Asthma
Conditions
Keywords
asthma, asthma attack, difficulty breathing, bronchial diseases, lung, lung diseases, inhaled drugs, bronchodilator, inhaled corticosteriod
Brief summary
This study is a randomized, double-blind, placebo-controlled, three-period cross-over study in approximately 54 subjects with asthma.
Detailed description
This is a randomized, double-blind, placebo-controlled, three-period cross-over study in asthma patients. The study will consist of a screening epoch, followed by a treatment epoch which consists of three treatment periods, and will conclude with an end of study epoch. Each subject will be assigned to 1 of 6 treatment sequences and will sequentially receive the investigational products and placebo during the trial.
Interventions
150 μg via Concept1 device
DRUGIndacaterol acetate
150 μg via Concept1 device
DRUGPlacebo
Capsule containing no active ingredients delivered via Concept1 device
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male and female patients aged ≥ 18 and above * Patients with a documented physician diagnosis of asthma for a period of at least 1 year prior to screening and who additionally meet the following criteria: Patients receiving daily treatment with an inhaled corticosteroid up to the maximum dose per day (as indicated in the package leaflet), on a stable regimen for at least 4 weeks prior to screening. * Pre-bronchodilator FEV1 ≥ 50 % and ≤ 90% of the predicted normal value for the patient during screening. * Patients who demonstrate an increase in FEV1 of ≥ 12% and ≥ 200 mL after administration of 400 μg salbutamol/360 μg albuterol (or equivalent dose) at screening. * Subjects must weigh at least 50 kg at screening to participate in the study, and must have a body mass index (BMI) within the range of 18 to 40 kg/m2. Key
Exclusion criteria
-Contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class, or any component thereof: Sympathomimetic amines / adrenoceptor agonist agents Lactose or any of the other excipients of the study drug (including patients with history of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption) * Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of screening. * Patients who have had a respiratory tract infection or asthma worsening within 4 weeks prior to screening. * Patients with a history of chronic lung diseases other than asthma * Patients who have a decline in PEF from the reference PEF (taken at screening) of ≥30% for 5 of 6 consecutive scheduled PEF readings (readings taken at morning and evening) during at least 3 days of screening epoch prior to randomization. * Patients who require the use of ≥12 puffs / 24 hours of rescue medication for 48 hours (over two consecutive days) during screening prior to randomization. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. * Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c \> 9%) at screening. * Current smokers (urine cotinine \> than the laboratory's lowest level of quantification (LoQ of 500 ng/mL or lower)) and patients who have smoked or inhaled tobacco products within the 6 month period prior to screening, or who have a smoking history of greater than 10 pack years (Note: 1 pack is equivalent to 20 cigarettes. 10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 | Day 14 of each of the three treatment periods | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of forced exhalation. Treatment differences in trough FEV1 after 14 days of treatment between indacaterol maleate 150 μg and placebo, between indacaterol acetate 150 μg and placebo and indacaterol maleate and indacaterol acetate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Concentration (Cmax) at Steady State (ss) | Day 14 of each of the three treatment periods | Maximal plasma concentrations of indacaterol maleate and indacaterol acetate at steady state. The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings. |
| Time of Maximal Plasma Concentration (Tmax) at Steady State | Day 14 of each of the three treatment periods | Time of maximal plasma concentration of indacaterol maleate and indacaterol acetate at steady state. Time to reach the maximum concentration after administration. In this analysis Tmax will be reported using blood samples taken on Days 14 |
| The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State | Day 14 of each of the three treatment periods | The lowest plasma (or serum or blood) concentration observed during a dosing interval at steady state. Only summary statistics was provided. |
| Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate | Day 14 | Relative bioavailability will be determined for AUC0-24h,ss and Cmax,ss comparing systemic exposure of indacaterol acetate and indacaterol maleate. |
| Time to Peak FEV1 on Day 14 | Day 14 of each of the three treatment periods | The differences in median time to peak FEV1 (h) between indacaterol maleate 150 µg and placebo |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1. Day 14, FEV1 was measured at 24hours post dose |
| Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | The FEV1 percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 % predicted indicates improvement in lung function. FEV1 % predicted was assessed at each post dose time point after 14 days |
| Pharmacokinetics AUC 0-24hours at Steady State | Day 14 of each of the three treatment periods | AUC 0-24hours of plasma concentrations of indacaterol maleate and indacaterol acetate at steady state.The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function. |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1/FVC at each post dose time point after 14 days. FEV1/FVC ratio is the percentage of the total FVC that is expelled from the lungs during the first second of forced exhalation. |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | The Forced Expiratory Flow (FEF) 25%-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test and is measured using spirometry at each post dose time point after 14 days |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. | Pre-dose to 4 hours post-dose on Day 14 of each of the three treatment periods | Standardized FEV1 AUC from pre-dose to 4 h post-dose. Evaluated the differences in standardized FEV1 AUC0-4h (L) after 14 days of treatment between indacaterol maleate 150 μg and placebo, and between indacaterol acetate 150 μg and placebo. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-4h) |
| Rescue Medication Usage | 14 days of treatment for each of the three treatment periods | The mean daily number of puffs of rescue medication usage as reported by subjects via diary. |
| Mean Overall Peak Expiratory Flow (PEF) | Days 8 through Day 14 of each of the three treatment periods | A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits LS Mean of change from baseline in mean morning PEF is calculated with the ANOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates |
| Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | Day 14 of each of the three treatment periods at at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min | Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants randomized to one of six treatment sequences | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol deviation | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 12.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 47 Participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 52 | 0 / 53 |
| other Total, other adverse events | 14 / 51 | 7 / 52 | 9 / 53 |
| serious Total, serious adverse events | 0 / 51 | 1 / 52 | 0 / 53 |
Outcome results
Primary
Trough FEV1
FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of forced exhalation. Treatment differences in trough FEV1 after 14 days of treatment between indacaterol maleate 150 μg and placebo, between indacaterol acetate 150 μg and placebo and indacaterol maleate and indacaterol acetate
Time frame: Day 14 of each of the three treatment periods
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Trough FEV1 | 2.4173 Liters | Standard Deviation 0.78214 |
| Indacaterol Acetate | Trough FEV1 | 2.3774 Liters | Standard Deviation 0.77679 |
| Placebo | Trough FEV1 | 2.2191 Liters | Standard Deviation 0.7235 |
p-value: <0.00195% CI: [0.1293, 0.2429]ANOVA
p-value: <0.00195% CI: [0.0898, 0.2029]ANOVA
95% CI: [-0.0942, 0.0147]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC.
Standardized FEV1 AUC from pre-dose to 4 h post-dose. Evaluated the differences in standardized FEV1 AUC0-4h (L) after 14 days of treatment between indacaterol maleate 150 μg and placebo, and between indacaterol acetate 150 μg and placebo. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-4h)
Time frame: Pre-dose to 4 hours post-dose on Day 14 of each of the three treatment periods
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. | 2.5179 Liters | Standard Error 0.11213 |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. | 2.5151 Liters | Standard Error 0.11205 |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. | 2.2703 Liters | Standard Error 0.11213 |
p-value: <0.00195% CI: [0.1857, 0.3095]ANOVA
p-value: <0.00195% CI: [0.183, 0.3066]ANOVA
95% CI: [-0.0647, 0.059]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75%
The Forced Expiratory Flow (FEF) 25%-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test and is measured using spirometry at each post dose time point after 14 days
Time frame: Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 5 min | 1.6968 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 15 min | 1.7454 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 30 min | 1.7347 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 1 hour | 1.7715 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 2 hour | 1.7907 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 4 hour | 1.7663 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 8 hour | 1.6755 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 12 hour | 1.6549 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 15 min | 1.6667 Liters/second |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 45 min | 1.6446 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 1 hour | 1.7349 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 12 hour | 1.5849 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 2 hour | 1.8074 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 15 min | 1.6257 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 4 hour | 1.7503 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 45 min | 1.6580 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 5 min | 1.6918 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 8 hour | 1.6774 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 15 min | 1.7458 Liters/second |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 30 min | 1.7413 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 15 min | 1.4531 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 1 hour | 1.4963 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 8 hour | 1.4217 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 5 min | 1.4962 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 2 hour | 1.5088 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 12 hour | 1.3862 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 45 min | 1.4584 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 23 hour 15 min | 1.4214 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 30 min | 1.4690 Liters/second |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% | 4 hour | 1.4843 Liters/second |
Comparison: 5 minp-value: <0.00195% CI: [0.1059, 0.2952]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.1979, 0.3867]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.1713, 0.3601]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.1808, 0.3696]ANOVA
Comparison: 2 hoursp-value: <0.00195% CI: [0.1875, 0.3763]ANOVA
Comparison: 4 hoursp-value: <0.00195% CI: [0.1874, 0.3766]ANOVA
Comparison: 8 hoursp-value: <0.00195% CI: [0.1585, 0.3492]ANOVA
Comparison: 12 hoursp-value: <0.00195% CI: [0.1732, 0.3643]ANOVA
Comparison: 23 hours 15 minp-value: <0.00195% CI: [0.1473, 0.3434]ANOVA
Comparison: 23 hours 45 minp-value: <0.00195% CI: [0.0882, 0.2842]ANOVA
Comparison: 5 minp-value: <0.00195% CI: [0.1012, 0.2899]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.1979, 0.3875]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.178, 0.3667]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.1445, 0.3328]ANOVA
Comparison: 2 hoursp-value: <0.00195% CI: [0.2042, 0.393]ANOVA
Comparison: 4 hoursp-value: <0.00195% CI: [0.1715, 0.3607]ANOVA
Comparison: 8 hoursp-value: <0.00195% CI: [0.1609, 0.3506]ANOVA
Comparison: 12 hoursp-value: <0.00195% CI: [0.1036, 0.2938]ANOVA
Comparison: 23 hours 15 minp-value: <0.00195% CI: [0.1071, 0.3017]ANOVA
Comparison: 23 hours 45 minp-value: <0.00195% CI: [0.1023, 0.297]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC
Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1/FVC at each post dose time point after 14 days. FEV1/FVC ratio is the percentage of the total FVC that is expelled from the lungs during the first second of forced exhalation.
Time frame: Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 5 min | 0.6979 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 15 min | 0.7002 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 30 min | 0.7012 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 1 hour | 0.7053 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 15 min | 0.6898 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 45 min | 0.6934 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 2 hour | 0.7085 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 4 hour | 0.7057 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 8 hour | 0.6962 Ratio |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 12 hour | 0.6958 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 1 hour | 0.7007 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 12 hour | 0.6885 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 4 hour | 0.7010 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 15 min | 0.6853 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 45 min | 0.6899 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 5 min | 0.6952 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 2 hour | 0.7085 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 15 min | 0.7017 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 30 min | 0.6996 Ratio |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 8 hour | 0.6967 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 8 hour | 0.6651 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 15 min | 0.6672 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 12 hour | 0.6599 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 5 min | 0.6729 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 2 hour | 0.6747 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 15 min | 0.6572 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 4 hour | 0.6732 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 30 min | 0.6706 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 23 hour 45 min | 0.6633 Ratio |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC | 1 hour | 0.6729 Ratio |
Comparison: 5 minp-value: <0.00195% CI: [0.0139, 0.0359]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.022, 0.044]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.0197, 0.0416]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.0214, 0.0434]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [0.0228, 0.0447]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [0.0215, 0.0435]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [0.02, 0.0422]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [0.0248, 0.047]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [0.0211, 0.044]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [0.0187, 0.0415]ANOVA
Comparison: 5 minp-value: <0.00195% CI: [0.0113, 0.0332]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.0234, 0.0454]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.018, 0.0399]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.0169, 0.0387]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [0.0228, 0.0447]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [0.0168, 0.0387]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [0.0206, 0.0426]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [0.0175, 0.0396]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [0.0167, 0.0394]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [0.0152, 0.0379]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints
Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1. Day 14, FEV1 was measured at 24hours post dose
Time frame: Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 12 hour | 2.4222 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 1 hour | 2.5279 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 45 min | 2.4585 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 8 hour | 2.4668 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 2 hour | 2.5286 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 15 min | 2.5005 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 5 min | 2.4795 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 15 min | 2.4678 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 30 min | 2.5204 Liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 4 hour | 2.5054 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 45 min | 2.4424 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 5 min | 2.4813 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 15 min | 2.4965 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 30 min | 2.5047 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 1 hour | 2.5018 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 2 hour | 2.5338 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 4 hour | 2.5103 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 8 hour | 2.4596 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 12 hour | 2.3836 Liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 15 min | 2.4022 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 15 min | 2.2398 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 8 hour | 2.2272 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 30 min | 2.2475 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 5 min | 2.2617 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 12 hour | 2.1779 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 15 min | 2.2282 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 2 hour | 2.2792 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 23 hour 45 min | 2.2631 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 4 hour | 2.2781 Liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints | 1 hour | 2.2670 Liter |
Comparison: at 5 minp-value: <0.00195% CI: [0.1482, 0.2872]ANOVA
Comparison: 15minp-value: <0.00195% CI: [0.203, 0.3417]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.2036, 0.3423]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.1915, 0.3302]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [0.18, 0.3188]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [0.1578, 0.2968]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [0.1697, 0.3096]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [0.1742, 0.3144]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [0.1563, 0.2997]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [0.1237, 0.2671]ANOVA
Comparison: 5 minp-value: <0.00195% CI: [0.1502, 0.2889]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.1988, 0.338]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.1879, 0.3266]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.1656, 0.304]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [0.1852, 0.3239]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [0.1627, 0.3017]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [0.1627, 0.302]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [0.1359, 0.2755]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [0.0912, 0.2337]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [0.108, 0.2505]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC)
Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function.
Time frame: Day 14 of each of the three treatment periods at at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 5 min | 3.5648 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 15 min | 3.5850 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 30 min | 3.6068 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 1 hour | 3.5946 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 8 hour | 3.5670 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 12 hour | 3.4941 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 15 min | 3.6055 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 2 hour | 3.5789 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 4 hour | 3.5674 liter |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 45 min | 3.5668 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 8 hour | 3.5617 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 5 min | 3.5912 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 12 hour | 3.4812 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 1 hour | 3.5886 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 15 min | 3.5773 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 2 hour | 3.5992 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 45 min | 3.5731 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 30 min | 3.6039 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 15 min | 3.5448 liter |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 4 hour | 3.5999 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 15 min | 3.4199 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 4 hour | 3.4053 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 8 hour | 3.3680 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 2 hour | 3.3987 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 12 hour | 3.3193 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 23 hour 45 min | 3.4185 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 5 min | 3.3783 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 15 min | 3.3600 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 1 hour | 3.3873 liter |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) | 30 min | 3.3664 liter |
Comparison: 5 minp-value: <0.00195% CI: [0.1121, 0.2611]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.1506, 0.2992]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.1661, 0.3148]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.133, 0.2817]ANOVA
Comparison: 2 hoursp-value: <0.00195% CI: [0.1059, 0.2545]ANOVA
Comparison: 4 hoursp-value: <0.00195% CI: [0.0876, 0.2366]ANOVA
Comparison: 8 hoursp-value: <0.00195% CI: [0.1239, 0.2742]ANOVA
Comparison: 12 hoursp-value: <0.00195% CI: [0.0994, 0.2501]ANOVA
Comparison: 23 hours 15 minp-value: <0.00195% CI: [0.1081, 0.2631]ANOVA
Comparison: 23 hours 45 minp-value: <0.00195% CI: [0.0709, 0.2259]ANOVA
Comparison: 5 minp-value: <0.00195% CI: [0.1386, 0.2873]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [0.1426, 0.292]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [0.1632, 0.3118]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [0.1272, 0.2754]ANOVA
Comparison: 2 hoursp-value: <0.00195% CI: [0.1262, 0.2749]ANOVA
Comparison: 4 hoursp-value: <0.00195% CI: [0.1201, 0.2691]ANOVA
Comparison: 8 hoursp-value: <0.00195% CI: [0.119, 0.2684]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [0.087, 0.2369]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [0.048, 0.2018]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [0.0777, 0.2315]ANOVA
Secondary
Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted)
Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function.
Time frame: Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 1 hour | 91.1 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 2 hours | 90.7 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 8 hours | 90.4 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 4 hours | 90.5 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 12 hours | 88.5 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 5 min | 90.4 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 45 min | 90.6 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 15 min | 90.8 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 30 min | 91.6 Percentage of predicted FVC |
| Indacaterol Maleate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 15 min | 91.5 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 1 hour | 91.1 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 15 min | 89.9 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 45 min | 90.6 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 2 hours | 91.4 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 4 hours | 91.3 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 8 hours | 90.3 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 30 min | 91.4 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 15 min | 90.7 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 12 hours | 88.2 Percentage of predicted FVC |
| Indacaterol Acetate | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 5 min | 91.2 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 12 hours | 84 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 5 min | 85.3 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 2 hours | 85.9 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 4 hours | 86.2 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 15 min | 86.9 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 23 hours 45 min | 86.5 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 15 min | 84.9 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 30 min | 85.1 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 1 hour | 85.6 Percentage of predicted FVC |
| Placebo | Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) | 8 hours | 85.4 Percentage of predicted FVC |
Comparison: 5 minp-value: <0.00195% CI: [3.1, 7]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [4, 7.9]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [4.6, 8.5]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [3.5, 7.4]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [2.8, 6.7]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [2.3, 6.3]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [3, 7]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [2.5, 6.5]ANOVA
Comparison: 23 hour 15 minp-value: <0.00195% CI: [2.6, 6.7]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [2, 6.2]ANOVA
Comparison: 5 minp-value: <0.00195% CI: [3.9, 7.8]ANOVA
Comparison: 15 minp-value: <0.00195% CI: [3.9, 7.8]ANOVA
Comparison: 30 minp-value: <0.00195% CI: [4.4, 8.3]ANOVA
Comparison: 1 hourp-value: <0.00195% CI: [3.5, 7.5]ANOVA
Comparison: 2 hourp-value: <0.00195% CI: [3.5, 7.4]ANOVA
Comparison: 4 hourp-value: <0.00195% CI: [3.1, 7]ANOVA
Comparison: 8 hourp-value: <0.00195% CI: [3, 7]ANOVA
Comparison: 12 hourp-value: <0.00195% CI: [2.2, 6.2]ANOVA
Comparison: 23 hour 15 minp-value: 0.00495% CI: [1, 5]ANOVA
Comparison: 23 hour 45 minp-value: <0.00195% CI: [2.1, 6.1]ANOVA
Secondary
Mean Overall Peak Expiratory Flow (PEF)
A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits LS Mean of change from baseline in mean morning PEF is calculated with the ANOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates
Time frame: Days 8 through Day 14 of each of the three treatment periods
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Mean Overall Peak Expiratory Flow (PEF) | 409.7 Liters/min | Standard Error 15.06 |
| Indacaterol Acetate | Mean Overall Peak Expiratory Flow (PEF) | 407.6 Liters/min | Standard Error 15.05 |
| Placebo | Mean Overall Peak Expiratory Flow (PEF) | 376.8 Liters/min | Standard Error 15.06 |
p-value: <0.00195% CI: [25.6, 40.3]ANOVA
p-value: <0.00195% CI: [23.5, 38.2]ANOVA
Secondary
Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints
The FEV1 percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 % predicted indicates improvement in lung function. FEV1 % predicted was assessed at each post dose time point after 14 days
Time frame: Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 4 hours | 78.8 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 30 min | 79.4 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 12 hours | 76.2 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 2 hours | 79.6 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 1 hour | 79.5 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 5 min | 78.2 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 45 min | 77.8 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 8 hours | 77.5 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 15 min | 78.7 Percent of predicted |
| Indacaterol Maleate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 15 min | 77.9 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 1 hour | 78.8 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 45 min | 77.2 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 5 min | 78.2 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 15 min | 78.5 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 30 min | 78.9 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 15 min | 76.1 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 2 hours | 79.8 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 4 hours | 79.1 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 8 hours | 77.5 Percent of predicted |
| Indacaterol Acetate | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 12 hours | 75.0 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 15 min | 70.2 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 15 min | 71.0 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 4 hours | 71.8 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 5 min | 71.1 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 12 hours | 68.6 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 8 hours | 70.2 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 1 hour | 71.4 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 30 min | 70.7 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 23 hours 45 min | 71.4 Percent of predicted |
| Placebo | Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints | 2 hours | 72.0 Percent of predicted |
Comparison: at 5 minp-value: <0.00195% CI: [5, 9.2]ANOVA
Comparison: at 15 minp-value: <0.00195% CI: [6.4, 10.6]ANOVA
Comparison: at 30p-value: <0.00195% CI: [6.5, 10.7]ANOVA
Comparison: at 1 hourp-value: <0.00195% CI: [6, 10.1]ANOVA
Comparison: at 2 hoursp-value: <0.00195% CI: [5.5, 9.7]ANOVA
Comparison: at 4 hoursp-value: <0.00195% CI: [5, 9.1]ANOVA
Comparison: at 8 hoursp-value: <0.00195% CI: [5.2, 9.4]ANOVA
Comparison: at 12 hoursp-value: <0.00195% CI: [5.5, 9.7]ANOVA
Comparison: at 23 hours 15 minp-value: <0.00195% CI: [4.8, 9.1]ANOVA
Comparison: at 23 hours 45 minp-value: <0.00195% CI: [4.2, 8.6]ANOVA
Comparison: at 5 minp-value: <0.00195% CI: [5, 9.2]ANOVA
Comparison: at 15 minp-value: <0.00195% CI: [6.2, 10.4]ANOVA
Comparison: at 30 minp-value: <0.00195% CI: [6, 10.2]ANOVA
Comparison: at 1 hourp-value: <0.00195% CI: [5.3, 9.4]ANOVA
Comparison: at 2 hoursp-value: <0.00195% CI: [5.7, 9.9]ANOVA
Comparison: at 4 hoursp-value: <0.00195% CI: [5.2, 9.4]ANOVA
Comparison: at 8 hoursp-value: <0.00195% CI: [5.3, 9.5]ANOVA
Comparison: at 12 hoursp-value: <0.00195% CI: [4.2, 8.4]ANOVA
Comparison: at 23 hours 15 minp-value: <0.00195% CI: [2.9, 7.2]ANOVA
Comparison: at 23 hours 45 minp-value: <0.00195% CI: [3.7, 8]ANOVA
Secondary
Pharmacokinetics AUC 0-24hours at Steady State
AUC 0-24hours of plasma concentrations of indacaterol maleate and indacaterol acetate at steady state.The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings
Time frame: Day 14 of each of the three treatment periods
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no major protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Pharmacokinetics AUC 0-24hours at Steady State | 2300 h*pg/mL | Standard Deviation 732 |
| Indacaterol Acetate | Pharmacokinetics AUC 0-24hours at Steady State | 2050 h*pg/mL | Standard Deviation 636 |
Secondary
Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate
Relative bioavailability will be determined for AUC0-24h,ss and Cmax,ss comparing systemic exposure of indacaterol acetate and indacaterol maleate.
Time frame: Day 14
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no major protocol deviations with relevant impact on PK data. Only summary statistics for relative bioavailability was provided.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate | 0.912 Ratio | Standard Deviation 0.201 |
| Indacaterol Acetate | Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate | 0.910 Ratio | Standard Deviation 0.242 |
Secondary
Rescue Medication Usage
The mean daily number of puffs of rescue medication usage as reported by subjects via diary.
Time frame: 14 days of treatment for each of the three treatment periods
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate | Rescue Medication Usage | 1.01 Puffs | Standard Error 0.228 |
| Indacaterol Acetate | Rescue Medication Usage | 1.01 Puffs | Standard Error 0.227 |
| Placebo | Rescue Medication Usage | 1.43 Puffs | Standard Error 0.228 |
p-value: 0.00995% CI: [-0.73, 0.11]ANOVA
p-value: 0.00895% CI: [-0.73, 0.11]ANOVA
Secondary
The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State
The lowest plasma (or serum or blood) concentration observed during a dosing interval at steady state. Only summary statistics was provided.
Time frame: Day 14 of each of the three treatment periods
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no major protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indacaterol Maleate | The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State | 56 pg/mL |
| Indacaterol Acetate | The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State | 52.3 pg/mL |
Secondary
The Maximum Concentration (Cmax) at Steady State (ss)
Maximal plasma concentrations of indacaterol maleate and indacaterol acetate at steady state. The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings.
Time frame: Day 14 of each of the three treatment periods
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no major protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indacaterol Maleate | The Maximum Concentration (Cmax) at Steady State (ss) | 249 pg/mL |
| Indacaterol Acetate | The Maximum Concentration (Cmax) at Steady State (ss) | 224 pg/mL |
Secondary
Time of Maximal Plasma Concentration (Tmax) at Steady State
Time of maximal plasma concentration of indacaterol maleate and indacaterol acetate at steady state. Time to reach the maximum concentration after administration. In this analysis Tmax will be reported using blood samples taken on Days 14
Time frame: Day 14 of each of the three treatment periods
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no major protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indacaterol Maleate | Time of Maximal Plasma Concentration (Tmax) at Steady State | 0.250 h |
| Indacaterol Acetate | Time of Maximal Plasma Concentration (Tmax) at Steady State | 0.467 h |
Secondary
Time to Peak FEV1 on Day 14
The differences in median time to peak FEV1 (h) between indacaterol maleate 150 µg and placebo
Time frame: Day 14 of each of the three treatment periods
Population: The PD analysis set included all patients with available PD parameter data who received any study drug and experienced no major protocol deviations with relevant impact on PD data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indacaterol Maleate | Time to Peak FEV1 on Day 14 | -0.02 h |
| Indacaterol Acetate | Time to Peak FEV1 on Day 14 | -0.02 h |
| Placebo | Time to Peak FEV1 on Day 14 | 0.00 h |
p-value: 0.82395% CI: [-0.83, 0.33]Wilcoxon (Mann-Whitney)
p-value: 0.80195% CI: [-0.82, 0.51]Wilcoxon (Mann-Whitney)
p-value: 0.98495% CI: [-0.5, 0.73]Wilcoxon (Mann-Whitney)