Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The study is intended to characterize the lung function profile of BI1744 in COPD patients where patients will perform pulmonary function tests at regular intervals for 24 hours at the end of a 6 week treatment period. Each patient will receive all four treatments.
Interventions
Low dose inhaled orally once daily from Respimat inhaler
DRUGPlacebo (for olodaterol BI1744)
Placebo (olodaterol low and high dose)delivered by Respimat
Placebo (Tiotropium 18 mcg) delivered by HandiHaler
High dose inhaled orally once daily from Respimat inhaler
18mcg inhaled once daily from Handihaler
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients willing to participate with confirmed diagnosis of COPD * 40 years of age or older * having a 10 pack year smoking history * able to perform serial pulmonary function tests * able to use both a Dry powder inhaler (DPI) and Respimat device
Exclusion criteria
* Significant other disease * clinically relevant abnormal hematology, chemistry, or urinalysis * history of asthma * diagnosis of thyrotoxicosis * paroxysmal tachycardia related to beta agonists * history of MI within 1 year, cardiac arrhythmia, hospitalization for heart failure within 1 year * active tuberculosis, cystic fibrosis, clinically evident bronchiectasis * significant alcohol or drug abuse * pulmonary resection * taking oral beta adrenergics * taking unstable oral steroids * daytime oxygen * enrolled in rehabilitation program * enrolled in another study or taking investigational products * pregnant or nursing women, women of child bearing potential not willing to use two methods of birth control * those who are not willing to comply with pulmonary medication washouts
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. |
| FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 1 h and 10 min prior to am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment | 1 hour (h) prior and 10 minutes (min) prior to first dose of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the last dose of treatment after six weeks of treatment. | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. |
| Peak FEV1 (0-3h) Response | Study baseline and first day of dosing | Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. |
| Trough FEV1 Response | Study baseline and 6 weeks | Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of first treatment period. Trough values were the mean of values obtained 23 hours and 23h 50min post the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. |
| Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment. | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 1 h and 10 min prior to dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment | 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the first visit of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres. |
| FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 1 hour (h) and 10 minutes (min) prior to dose on the first day of the treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| Peak FVC (0-3h) Response | Study baseline and 6 weeks | Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose in first treatment period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. |
| Trough FVC Response | Study baseline and 6 weeks | Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose in first treatment period. Trough values were mean of the values obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 6 weeks | Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations). |
| FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment. | Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres. |
| Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment | 1 hour (h) prior and 10 minutes (min) prior to first dose of the first period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period | Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres. |
Countries
Belgium, Denmark, Germany, Hungary
Participant flow
Pre-assignment details
This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments.
Participants by arm
| Arm | Count |
|---|---|
| Study Total Total number of patients treated in the study. This was a randomised, double-blind, double dummy, placebo- and active-controlled, 4 way crossover trial. 108 patients were assigned randomly to one of 4 treatment sequences in which they received each of 4 treatments, two doses (5 microgram (mcg) or 10 mcg) of Olodaterol (Olo) once daily (qd) delivered via the Respimat inhaler or Tiotropium (Tio) 18 mcg once daily (qd) delivered via the HandiHaler or equivalent placebo. The duration of each treatment period was 6 weeks with a 3 week washout period between treatments. | 108 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 4 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Other reasons not listed above | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 102 | 14 / 101 | 6 / 101 | 10 / 101 |
| serious Total, serious adverse events | 5 / 102 | 1 / 101 | 0 / 101 | 5 / 101 |
Outcome results
Primary
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-12h was calculated from 0-12 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 hour (h) , 3 h, 4 h, 6 h, 8 h, 10 h, 12 h relative to am dose after six weeks of treatment
Population: Full analysis set (FAS). FAS is defined as all patients with baseline (pre-dose) data and any evaluable post-dosing data for either co-primary endpoint from the same treatment period. FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | -0.054 Liter | Standard Error 0.02 |
| Olo 5 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.131 Liter | Standard Error 0.02 |
| Olo 10 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.152 Liter | Standard Error 0.02 |
| Tio 18 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.119 Liter | Standard Error 0.02 |
p-value: <0.000195% CI: [0.145, 0.224]Mixed Models Analysis
p-value: <0.000195% CI: [0.167, 0.246]Mixed Models Analysis
p-value: <0.000195% CI: [0.133, 0.212]Mixed Models Analysis
Primary
FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the -1 hour and -10 minute measurements performed in the morning of the first treatment visit for the first period, just prior to administration of the morning dose of randomized treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 12-24h was calculated from 12-24 hours post-dose using the trapezoidal rule, divided by the observation time (12h) to report in litres.
Time frame: 1 h and 10 min prior to am dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | -0.095 Liter | Standard Error 0.021 |
| Olo 5 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.036 Liter | Standard Error 0.021 |
| Olo 10 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.082 Liter | Standard Error 0.021 |
| Tio 18 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.027 Liter | Standard Error 0.021 |
p-value: <0.000195% CI: [0.09, 0.173]Mixed Models Analysis
p-value: <0.000195% CI: [0.136, 0.219]Mixed Models Analysis
p-value: <0.000195% CI: [0.081, 0.164]Mixed Models Analysis
Secondary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations).
Time frame: 6 weeks
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0.0 percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0.0 percentage of participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0.0 percentage of participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0.0 percentage of participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 1.0 percentage of participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0.0 percentage of participants |
| Tio 18 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0.0 percentage of participants |
| Tio 18 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0.0 percentage of participants |
Secondary
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values at the first visit of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-24h was calculated from 0-24 hours post-dose using the trapezoidal rule, divided by the observation time (24h) to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to am dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to am dose after six weeks of treatment
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment | -0.075 Liter | Standard Error 0.02 |
| Olo 5 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment | 0.083 Liter | Standard Error 0.02 |
| Olo 10 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment | 0.117 Liter | Standard Error 0.02 |
| Tio 18 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-24 h (AUC 0-24h) Response After Six Weeks of Treatment | 0.073 Liter | Standard Error 0.02 |
p-value: <0.000195% CI: [0.121, 0.196]Mixed Models Analysis
p-value: <0.000195% CI: [0.155, 0.23]Mixed Models Analysis
p-value: <0.000195% CI: [0.11, 0.185]Mixed Models Analysis
Secondary
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the first dose of treatment period
Population: FAS including all patients with evaluable data after first dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment | -0.021 Liter | Standard Error 0.017 |
| Olo 5 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment | 0.161 Liter | Standard Error 0.017 |
| Olo 10 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment | 0.191 Liter | Standard Error 0.017 |
| Tio 18 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After First Dose of Treatment | 0.111 Liter | Standard Error 0.017 |
p-value: <0.000195% CI: [0.147, 0.216]Mixed Models Analysis
p-value: <0.000195% CI: [0.178, 0.247]Mixed Models Analysis
p-value: <0.000195% CI: [0.097, 0.167]Mixed Models Analysis
Secondary
Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment
Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FEV1 AUC 0-3h was calculated from 0-3hours post-dose using the trapezoidal rule, divided by the observation time (3 h) to report in litres.
Time frame: 1 hour (h) prior and 10 minutes (min) prior to first dose of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h , 3 h, relative to the last dose of treatment after six weeks of treatment.
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment | -0.045 Liter | Standard Error 0.019 |
| Olo 5 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment | 0.161 Liter | Standard Error 0.019 |
| Olo 10 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment | 0.170 Liter | Standard Error 0.019 |
| Tio 18 mcg qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve 0-3 h (AUC 0-3h) Response After Six Weeks of Treatment | 0.137 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.17, 0.243]Mixed Models Analysis
p-value: <0.000195% CI: [0.179, 0.252]Mixed Models Analysis
p-value: <0.000195% CI: [0.146, 0.219]Mixed Models Analysis
Secondary
Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-12h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min (zero time), 30 min, 60 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12h relative to last dose after six weeks of treatment.
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | -0.110 Liter | Standard Error 0.038 |
| Olo 5 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.172 Liter | Standard Error 0.038 |
| Olo 10 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.192 Liter | Standard Error 0.038 |
| Tio 18 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.166 Liter | Standard Error 0.038 |
p-value: <0.000195% CI: [0.216, 0.348]Mixed Models Analysis
p-value: <0.000195% CI: [0.237, 0.368]Mixed Models Analysis
p-value: <0.000195% CI: [0.21, 0.342]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose in first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h, 4 h, 6h, 8h, 10h, 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment.
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | -0.138 Liter | Standard Error 0.037 |
| Olo 5 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.101 Liter | Standard Error 0.037 |
| Olo 10 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.139 Liter | Standard Error 0.037 |
| Tio 18 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.091 Liter | Standard Error 0.037 |
p-value: <0.000195% CI: [0.178, 0.301]Mixed Models Analysis
p-value: <0.000195% CI: [0.216, 0.339]Mixed Models Analysis
p-value: <0.000195% CI: [0.168, 0.291]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to first dose of treatment
Population: FAS including all patients with evaluable data after first dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | -0.024 Liter | Standard Error 0.037 |
| Olo 5 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.244 Liter | Standard Error 0.037 |
| Olo 10 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.288 Liter | Standard Error 0.037 |
| Tio 18 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.191 Liter | Standard Error 0.037 |
p-value: <0.000195% CI: [0.207, 0.33]Mixed Models Analysis
p-value: <0.000195% CI: [0.251, 0.374]Mixed Models Analysis
p-value: <0.000195% CI: [0.153, 0.277]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to the first dose in the first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 0-3h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 hour (h) and 10 minutes (min) prior to dose on the first day of the first treatment period (study baseline) and -30 min, 30 min, 60 min, 2 h, 3 h relative to last dose after six weeks of treatment.
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | -0.083 Liter | Standard Error 0.04 |
| Olo 5 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.234 Liter | Standard Error 0.04 |
| Olo 10 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.235 Liter | Standard Error 0.04 |
| Tio 18 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.219 Liter | Standard Error 0.04 |
p-value: <0.000195% CI: [0.246, 0.388]Mixed Models Analysis
p-value: <0.000195% CI: [0.247, 0.388]Mixed Models Analysis
p-value: <0.000195% CI: [0.231, 0.373]Mixed Models Analysis
Secondary
FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response
Response was defined as change from baseline. Study baseline FVC was defined as the mean of the available pre-dose FVC values prior to first dose of first treatment period. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate. FVC AUC 12-24h was calculated using the trapezoidal rule, divided by the observation time to report in litres.
Time frame: 1 h and 10 min prior to dose on the first day of the first treatment period (study baseline) and 12 h, 22 h, 23 h, and 23 h 50 min relative to last dose after six weeks of treatment
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | -0.166 Liter | Standard Error 0.039 |
| Olo 5 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.030 Liter | Standard Error 0.039 |
| Olo 10 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.086 Liter | Standard Error 0.039 |
| Tio 18 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.018 Liter | Standard Error 0.039 |
p-value: <0.000195% CI: [0.131, 0.262]Mixed Models Analysis
p-value: <0.000195% CI: [0.187, 0.318]Mixed Models Analysis
p-value: <0.000195% CI: [0.118, 0.249]Mixed Models Analysis
Secondary
Peak FEV1 (0-3h) Response
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time frame: Study baseline and 6 weeks
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 (0-3h) Response | 0.019 Liter | Standard Error 0.022 |
| Olo 5 mcg qd | Peak FEV1 (0-3h) Response | 0.232 Liter | Standard Error 0.022 |
| Olo 10 mcg qd | Peak FEV1 (0-3h) Response | 0.253 Liter | Standard Error 0.022 |
| Tio 18 mcg qd | Peak FEV1 (0-3h) Response | 0.220 Liter | Standard Error 0.022 |
p-value: <0.000195% CI: [0.168, 0.258]Mixed Models Analysis
p-value: <0.000195% CI: [0.189, 0.279]Mixed Models Analysis
p-value: <0.000195% CI: [0.156, 0.246]Mixed Models Analysis
Secondary
Peak FEV1 (0-3h) Response
Response was defined as change from baseline. Study baseline peak FEV1 was defined as the mean of the available pre-dose peak FEV1 values prior to first dose of first treatment period. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the first dose of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time frame: Study baseline and first day of dosing
Population: FAS including all patients with evaluable data after first dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 (0-3h) Response | 0.040 Liter | Standard Error 0.018 |
| Olo 5 mcg qd | Peak FEV1 (0-3h) Response | 0.253 Liter | Standard Error 0.018 |
| Olo 10 mcg qd | Peak FEV1 (0-3h) Response | 0.279 Liter | Standard Error 0.018 |
| Tio 18 mcg qd | Peak FEV1 (0-3h) Response | 0.201 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.177, 0.249]Mixed Models Analysis
p-value: <0.000195% CI: [0.203, 0.275]Mixed Models Analysis
p-value: <0.000195% CI: [0.125, 0.197]Mixed Models Analysis
Secondary
Peak FVC (0-3h) Response
Response was defined as change from baseline. Study baseline peak FVC was defined as the mean of the available pre-dose peak FVC values prior to first dose in first treatment period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last dose of study drug after 6 weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time frame: Study baseline and 6 weeks
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC (0-3h) Response | 0.086 Liter | Standard Error 0.043 |
| Olo 5 mcg qd | Peak FVC (0-3h) Response | 0.386 Liter | Standard Error 0.043 |
| Olo 10 mcg qd | Peak FVC (0-3h) Response | 0.383 Liter | Standard Error 0.043 |
| Tio 18 mcg qd | Peak FVC (0-3h) Response | 0.381 Liter | Standard Error 0.043 |
p-value: <0.000195% CI: [0.222, 0.378]Mixed Models Analysis
p-value: <0.000195% CI: [0.22, 0.375]Mixed Models Analysis
p-value: <0.000195% CI: [0.217, 0.373]Mixed Models Analysis
Secondary
Trough FEV1 Response
Response was defined as change from baseline. Study baseline trough FEV1 was defined as the mean of the available pre-dose trough FEV1 values prior to first dose of first treatment period. Trough values were the mean of values obtained 23 hours and 23h 50min post the last dose of study drug after six weeks of treatment . Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time frame: Study baseline and 6 weeks
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | -0.043 Liter | Standard Error 0.02 |
| Olo 5 mcg qd | Trough FEV1 Response | 0.090 Liter | Standard Error 0.02 |
| Olo 10 mcg qd | Trough FEV1 Response | 0.104 Liter | Standard Error 0.02 |
| Tio 18 mcg qd | Trough FEV1 Response | 0.054 Liter | Standard Error 0.02 |
p-value: <0.000195% CI: [0.096, 0.17]Mixed Models Analysis
p-value: <0.000195% CI: [0.11, 0.184]Mixed Models Analysis
p-value: <0.000195% CI: [0.06, 0.134]Mixed Models Analysis
Secondary
Trough FVC Response
Response was defined as change from baseline. Study baseline trough FVC was defined as the mean of the available pre-dose trough FVC values prior to first dose in first treatment period. Trough values were mean of the values obtained 23 h and 23 h 50 min after the last dose of study drug after six weeks of treatment. Means are adjusted using a mixed effects model with treatment and period as fixed effects and patient as a random effect and study baseline as a continuous covariate.
Time frame: Study baseline and 6 weeks
Population: FAS including all patients with evaluable data after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | -0.082 Liter | Standard Error 0.041 |
| Olo 5 mcg qd | Trough FVC Response | 0.103 Liter | Standard Error 0.041 |
| Olo 10 mcg qd | Trough FVC Response | 0.130 Liter | Standard Error 0.041 |
| Tio 18 mcg qd | Trough FVC Response | 0.046 Liter | Standard Error 0.041 |
p-value: <0.000195% CI: [0.115, 0.255]Mixed Models Analysis
p-value: <0.000195% CI: [0.143, 0.282]Mixed Models Analysis
p-value: 0.000395% CI: [0.059, 0.199]Mixed Models Analysis