Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The study is intended to characterize the lung function profile of BI1744 in Chronic Obstructive Pulmonary Disease (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
High dose inhaled orally once daily from Respimat inhaler
18 mcg inhaled once daily from HandiHaler
DRUGPlacebo (for Olodaterol (BI1744)l)
Placebo (olodaterol low and high dose) delivered by Respimat
Placebo (Tiotropium 18 mcg) delivered by 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 the 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 first 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 the 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 first 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 the am 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 the first 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 treatment for the first 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 treatment for the first 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 treatment for the first period. Trough values were the mean of values obtained 23h 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. |
| Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 1 hour (h) and 10 minutes (min) prior to the am 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 of treatment for the first 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 the 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 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 treatment for the first 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 prior to the first dose at the first randomized treatment visit for the first 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. |
| 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 of treatment for the first period. Trough values were the mean of 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. |
| FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 1 hour (h) and 10 minutes (min) prior to the am 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 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 of treatment for the first 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 of treatment for the first period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last am 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. |
| 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 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 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 treatment for the first 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 the am 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 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 treatment at the first treatment visit for the first 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
Germany, Netherlands, Norway, United States
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. 122 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. | 122 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 8 | 0 | 4 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 1 |
| Overall Study | Other reasons not listed above | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 7.9 |
| Sex: Female, Male Female | 47 Participants |
| Sex: Female, Male Male | 75 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 | 8 / 109 | 14 / 115 | 6 / 113 | 4 / 113 |
| serious Total, serious adverse events | 5 / 109 | 3 / 115 | 8 / 113 | 2 / 113 |
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 first 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 the 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 of the co-primary endpoints. FAS including all patients with evaluable data for this endpoint 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 | -0.008 Liter | Standard Error 0.019 |
| Olo 5 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.189 Liter | Standard Error 0.019 |
| Olo 10 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.213 Liter | Standard Error 0.019 |
| Tio 18 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After Six Weeks of Treatment | 0.213 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.163, 0.231]Mixed Models Analysis
p-value: <0.000195% CI: [0.186, 0.255]Mixed Models Analysis
p-value: <0.000195% CI: [0.187, 0.255]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 first 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 the 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | -0.059 Liter | Standard Error 0.018 |
| Olo 5 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.094 Liter | Standard Error 0.018 |
| Olo 10 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.111 Liter | Standard Error 0.018 |
| Tio 18 mcg qd | FEV1 Area Under Curve 12-24h (AUC 12-24h) Response After Six Weeks of Treatment | 0.105 Liter | Standard Error 0.018 |
p-value: <0.000195% CI: [0.117, 0.188]Mixed Models Analysis
p-value: <0.000195% CI: [0.134, 0.205]Mixed Models Analysis
p-value: <0.000195% CI: [0.128, 0.199]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 | Potassium increased | 1 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrial fibrillation | 0 participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Potassium increased | 0 participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0 participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrial fibrillation | 0 participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrial fibrillation | 1 participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Potassium increased | 0 participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 1 participants |
| Tio 18 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Potassium increased | 0 participants |
| Tio 18 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Palpitations | 0 participants |
| Tio 18 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Atrial fibrillation | 0 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 prior to the first dose at the first randomized treatment visit for the first 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 for this endpoint 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 | -0.033 Liter | Standard Error 0.019 |
| 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 | 0.142 Liter | Standard Error 0.018 |
| 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 | 0.158 Liter | Standard Error 0.018 |
| 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 | 0.159 Liter | Standard Error 0.018 |
p-value: <0.000195% CI: [0.141, 0.208]Mixed Models Analysis
p-value: <0.000195% CI: [0.157, 0.225]Mixed Models Analysis
p-value: <0.000195% CI: [0.159, 0.226]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 treatment at the first treatment visit for the first 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 the am 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 the first dose of treatment period
Population: FAS including all patients with evaluable data for this endpoint 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 | 0.018 Liter | Standard Error 0.018 |
| 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 | 0.232 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 | 0.256 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 | 0.169 Liter | Standard Error 0.018 |
p-value: <0.000195% CI: [0.181, 0.248]Mixed Models Analysis
p-value: <0.000195% CI: [0.205, 0.272]Mixed Models Analysis
p-value: <0.000195% CI: [0.119, 0.185]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 treatment for the first 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 the am 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 the first dose of treatment after six weeks of treatment
Population: FAS including all patients with evaluable data for this endpoint 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 | 0.011 Liter | Standard Error 0.02 |
| 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 | 0.225 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 | 0.255 Liter | Standard Error 0.02 |
| 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 | 0.246 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.178, 0.251]Mixed Models Analysis
p-value: <0.000195% CI: [0.208, 0.282]Mixed Models Analysis
p-value: <0.000195% CI: [0.199, 0.271]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 of treatment for the first 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 the am 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | -0.006 Liter | Standard Error 0.035 |
| Olo 5 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.324 Liter | Standard Error 0.034 |
| Olo 10 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.321 Liter | Standard Error 0.035 |
| Tio 18 mcg qd | Forced Vital Capacity (FVC) Area Under Curve 0-12 Hours (AUC 0-12h) Response | 0.364 Liter | Standard Error 0.035 |
p-value: <0.000195% CI: [0.276, 0.384]Mixed Models Analysis
p-value: <0.000195% CI: [0.272, 0.381]Mixed Models Analysis
p-value: <0.000195% CI: [0.316, 0.424]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 of treatment for the first 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 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 last dose after six weeks of treatment
Population: FAS including all patients with evaluable data for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | -0.057 Liter | Standard Error 0.036 |
| Olo 5 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.247 Liter | Standard Error 0.035 |
| Olo 10 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.226 Liter | Standard Error 0.036 |
| Tio 18 mcg qd | FVC Area Under Curve 0-24 Hours (AUC 0-24h) Response | 0.278 Liter | Standard Error 0.035 |
p-value: <0.000195% CI: [0.244, 0.363]Mixed Models Analysis
p-value: <0.000195% CI: [0.222, 0.343]Mixed Models Analysis
p-value: <0.000195% CI: [0.275, 0.395]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 of treatment for the first 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 the am 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 first dose of treatment
Population: FAS including all patients with evaluable data for this endpoint after first dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.053 Liter | Standard Error 0.035 |
| Olo 5 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.423 Liter | Standard Error 0.034 |
| Olo 10 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.419 Liter | Standard Error 0.034 |
| Tio 18 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.316 Liter | Standard Error 0.034 |
p-value: <0.000195% CI: [0.309, 0.43]Mixed Models Analysis
p-value: <0.000195% CI: [0.306, 0.426]Mixed Models Analysis
p-value: <0.000195% CI: [0.202, 0.322]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 of treatment for the first 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 the am 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 of treatment after six weeks of treatment
Population: FAS including all patients with evaluable data for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.044 Liter | Standard Error 0.035 |
| Olo 5 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.388 Liter | Standard Error 0.034 |
| Olo 10 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.397 Liter | Standard Error 0.035 |
| Tio 18 mcg qd | FVC Area Under Curve 0-3 Hours (AUC 0-3h) Response | 0.414 Liter | Standard Error 0.034 |
p-value: <0.000195% CI: [0.287, 0.401]Mixed Models Analysis
p-value: <0.000195% CI: [0.296, 0.411]Mixed Models Analysis
p-value: <0.000195% CI: [0.314, 0.427]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 treatment for the first 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 the 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 last dose after six weeks of treatment
Population: FAS including all patients with evaluable data for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | -0.109 Liter | Standard Error 0.036 |
| Olo 5 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.169 Liter | Standard Error 0.035 |
| Olo 10 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.155 Liter | Standard Error 0.036 |
| Tio 18 mcg qd | FVC Area Under Curve 12-24 Hours (AUC 12-24h) Response | 0.192 Liter | Standard Error 0.035 |
p-value: <0.000195% CI: [0.214, 0.342]Mixed Models Analysis
p-value: <0.000195% CI: [0.2, 0.329]Mixed Models Analysis
p-value: <0.000195% CI: [0.238, 0.366]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 treatment for the first 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 (0-3h) Response | 0.082 Liter | Standard Error 0.02 |
| Olo 5 mcg qd | Peak FEV1 (0-3h) Response | 0.290 Liter | Standard Error 0.02 |
| Olo 10 mcg qd | Peak FEV1 (0-3h) Response | 0.325 Liter | Standard Error 0.02 |
| Tio 18 mcg qd | Peak FEV1 (0-3h) Response | 0.325 Liter | Standard Error 0.02 |
p-value: <0.000195% CI: [0.169, 0.246]Mixed Models Analysis
p-value: <0.000195% CI: [0.205, 0.282]Mixed Models Analysis
p-value: <0.000195% CI: [0.205, 0.282]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 treatment for the first 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 for this endpoint after first dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FEV1 (0-3h) Response | 0.076 Liter | Standard Error 0.019 |
| Olo 5 mcg qd | Peak FEV1 (0-3h) Response | 0.313 Liter | Standard Error 0.019 |
| Olo 10 mcg qd | Peak FEV1 (0-3h) Response | 0.342 Liter | Standard Error 0.019 |
| Tio 18 mcg qd | Peak FEV1 (0-3h) Response | 0.251 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.201, 0.273]Mixed Models Analysis
p-value: <0.000195% CI: [0.23, 0.302]Mixed Models Analysis
p-value: <0.000195% CI: [0.138, 0.211]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 of treatment for the first period. Peak FVC (0-3h) was obtained within 0 - 3 hours after the last am 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Peak FVC (0-3h) Response | 0.191 Liter | Standard Error 0.037 |
| Olo 5 mcg qd | Peak FVC (0-3h) Response | 0.526 Liter | Standard Error 0.036 |
| Olo 10 mcg qd | Peak FVC (0-3h) Response | 0.537 Liter | Standard Error 0.037 |
| Tio 18 mcg qd | Peak FVC (0-3h) Response | 0.569 Liter | Standard Error 0.037 |
p-value: <0.000195% CI: [0.272, 0.396]Mixed Models Analysis
p-value: <0.000195% CI: [0.283, 0.408]Mixed Models Analysis
p-value: <0.000195% CI: [0.316, 0.44]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 treatment for the first period. Trough values were the mean of values obtained 23h 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.003 Liter | Standard Error 0.019 |
| Olo 5 mcg qd | Trough FEV1 Response | 0.137 Liter | Standard Error 0.019 |
| Olo 10 mcg qd | Trough FEV1 Response | 0.146 Liter | Standard Error 0.019 |
| Tio 18 mcg qd | Trough FEV1 Response | 0.161 Liter | Standard Error 0.019 |
p-value: <0.000195% CI: [0.097, 0.171]Mixed Models Analysis
p-value: <0.000195% CI: [0.105, 0.181]Mixed Models Analysis
p-value: <0.000195% CI: [0.12, 0.195]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 of treatment for the first period. Trough values were the mean of 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 for this endpoint after six weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | -0.001 Liter | Standard Error 0.037 |
| Olo 5 mcg qd | Trough FVC Response | 0.243 Liter | Standard Error 0.036 |
| Olo 10 mcg qd | Trough FVC Response | 0.215 Liter | Standard Error 0.037 |
| Tio 18 mcg qd | Trough FVC Response | 0.255 Liter | Standard Error 0.037 |
p-value: <0.000195% CI: [0.179, 0.309]Mixed Models Analysis
p-value: <0.000195% CI: [0.15, 0.282]Mixed Models Analysis
p-value: <0.000195% CI: [0.191, 0.321]Mixed Models Analysis