Asthma
Conditions
Keywords
Asthma, Tolerability, Safety, Pharmacokinetics, GW642444
Brief summary
This study will investigate the effect of dosing paedeatric asthmatic subjects with GW642444, an orally inhaled long-acting agonist of the β2-adrenoceptor.
Detailed description
This study will investigate the effect of dosing with 25 μg GW642444, an orally inhaled long-acting agonist of the β2-adrenoceptor, in asthmatic subjects aged 5 to 11. GW642444 is currently under development as the long-acting beta-agonist component of a combination product containing an inhaled corticosteroid and a longacting beta-agonist. Subjects will receive a single dose via a novel dry powder inhaler, then 7 days once-daily repeat dosing following a washout period. The study will be a randomized two-way crossover, with a placebo control. Approximately 26 subjects will be recruited to this study, with the aim that 20 will complete the study. Safety, tolerability, pharmacokinetics and glucose and potassium levels will be investigated.
Interventions
DRUGGW642444
GW642444 25 μg; Novel dry powder inhaler
DRUGPlacebo
Matching placebo; Novel dry powder inhaler
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Male and pre-menarchial female subjects aged 5-11 years on the last planned treatment day are eligible for this study. Pre-menarchial females are defined as any female who has yet to begin menses and is considered Tanner Stage 2 or less. * Diagnosis of asthma at least 6 months prior to screening. * Patients must be controlled on their existing asthma treatment at Screening as defined by a Childhood Asthma Control Test score of \>19 and PEF (Peak Expiratory Flow) \>75 % predicted. * Subjects must be taking a stable regimen of fluticasone propionate (≤200 μg (micrograms) twice daily or equivalent) and short acting beta-agonist inhaler on an as-need basis for at least 4 weeks prior to screening. * Apart from asthma, eczema and rhinitis, subjects should be healthy and suffer from no other significant medical conditions. * Subjects must weigh at least 15 kg (kilograms). * Subjects must demonstrate ability to accept and effectively use the GW642444 device using the demonstration kits provided to the site. * The subject and parent or guardian are able to understand and comply with protocol requirements, instructions, and protocol-stated restrictions. The parent or guardian must have the ability to read, write and record diary information collected throughout the study. The parent or guardian must also have the ability to manage study drug administration and PEF assessments. * At least one parent or guardian has signed and dated the written informed consent prior to admission to the study. This will be accompanied by informed assent from the subject.
Exclusion criteria
* Subjects currently receiving (or have received within 4 weeks of screening) any of the following asthma therapies: theophyllines, long-acting inhaled beta-agonists, oral beta-agonist. * Subjects who have changed their asthma medication within 4 weeks of screening. * Clinical visual evidence of oral candidiasis at screening. * Any clinically relevant abnormality identified on the screening medical assessment * Any medical condition or circumstance making the subject unsuitable for participation in the study (e.g. history of life-threatening asthma) * Asthma exacerbation requiring systemic corticosteroids (oral, intramuscular, intravenous) or Emergency Room attendance within 3 months or asthma exacerbation requiring hospitalization within 6 months prior to the screening visit. * Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract which is not resolved within 4 weeks of the screening visit. * Any adverse reaction including immediate or delayed hypersensitivity to any betaagonist therapy. * Known or suspected sensitivity to the constituents of the novel dry powder inhaler (i.e., lactose or magnesium stearate), for example, history of severe milk protein allergy. * The parent or guardian has history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (e.g., inability to read, comprehend or write) which will limit the validity of consent to participate in this study. * A subject will not be eligible for this study if he/she is an immediate family member of the participating Investigator, sub-Investigator, study coordinator, or employee of the participating Investigator. * Children who are wards of the state or government. * Evidence of clinically significant abnormality in the 12-lead ECG (electrocardiogram) at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Hematocrit Value at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Mean Corpuscle Volume (MCV) Value at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Mean Corpuscle Hemoglobin (MCH) Value at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| 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 | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Albumin and Total Protein Values at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| 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 | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period | Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period | Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Weighted Mean Heart Rate at Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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). |
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | From the start of study medication until Week 11 (Visit 8)/Early Withdrawal | 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. |
| Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax on Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Tmax, t1/2, and t at Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period | Day 1 and Day 14 of the respective treatment period (up to Study Day 49) | 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. |
| AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period | Day 14 of the respective treatment period (up to Study Day 49) | 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. |
Countries
United States
Participant flow
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.
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| VI 25 µg/Placebo or Placebo/VI 25 µg 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. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 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
| Characteristic | VI 25 µg/Placebo or Placebo/VI 25 µg |
|---|---|
| Age, Continuous | 8.0 Years STANDARD_DEVIATION 1.9 |
| Gender Female | 10 Participants |
| Gender Male | 18 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 5 Participants |
| Race/Ethnicity, Customized Mixed Race | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 26 | 9 / 27 |
| serious Total, serious adverse events | 0 / 26 | 0 / 27 |
Outcome results
Primary
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
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 13.6 International units per liter (IU/L) | Standard Deviation 3.51 |
| VI 25 µg | 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 | 13.5 International units per liter (IU/L) | Standard Deviation 3.56 |
| VI 25 µg | 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 | 25.5 International units per liter (IU/L) | Standard Deviation 4.52 |
| VI 25 µg | 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 | 273.4 International units per liter (IU/L) | Standard Deviation 103.51 |
Primary
Albumin and Total Protein Values at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Albumin and Total Protein Values at Day 14 of the Respective Treatment Period | Albumin, n=22, 25 | 43.2 Grams per liter | Standard Deviation 1.96 |
| VI 25 µg | Albumin and Total Protein Values at Day 14 of the Respective Treatment Period | Total protein, n=22, 25 | 68.6 Grams per liter | Standard Deviation 3.16 |
Primary
Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 0.131 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 6.30 10^9 cells per liter (GI/L) | Standard Deviation 1.64 |
| VI 25 µg | 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 | 0.034 10^9 cells per liter (GI/L) | Standard Deviation 0.0185 |
| VI 25 µg | 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 | 0.348 10^9 cells per liter (GI/L) | Standard Deviation 0.3458 |
| VI 25 µg | 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 | 2.419 10^9 cells per liter (GI/L) | Standard Deviation 0.8729 |
| VI 25 µg | 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 | 0.376 10^9 cells per liter (GI/L) | Standard Deviation 0.1419 |
| VI 25 µg | 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 | 3.127 10^9 cells per liter (GI/L) | Standard Deviation 0.9625 |
| VI 25 µg | 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 | 279.4 10^9 cells per liter (GI/L) | Standard Deviation 54.71 |
Primary
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
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 2.3 |
| Placebo | 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 |
| Placebo | 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 3.9 |
| Placebo | 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 |
| Placebo | 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 0.51 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 4.48 Millimoles per liter (mmol/L) | Standard Deviation 1.15 |
| VI 25 µg | 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 | 2.359 Millimoles per liter (mmol/L) | Standard Deviation 0.0666 |
| VI 25 µg | 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 | 105.1 Millimoles per liter (mmol/L) | Standard Deviation 2.01 |
| VI 25 µg | 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 | 18.1 Millimoles per liter (mmol/L) | Standard Deviation 1.98 |
| VI 25 µg | 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 | 5.04 Millimoles per liter (mmol/L) | Standard Deviation 0.513 |
| VI 25 µg | 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 | 4.33 Millimoles per liter (mmol/L) | Standard Deviation 0.242 |
| VI 25 µg | 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 | 137.8 Millimoles per liter (mmol/L) | Standard Deviation 2.12 |
Primary
Hematocrit Value at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hematocrit Value at Day 14 of the Respective Treatment Period | 0.3948 proportion of 1 | Standard Deviation 0.0343 |
| VI 25 µg | Hematocrit Value at Day 14 of the Respective Treatment Period | 0.3863 proportion of 1 | Standard Deviation 0.02617 |
Primary
Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 11.3 |
| Placebo | 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 5.5 |
| VI 25 µg | Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period | Hemoglobin, n=24, 25 | 130.7 Grams per liter (g/L) | Standard Deviation 11.22 |
| VI 25 µg | Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period | MCHC, n=24, 25 | 338.3 Grams per liter (g/L) | Standard Deviation 11.6 |
Primary
Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period | Day 1 maximum HR (0-2 hr), n=26, 28 | 86.1 Beats per minute | Standard Error 1.4 |
| VI 25 µg | Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period | Day 14 maximum HR (0-2 hr), n=24, 26 | 85.0 Beats per minute | Standard Error 1.35 |
| VI 25 µg | Maximum Heart Rate at Day 1 and Day 14 of the Respective Treatment Period | Day 14 maximum HR (0-8 hr), n=24, 26 | 88.6 Beats per minute | Standard Error 1.41 |
95% CI: [-0.8, 5.7]
95% CI: [-2.4, 3.7]
95% CI: [-2.6, 3.6]
Primary
Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period | Day 1 maximum QTcF (0-2 hr), n=26, 28 | 406.6 milliseconds | Standard Error 2.22 |
| VI 25 µg | Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period | Day 14 maximum QTcF (0-2 hr), n=24, 26 | 407.7 milliseconds | Standard Error 2 |
| VI 25 µg | Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period | Day 14 maximum QTcF (0-8 hr), n=24, 26 | 409.2 milliseconds | Standard Error 1.82 |
95% CI: [-4.5, 6.6]
95% CI: [-3.2, 6.3]
95% CI: [-3, 5.7]
Primary
Mean Corpuscle Hemoglobin (MCH) Value at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| VI 25 µg | Mean Corpuscle Hemoglobin (MCH) Value at Day 14 of the Respective Treatment Period | 29.29 10^12 picograms (pg) per cell | Standard Deviation 1.464 |
Primary
Mean Corpuscle Volume (MCV) Value at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| VI 25 µg | Mean Corpuscle Volume (MCV) Value at Day 14 of the Respective Treatment Period | 86.6 10^15 femtoliters (fL) per cell | Standard Deviation 3.59 |
Primary
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period
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.
Time frame: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | Any AE | 6 Participants |
| Placebo | Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | Any SAE | 0 Participants |
| VI 25 µg | Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | Any AE | 9 Participants |
| VI 25 µg | Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | Any SAE | 0 Participants |
Primary
Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 75.9 |
| Placebo | 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 |
| VI 25 µg | Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period | Day 14, Pre-dose, n=24, 26 | 239.0 liters/minute | Standard Deviation 72.02 |
| VI 25 µg | Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period | Day 1, Baseline, n=26, 28 | 233.0 liters/minute | Standard Deviation 68.55 |
| VI 25 µg | 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 | 240.7 liters/minute | Standard Deviation 65.66 |
| VI 25 µg | 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 | 245.6 liters/minute | Standard Deviation 73.47 |
| VI 25 µg | 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 | 248.1 liters/minute | Standard Deviation 76.2 |
| VI 25 µg | Peak Expiratory Flow on Day 1, Day 8, and Day 14 of the Respective Treatment Period | Day 8, Pre-dose, n=26, 28 | 228.8 liters/minute | Standard Deviation 64.42 |
Primary
Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period | Reticulocytes, n=24, 25 | 0.05275 10^12 cells per liter (TI/L) | Standard Deviation 0.024571 |
| VI 25 µg | Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period | RBCs, n=24, 25 | 4.47 10^12 cells per liter (TI/L) | Standard Deviation 0.339 |
Primary
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 7.8 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 5.7 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 62.2 Millimeters of mercury (mmHg) | Standard Deviation 7.9 |
| VI 25 µg | 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 | 62.1 Millimeters of mercury (mmHg) | Standard Deviation 6.38 |
| VI 25 µg | 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 | 102.9 Millimeters of mercury (mmHg) | Standard Deviation 9.21 |
| VI 25 µg | 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 | 63.3 Millimeters of mercury (mmHg) | Standard Deviation 7.29 |
| VI 25 µg | 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 | 102.4 Millimeters of mercury (mmHg) | Standard Deviation 7.69 |
| VI 25 µg | 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 | 63.5 Millimeters of mercury (mmHg) | Standard Deviation 4.08 |
| VI 25 µg | 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 | 103.5 Millimeters of mercury (mmHg) | Standard Deviation 6.89 |
| VI 25 µg | 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 | 63.8 Millimeters of mercury (mmHg) | Standard Deviation 8.14 |
| VI 25 µg | 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 | 103.5 Millimeters of mercury (mmHg) | Standard Deviation 7.05 |
| VI 25 µg | 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 | 62.6 Millimeters of mercury (mmHg) | Standard Deviation 4.29 |
| VI 25 µg | 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 | 104.4 Millimeters of mercury (mmHg) | Standard Deviation 6.81 |
| VI 25 µg | 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 | 63.6 Millimeters of mercury (mmHg) | Standard Deviation 6.34 |
| VI 25 µg | 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 | 104.8 Millimeters of mercury (mmHg) | Standard Deviation 7.82 |
| VI 25 µg | 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 | 63.3 Millimeters of mercury (mmHg) | Standard Deviation 5.99 |
| VI 25 µg | 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 | 103.7 Millimeters of mercury (mmHg) | Standard Deviation 8.64 |
| VI 25 µg | 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 | 102.9 Millimeters of mercury (mmHg) | Standard Deviation 7.31 |
| VI 25 µg | 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 | 62.7 Millimeters of mercury (mmHg) | Standard Deviation 7.07 |
| VI 25 µg | 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 | 103.6 Millimeters of mercury (mmHg) | Standard Deviation 7.17 |
| VI 25 µg | 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 | 64.4 Millimeters of mercury (mmHg) | Standard Deviation 7.91 |
| VI 25 µg | 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 | 103.9 Millimeters of mercury (mmHg) | Standard Deviation 6.15 |
| VI 25 µg | 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 | 63.9 Millimeters of mercury (mmHg) | Standard Deviation 6.59 |
| VI 25 µg | 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 | 103.7 Millimeters of mercury (mmHg) | Standard Deviation 6.7 |
| VI 25 µg | 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 | 63.4 Millimeters of mercury (mmHg) | Standard Deviation 5.49 |
| VI 25 µg | 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 | 102.9 Millimeters of mercury (mmHg) | Standard Deviation 8.91 |
| VI 25 µg | 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 | 63.7 Millimeters of mercury (mmHg) | Standard Deviation 7.88 |
| VI 25 µg | 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 | 103.4 Millimeters of mercury (mmHg) | Standard Deviation 7.03 |
| VI 25 µg | 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 | 62.8 Millimeters of mercury (mmHg) | Standard Deviation 5.58 |
| VI 25 µg | 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 | 103.9 Millimeters of mercury (mmHg) | Standard Deviation 6.36 |
| VI 25 µg | 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 | 63.3 Millimeters of mercury (mmHg) | Standard Deviation 5.5 |
| VI 25 µg | 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 | 106.0 Millimeters of mercury (mmHg) | Standard Deviation 5.2 |
| VI 25 µg | 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 | 62.4 Millimeters of mercury (mmHg) | Standard Deviation 7.26 |
| VI 25 µg | 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 | 102.9 Millimeters of mercury (mmHg) | Standard Deviation 6.42 |
| VI 25 µg | 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 | 64.5 Millimeters of mercury (mmHg) | Standard Deviation 4.68 |
| VI 25 µg | 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 7.76 |
Primary
Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Uric acid, n=22, 25 | 245.6 Micromoles per liter (µmol/L) | Standard Deviation 47.27 |
| VI 25 µg | Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Total bilirubin, n=22, 25 | 5.8 Micromoles per liter (µmol/L) | Standard Deviation 1.99 |
| VI 25 µg | Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Creatinine, n=22, 25 | 39.35 Micromoles per liter (µmol/L) | Standard Deviation 6.731 |
| VI 25 µg | Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Direct bilirubin, n=22, 25 | 1.2 Micromoles per liter (µmol/L) | Standard Deviation 1 |
Primary
Weighted Mean Heart Rate at Day 1 and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 79.20 Beats per minute | Standard Error 1.285 |
| VI 25 µg | 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 | 77.67 Beats per minute | Standard Error 1.264 |
| VI 25 µg | 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 | 80.65 Beats per minute | Standard Error 1.404 |
95% CI: [-0.8, 5.7]
95% CI: [-2.4, 3.7]
95% CI: [-2.6, 3.6]
Primary
Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period
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).
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 396.22 milliseconds | Standard Error 1.96 |
| VI 25 µg | 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 | 398.03 milliseconds | Standard Error 2.024 |
| VI 25 µg | 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 | 396.62 milliseconds | Standard Error 1.793 |
95% CI: [-2.59, 6.61]
95% CI: [-1.93, 7.81]
95% CI: [-0.7, 7.08]
Secondary
AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period
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.
Time frame: 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).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| VI 25 µg | AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period | AUC(0-t), n=25 | 132.8 picograms*hour per milliliter (pg*hr/mL) |
| VI 25 µg | AUC(0-t) and AUC(0-8) on Day 14 of the Respective Treatment Period | AUC(0-8), n=19 | 181.7 picograms*hour per milliliter (pg*hr/mL) |
Secondary
Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 9.44 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | 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 | 61.79 Liters per minute (L/min) | Standard Deviation 15.348 |
| VI 25 µg | 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 | 42.23 Liters per minute (L/min) | Standard Deviation 10.952 |
| VI 25 µg | 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 | 61.41 Liters per minute (L/min) | Standard Deviation 16.513 |
| VI 25 µg | 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 | 42.08 Liters per minute (L/min) | Standard Deviation 10.191 |
Secondary
Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=15, 13 | 4.42 centimeters squared (cm^2) | Standard Deviation 2.31 |
| VI 25 µg | Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=14, 15 | 5.16 centimeters squared (cm^2) | Standard Deviation 2.139 |
Secondary
Blood Glucose and Potassium on Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 0.04 |
| Placebo | 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 0.06 |
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Weighted Mean Potassium (0-8 hr), n=17, 22 | 4.11 Millimoles per liter (mmol/L) | Standard Error 0.049 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Maximum Glucose (0-2 hr), n=24, 26 | 5.57 Millimoles per liter (mmol/L) | Standard Error 0.182 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Minimum Potassium (0-2 hr), n=23, 26 | 4.00 Millimoles per liter (mmol/L) | Standard Error 0.038 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Maximum Glucose (0-8 hr), n=24, 26 | 6.03 Millimoles per liter (mmol/L) | Standard Error 0.183 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Weighted Mean Potassium (0-2 hr), n=19, 22 | 4.23 Millimoles per liter (mmol/L) | Standard Error 0.046 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Weighted Mean Glucose (0-2 hr), n=21, 25 | 5.06 Millimoles per liter (mmol/L) | Standard Error 0.109 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Minimum Potassium (0-8 hr), n=24, 26 | 3.87 Millimoles per liter (mmol/L) | Standard Error 0.059 |
| VI 25 µg | Blood Glucose and Potassium on Day 14 of the Respective Treatment Period | Weighted Mean Glucose (0-8 hr), n=19, 24 | 5.21 Millimoles per liter (mmol/L) | Standard Error 0.1 |
Secondary
Cmax on Day 14 of the Respective Treatment Period
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.
Time frame: Day 14 of the respective treatment period (up to Study Day 49)
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| VI 25 µg | Cmax on Day 14 of the Respective Treatment Period | 97.44 picograms per milliliter (pg/mL) |
Secondary
Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=15, 13 | 18.26 centimeters (cm) | Standard Deviation 1.824 |
| VI 25 µg | Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=14, 15 | 18.41 centimeters (cm) | Standard Deviation 1.276 |
Secondary
Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VI 25 µg | 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 |
| VI 25 µg | 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 |
| VI 25 µg | 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 |
| VI 25 µg | 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 |
| VI 25 µg | 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 |
| VI 25 µg | 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 |
Secondary
Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=23, 25 | 1.36 Seconds (sec) | Standard Deviation 0.551 |
| VI 25 µg | Inhalation Time on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=23, 25 | 1.34 Seconds (sec) | Standard Deviation 0.476 |
Secondary
Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=23, 25 | 0.92 Liters | Standard Deviation 0.343 |
| VI 25 µg | Inhaled Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=23, 25 | 0.95 Liters | Standard Deviation 0.417 |
Secondary
Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=15, 13 | 78.60 cm^3 | Standard Deviation 39.296 |
| VI 25 µg | Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=14, 15 | 93.35 cm^3 | Standard Deviation 37.19 |
Secondary
Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| VI 25 µg | Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period | Day 1, n=23, 25 | 3.33 Kilopascal (kpa) | Standard Deviation 1.632 |
| VI 25 µg | Peak Pressure Drop on Day 1 and Day 14 of the Respective Treatment Period | Day 14, n=23, 25 | 3.33 Kilopascal (kpa) | Standard Deviation 1.35 |
Secondary
Tmax, t1/2, and t at Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VI 25 µg | Tmax, t1/2, and t at Day 14 of the Respective Treatment Period | t, n=23 | 6.00 hours |
| VI 25 µg | Tmax, t1/2, and t at Day 14 of the Respective Treatment Period | tmax, n=23 | 0.20 hours |
| VI 25 µg | Tmax, t1/2, and t at Day 14 of the Respective Treatment Period | t1/2, n=14 | 3.131 hours |
Secondary
Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VI 25 µg | Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period | Minimum TED | 20.24 micrograms | Standard Deviation 0.188 |
| VI 25 µg | Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period | Nominal TED | 20.28 micrograms | Standard Deviation 0.177 |
| VI 25 µg | Total Emitted Dose (TED) on Day 1 and Day 14 of the Respective Treatment Period | Maximum TED | 20.31 micrograms | Standard Deviation 0.173 |