeters of mercury (mmHg) Standard Deviation 8.38	103.6 Millimeters of mercury (mmHg) Standard Deviation 7.17
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, Pre-dose, n=24, 26	101.5 Millimeters of mercury (mmHg) Standard Deviation 9.18	103.9 Millimeters of mercury (mmHg) Standard Deviation 6.15
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 10 minutes PD, n=24, 26	101.3 Millimeters of mercury (mmHg) Standard Deviation 9.98	103.7 Millimeters of mercury (mmHg) Standard Deviation 6.70
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 30 minutes PD, n=24, 26	103.9 Millimeters of mercury (mmHg) Standard Deviation 8.72	102.9 Millimeters of mercury (mmHg) Standard Deviation 8.91
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 45 minutes PD, n=24, 26	103.6 Millimeters of mercury (mmHg) Standard Deviation 7.95	103.4 Millimeters of mercury (mmHg) Standard Deviation 7.03
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 75 minues PD, n=24, 26	104.9 Millimeters of mercury (mmHg) Standard Deviation 8.33	103.9 Millimeters of mercury (mmHg) Standard Deviation 6.36
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 4 hours PD, n=24, 26	102.2 Millimeters of mercury (mmHg) Standard Deviation 7.80	106.0 Millimeters of mercury (mmHg) Standard Deviation 5.20
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 2 hours PD, n=24, 26	103.0 Millimeters of mercury (mmHg) Standard Deviation 6.68	102.9 Millimeters of mercury (mmHg) Standard Deviation 6.42
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 SBP, 8 hours PD, n=24, 26	104.7 Millimeters of mercury (mmHg) Standard Deviation 8.92	104.7 Millimeters of mercury (mmHg) Standard Deviation 7.76
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, Baseline, n=26, 28	62.0 Millimeters of mercury (mmHg) Standard Deviation 5.12	62.1 Millimeters of mercury (mmHg) Standard Deviation 6.38
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, 10 minutes PD, n=26, 28	62.4 Millimeters of mercury (mmHg) Standard Deviation 7.16	63.5 Millimeters of mercury (mmHg) Standard Deviation 4.08
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, 30 minutes PD, n=26, 28	62.4 Millimeters of mercury (mmHg) Standard Deviation 6.55	62.6 Millimeters of mercury (mmHg) Standard Deviation 4.29
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, 45 minutes PD, n=26, 28	63.0 Millimeters of mercury (mmHg) Standard Deviation 7.93	63.3 Millimeters of mercury (mmHg) Standard Deviation 5.99
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, 75 minutes PD, n=26, 28	63.3 Millimeters of mercury (mmHg) Standard Deviation 5.74	64.4 Millimeters of mercury (mmHg) Standard Deviation 7.91
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 1 DBP, 2 hours PD, n=26, 28	63.0 Millimeters of mercury (mmHg) Standard Deviation 4.81	63.4 Millimeters of mercury (mmHg) Standard Deviation 5.49
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 DBP, Pre-dose, n=25, 28	63.7 Millimeters of mercury (mmHg) Standard Deviation 8.17	62.8 Millimeters of mercury (mmHg) Standard Deviation 5.58
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 DBP, 30 minutes PD, n=25, 28	62.3 Millimeters of mercury (mmHg) Standard Deviation 9.19	62.4 Millimeters of mercury (mmHg) Standard Deviation 7.26
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 8 DBP, 1 hour PD, n=25, 28	63.2 Millimeters of mercury (mmHg) Standard Deviation 6.68	62.2 Millimeters of mercury (mmHg) Standard Deviation 7.90
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, Pre-dose, n=24, 26	60.8 Millimeters of mercury (mmHg) Standard Deviation 5.70	63.8 Millimeters of mercury (mmHg) Standard Deviation 8.14
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 10 minutes PD, n=24, 26	60.9 Millimeters of mercury (mmHg) Standard Deviation 6.55	62.7 Millimeters of mercury (mmHg) Standard Deviation 7.07
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 45 minutes PD, n=24, 26	61.9 Millimeters of mercury (mmHg) Standard Deviation 4.05	64.5 Millimeters of mercury (mmHg) Standard Deviation 4.68
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 75 minutes PD, n=23, 26	63.0 Millimeters of mercury (mmHg) Standard Deviation 5.12	63.6 Millimeters of mercury (mmHg) Standard Deviation 6.34
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 2 hours PD, n=23, 26	64.1 Millimeters of mercury (mmHg) Standard Deviation 7.33	63.3 Millimeters of mercury (mmHg) Standard Deviation 5.50
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 4 hours PD, n=23, 26	62.3 Millimeters of mercury (mmHg) Standard Deviation 8.56	63.9 Millimeters of mercury (mmHg) Standard Deviation 6.59
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period Day 14 DBP, 8 hours PD, n=23, 26	63.2 Millimeters of mercury (mmHg) Standard Deviation 4.78	63.3 Millimeters of mercury (mmHg) Standard Deviation 7.29

Measure	Placebo n=26 participants at risk All participants who received matching placebo in one or both of the two 14-day 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.	VI 25 µg n=27 participants at risk All participants who received VI 25 µg in one or both of the 14-day 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.
Infections and infestations Upper respiratory tract infection	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	11.1% 3/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Infections and infestations Otitis media	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Infections and infestations Sinusitis	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Infections and infestations Urinary tract infection	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Nervous system disorders Headache	7.7% 2/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.4% 2/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
General disorders Pyrexia	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.4% 2/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
General disorders Chest pain	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Injury, poisoning and procedural complications Limb injury	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Injury, poisoning and procedural complications Spinal column injury	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Cardiac disorders Sinus bradycardia	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Eye disorders Conjunctivitis	0.00% 0/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	3.7% 1/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Dyspepsia	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Psychiatric disorders Conversion disorder	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Psychiatric disorders Disorientation	3.8% 1/26 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/27 Serious adverse events (SAEs) and non-serious AEs were collected in members of the All Subjects Population, comprised of all participants who received at least one dose of study medication.