Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The purpose of this study is to evaluate the effects on lung function of a combination of ADOAIR 50/250mcg twice daily plus tiotropium bromide 18mcg once daily compared with the individual treatments (tiotropium bromide 18mcg once daily alone and ADOAIR 50/250mcg twice daily alone) in Japanese subjects with COPD. The study will utilize a three-way cross-over design with a 2-week wash-out period between each 4-week consecutive treatment period. The aim is to support the rationale for triple combination therapy by demonstrating that treatment with both ADOAIR and tiotropium can potentially produce improved, clinically relevant effects compared with either treatment alone. This study will utilize a range of lung function measures in order to fully assess the benefits of triple therapy. The primary endpoint will be based on airways conductance measured using plethysmography (sGaw measured over 4hours post dose (AUC 0-4hr) on Day 28). Secondary endpoints will include lung function measures based on plethysmography and spirometry. The lung function measures will be supported by measurement of the use of relief salbutamol .
Interventions
250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design)
DRUGtiotropium bromide
18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
DRUGfluticasone propionate/salmeterol plus tiotropium bromide
250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged 40 - 80 years inclusive * Has an established clinical history of COPD (defined as per the GOLD definition) * A signed and dated written informed consent is obtained from the subject prior to study participation * The subject has a post-bronchodilator FEV1 of \>=30% to =\<75% of predicted normal at Visit 1 * The subject has a post-bronchodilator FEV1/ FVC ratio \<70% at Visit 1 * The subject achieves a score of 1 on the Modified Medical Research Council (mMRC) Dyspnoea Scale at Visit 1 * The subject is a current or ex-smoker with a smoking history of \> 10 pack-years (10 pack years is defined as 20 cigarettes per day for 10 years, or 10 cigarettes (or equivalent if subject smoked cigars or a pipe) per day for 20 years). Ex-smokers are required to have stopped smoking for at least 6 months prior to visit 1. Ex-smokers who stopped smoking less than 6 months ago will be defined as current smokers. * QTc \<450 msec at Visit 1; or for patients with Bundle Branch Block QTc should be \<480 msec. (QTc(F) \<450msec, or \<480 in subjects with right bundle branch block, should be confirmed by the mean of three readings or one reading) * ALT \< 2xULN and bilirubin/ALP \< 1.5xULN (\>35% direct bilirubin) * A female is eligible to enter this study if she is: i)of non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal), ii)of child-bearing potential, but has a negative urinary pregnancy test at screening and agrees to take contraceptive precautions (including abstinence) which are adequate to prevent pregnancy during the study or iii)not a nursing mother
Exclusion criteria
* Has had a COPD exacerbation within the 4 weeks prior to Visit 1 * Had any changes in COPD medication in the 4 weeks prior to Visit 1 * Has plan to change the dosage of Xanthines or to stop receiving it during the study * Has a current medical diagnosis of asthma * Has a medical diagnosis of narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction that in the opinion of the investigator should prevent them from entering the study Note: As with other anticholinergic drugs, subjects with narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction should only be entered into the study at the Investigator's discretion * Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis) * Has undergone lung surgery e.g., lung transplant and/or lung volume reduction * Is currently receiving pulmonary rehabilitation * Had a chest X-ray indicating diagnosis other than COPD that might interfere with the study (chest X-ray to be taken at entry, if subject has not had one or CT image taken within 3 months of Visit 1) * Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as . 12 hours oxygen use per day) * Requires regular treatment with oral, parenteral, or depot corticosteroids or has received 2 or more periods of oral corticosteroids for COPD exacerbation in the last 6 months * Received oral, parenteral, or depot corticosteroids in the 4 weeks prior to Visit 1 * Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Visit 1 * Has been hospitalized for a COPD exacerbation in the last year * Receiving non-selective β-blockers (except eye drops) * Has serious, uncontrolled disease likely to interfere with the study (e.g. Left Ventricular failure, anaemia, renal or hepatic disease or serious psychological disorders) * Received any other investigational drugs within 4 weeks (or 5 half lives) prior to Visit 1 * Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse * Has a known or suspected hypersensitivity to β2-agonists, inhaled steroids, anticholinergic treatments or any components of the formulations (e.g. lactose or milk protein) * Has previously been enrolled and randomized to this study * Are not considered able to tolerate three 2-weeks wash-out periods according to the study schedule with all COPD medications removed apart from rescue use of SALBUTAMOL via MDI (inhaled PRN use). * Is not eligible to participate this study in the opinion of the investigator/subinvestigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect. |
| Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect. |
| Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose. |
| Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose. |
| AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means. |
| Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. |
| Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. |
| Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. |
| Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms. |
| Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | Day 28 of each treatment period (up to 35 days) | sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose. |
Countries
Japan
Participant flow
Recruitment details
A total of 53 Japanese participants with moderate or severe chronic obstructive pulmonary disease (COPD) entered the run-in period.
Pre-assignment details
Participants, who met eligibility criteria, completed a 2-week Run-in Period prior to being randomized to 1 of 6 treatment sequences. The treatment phase was comprised of three 4 week treatment periods, each separated by a 2-week washout period.
Participants by arm
| Arm | Count |
|---|---|
| Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg All participants received one of the following 3 treatments in one of three 4-week treatment periods separated by a 2-week washout period:Ado 50/250 µg BID (morning and evening) + Tio 18 µg QD (morning), Ado 50/250 µg BID (morning and evening) + Tio matching placebo QD (morning), and Tio 18 µg QD (morning) + Ado matching placebo BID (morning and evening). Participants were randomized to one of the 6 following treatment sequences: (1) Ado 50/250 µg+Tio 18 µg, Tio 18 µg, Ado 50/250 µg (2) Tio 18 µg, Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg (3) Ado 50/250 µg, Ado 50/250 µg+Tio 18 µg, Tio 18 µg (4) Ado 50/250 µg, Tio 18 µg, Ado 50/250 µg+Tio 18 µg (5) Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg (6) Tio 18 µg, Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg. Ado 50/250 µg and its matching placebo were administered via DISKUS inhaler and Tio 18 µg and its matching placebo were administered via HandiHaler inhaler. Participants used salbutamol inhaler as relief medication throughout the study. | 53 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (4 Weeks) | Adverse Event | 0 | 0 | 0 | 1 | 1 | 0 |
| Treatment Period 3 (4 Weeks) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Ado 50/250 µg+Tio 18 µg, Ado 50/250 µg, Tio 18 µg |
|---|---|
| Age, Continuous | 67.2 Years STANDARD_DEVIATION 6.56 |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 53 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 52 | 8 / 51 | 11 / 51 |
| serious Total, serious adverse events | 2 / 52 | 0 / 51 | 0 / 51 |
Outcome results
Primary
Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least one dose of study medication and completed at least two treatment periods and also had a Baseline and at least one on treatment sGaw assessment measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period | 0.854 1/kilopascal*second (1/kPa*s) | Standard Error 0.0183 |
| Tio 18 µg QD | Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period | 0.737 1/kilopascal*second (1/kPa*s) | Standard Error 0.0183 |
| Ado 50/250 µg BID | Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period | 0.663 1/kilopascal*second (1/kPa*s) | Standard Error 0.0182 |
p-value: <0.00195% CI: [1.1, 1.219]Mixed Models Analysis
p-value: <0.00195% CI: [1.224, 1.355]Mixed Models Analysis
Secondary
AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period | 1.181 kPa*s | Standard Error 0.0188 |
| Tio 18 µg QD | AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period | 1.380 kPa*s | Standard Error 0.0189 |
| Ado 50/250 µg BID | AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period | 1.525 kPa*s | Standard Error 0.0188 |
p-value: <0.00195% CI: [0.812, 0.902]Mixed Models Analysis
p-value: <0.00195% CI: [0.735, 0.816]Mixed Models Analysis
Secondary
Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FEV1 | 1.766 Liters (L) | Standard Error 0.0269 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FVC | 3.535 Liters (L) | Standard Error 0.0403 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | IC | 2.344 Liters (L) | Standard Error 0.0415 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | RV | 3.045 Liters (L) | Standard Error 0.0543 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TLC | 6.487 Liters (L) | Standard Error 0.0395 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TGV | 4.147 Liters (L) | Standard Error 0.0414 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TGV | 4.239 Liters (L) | Standard Error 0.0414 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FEV1 | 1.605 Liters (L) | Standard Error 0.0269 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | RV | 3.275 Liters (L) | Standard Error 0.0542 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TLC | 6.588 Liters (L) | Standard Error 0.0394 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FVC | 3.430 Liters (L) | Standard Error 0.0403 |
| Tio 18 µg QD | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | IC | 2.351 Liters (L) | Standard Error 0.0414 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FVC | 3.387 Liters (L) | Standard Error 0.0403 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | IC | 2.351 Liters (L) | Standard Error 0.0405 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TGV | 4.238 Liters (L) | Standard Error 0.0405 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | RV | 3.234 Liters (L) | Standard Error 0.0533 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | FEV1 | 1.664 Liters (L) | Standard Error 0.0269 |
| Ado 50/250 µg BID | Post-dose FEV1, FVC, IC, RV, TLC and TGV (Measured at Trough) at Day 28 of Each Treatment Period | TLC | 6.592 Liters (L) | Standard Error 0.0386 |
p-value: <0.00195% CI: [0.086, 0.236]Mixed Models Analysis
p-value: 0.00895% CI: [0.028, 0.178]Mixed Models Analysis
p-value: 0.05195% CI: [0, 0.209]Mixed Models Analysis
p-value: 0.00695% CI: [0.043, 0.253]Mixed Models Analysis
p-value: 0.8995% CI: [-0.12, 0.104]Mixed Models Analysis
p-value: 0.8995% CI: [-0.118, 0.103]Mixed Models Analysis
p-value: <0.00195% CI: [-0.355, -0.103]Mixed Models Analysis
p-value: 0.00395% CI: [-0.314, -0.064]Mixed Models Analysis
p-value: 0.05595% CI: [-0.204, 0.002]Mixed Models Analysis
p-value: 0.04495% CI: [-0.206, -0.003]Mixed Models Analysis
p-value: 0.08595% CI: [-0.197, 0.013]Mixed Models Analysis
p-value: 0.08395% CI: [-0.195, 0.012]Mixed Models Analysis
Secondary
Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period | 0.500 Ratio of FEV1/FVC | Standard Error 0.0052 |
| Tio 18 µg QD | Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period | 0.472 Ratio of FEV1/FVC | Standard Error 0.0052 |
| Ado 50/250 µg BID | Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period | 0.492 Ratio of FEV1/FVC | Standard Error 0.0052 |
p-value: <0.00195% CI: [0.014, 0.041]Mixed Models Analysis
p-value: 0.22395% CI: [-0.005, 0.021]Mixed Models Analysis
Secondary
Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 0.833 1/kPa*s | Standard Error 0.0241 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 0.873 1/kPa*s | Standard Error 0.0241 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 0.885 1/kPa*s | Standard Error 0.0241 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 0.855 1/kPa*s | Standard Error 0.0241 |
| Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 0.750 1/kPa*s | Standard Error 0.0241 |
| Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 0.705 1/kPa*s | Standard Error 0.0241 |
| Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 0.769 1/kPa*s | Standard Error 0.0241 |
| Tio 18 µg QD | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 0.743 1/kPa*s | Standard Error 0.0241 |
| Ado 50/250 µg BID | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 0.690 1/kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 0.652 1/kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 0.680 1/kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 0.639 1/kPa*s | Standard Error 0.024 |
p-value: <0.00195% CI: [1.104, 1.263]Mixed Models Analysis
p-value: <0.00195% CI: [1.219, 1.393]Mixed Models Analysis
p-value: <0.00195% CI: [1.099, 1.257]Mixed Models Analysis
p-value: <0.00195% CI: [1.253, 1.432]Mixed Models Analysis
p-value: <0.00195% CI: [1.076, 1.231]Mixed Models Analysis
p-value: <0.00195% CI: [1.217, 1.391]Mixed Models Analysis
p-value: <0.00195% CI: [1.067, 1.22]Mixed Models Analysis
p-value: <0.00195% CI: [1.159, 1.325]Mixed Models Analysis
Secondary
Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 1.129 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 1.201 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 1.170 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID+Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 1.146 kPa*s | Standard Error 0.024 |
| Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 1.300 kPa*s | Standard Error 0.024 |
| Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 1.348 kPa*s | Standard Error 0.024 |
| Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 1.419 kPa*s | Standard Error 0.024 |
| Tio 18 µg QD | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 1.334 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 75 min | 1.535 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 30 min | 1.567 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 240 min | 1.446 kPa*s | Standard Error 0.024 |
| Ado 50/250 µg BID | Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period | 120 min | 1.468 kPa*s | Standard Error 0.024 |
p-value: <0.00195% CI: [0.792, 0.905]Mixed Models Analysis
p-value: <0.00195% CI: [0.717, 0.819]Mixed Models Analysis
p-value: <0.00195% CI: [0.795, 0.909]Mixed Models Analysis
p-value: <0.00195% CI: [0.698, 0.798]Mixed Models Analysis
p-value: <0.00195% CI: [0.812, 0.928]Mixed Models Analysis
p-value: <0.00195% CI: [0.719, 0.822]Mixed Models Analysis
p-value: <0.00195% CI: [0.82, 0.938]Mixed Models Analysis
p-value: <0.00195% CI: [0.757, 0.865]Mixed Models Analysis
Secondary
Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.513 Ratio of FEV1/FVC | Standard Error 0.0032 |
| Tio 18 µg QD | Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.481 Ratio of FEV1/FVC | Standard Error 0.0032 |
| Ado 50/250 µg BID | Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.496 Ratio of FEV1/FVC | Standard Error 0.0032 |
p-value: <0.00195% CI: [0.023, 0.041]Mixed Models Analysis
p-value: <0.00195% CI: [0.008, 0.026]Mixed Models Analysis
Secondary
Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGV) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FEV1 | 1.823 Liters (L) | Standard Error 0.0147 |
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FVC | 3.575 Liters (L) | Standard Error 0.0182 |
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | IC | 2.460 Liters (L) | Standard Error 0.0177 |
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | RV | 3.021 Liters (L) | Standard Error 0.0282 |
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TLC | 6.511 Liters (L) | Standard Error 0.0189 |
| Ado 50/250 µg BID+Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TGV | 4.053 Liters (L) | Standard Error 0.0206 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TGV | 4.118 Liters (L) | Standard Error 0.021 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FEV1 | 1.666 Liters (L) | Standard Error 0.0147 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | RV | 3.129 Liters (L) | Standard Error 0.0286 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TLC | 6.524 Liters (L) | Standard Error 0.0191 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FVC | 3.493 Liters (L) | Standard Error 0.0182 |
| Tio 18 µg QD | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | IC | 2.406 Liters (L) | Standard Error 0.0179 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FVC | 3.439 Liters (L) | Standard Error 0.0182 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | IC | 2.395 Liters (L) | Standard Error 0.0174 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TGV | 4.129 Liters (L) | Standard Error 0.0204 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | RV | 3.123 Liters (L) | Standard Error 0.0278 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | FEV1 | 1.706 Liters (L) | Standard Error 0.0147 |
| Ado 50/250 µg BID | Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGV at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | TLC | 6.525 Liters (L) | Standard Error 0.0186 |
p-value: <0.00195% CI: [0.116, 0.198]Mixed Models Analysis
p-value: <0.00195% CI: [0.077, 0.159]Mixed Models Analysis
p-value: 0.00295% CI: [0.031, 0.133]Mixed Models Analysis
p-value: <0.00195% CI: [0.084, 0.186]Mixed Models Analysis
p-value: 0.03595% CI: [0.004, 0.104]Mixed Models Analysis
p-value: 0.01195% CI: [0.015, 0.114]Mixed Models Analysis
p-value: 0.00995% CI: [-0.187, -0.028]Mixed Models Analysis
p-value: 0.01295% CI: [-0.18, -0.023]Mixed Models Analysis
p-value: 0.63295% CI: [-0.066, 0.04]Mixed Models Analysis
p-value: 0.59695% CI: [-0.067, 0.038]Mixed Models Analysis
p-value: 0.02895% CI: [-0.123, -0.007]Mixed Models Analysis
p-value: 0.0195% CI: [-0.133, -0.018]Mixed Models Analysis
Secondary
Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.720 1/kPa*s | Standard Error 0.0287 |
| Tio 18 µg QD | Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.600 1/kPa*s | Standard Error 0.0285 |
| Ado 50/250 µg BID | Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 0.577 1/kPa*s | Standard Error 0.0284 |
p-value: <0.00195% CI: [1.108, 1.301]Mixed Models Analysis
p-value: <0.00195% CI: [1.153, 1.352]Mixed Models Analysis
Secondary
Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period
sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 1.391 kPa*s | Standard Error 0.0288 |
| Tio 18 µg QD | Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 1.666 kPa*s | Standard Error 0.0286 |
| Ado 50/250 µg BID | Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period | 1.732 kPa*s | Standard Error 0.0284 |
p-value: <0.00195% CI: [0.77, 0.905]Mixed Models Analysis
p-value: <0.00195% CI: [0.741, 0.869]Mixed Models Analysis
Secondary
Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period
Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms.
Time frame: Day 28 of each treatment period (up to 35 days)
Population: mITT Population. Only those participants available who used rescue medication at the specified periods were analyzed (represented by n=X, X, X in the category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ado 50/250 µg BID+Tio 18 µg QD | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Treatment, n=20, 18, 17 | 0.2 Number of occasions | Standard Deviation 0.62 |
| Ado 50/250 µg BID+Tio 18 µg QD | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Washout, n=15, 15, 11 | 0.4 Number of occasions | Standard Deviation 0.81 |
| Tio 18 µg QD | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Treatment, n=20, 18, 17 | 0.3 Number of occasions | Standard Deviation 0.82 |
| Tio 18 µg QD | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Washout, n=15, 15, 11 | 0.5 Number of occasions | Standard Deviation 1.24 |
| Ado 50/250 µg BID | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Treatment, n=20, 18, 17 | 0.2 Number of occasions | Standard Deviation 0.55 |
| Ado 50/250 µg BID | Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period | Washout, n=15, 15, 11 | 0.4 Number of occasions | Standard Deviation 1.01 |