Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The primary objective of the trial is to determine the effect of BI 17444Cl on the lung function over a 24-hour period, when it is inhaled using the Respimat inhaler in patients with chronic obstructive pulmonary disease. In the trial four treatments of each 3 weeks of duration are included: 2 dosages in a once daily administration and 2 dosages for administration twice daily.
Interventions
DRUGBI 1744 CL
Sponsors
Boehringer Ingelheim
Study design
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions 2. All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator FEV1 \< 80% of predicted normal and a post-bronchodilator FEV1 / FVC \< 70% at Visit 1 3. Male or female patients, 40 years of age or older 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years 5. Patients must be able to perform technically acceptable pulmonary function tests 6. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a metered dose inhaler (MDI).
Exclusion criteria
1. Patients with a significant disease other than COPD. 2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT \> x2 ULN, SGPT \> x2 ULN, bilirubin \> x2 ULN or creatinine \> x2 ULN will be excluded regardless of clinical condition. 3. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count more than 600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition. 4. Patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period. 5. Patients with any of the following conditions: a diagnosis of thyrotoxicosis; a diagnosis of paroxysmal tachycardia (\>100 beats per minute) 6. Patients with any of the following conditions: a history of myocardial infarction within 1 year of screening visit (Visit 1); unstable or life-threatening cardiac arrhythmia; have been hospitalized for heart failure within the past year; known active tuberculosis; a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed); a history of life-threatening pulmonary obstruction; a history of cystic fibrosis; clinically evident bronchiectasis; a history of significant alcohol or drug abuse 7. Patients who have undergone thoracotomy with pulmonary resection 8. Patients being treated with any of the following concomitant medications: oral beta2-adrenergics; oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. 9. Patients who regularly use daytime oxygen therapy for more than one hour per day. 10. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the Screening Visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program 11. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit 12. Patients with known hypersensitivity to beta-adrenergics drugs, BAC, EDTA or any other component of the Respimat inhalation solution delivery system 13. Pregnant or nursing women 14. Women of childbearing potential not using two effective methods of birth control (one barrier, one non-barrier). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years 15. Patients who have previously been randomized in this study or are currently participating in another study 16. Patients who are unable to comply with pulmonary medication restrictions prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose | Response was defined as change from baseline. Baseline FEV1 AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose | Response was defined as change from baseline. Baseline FEV1 AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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 |
|---|---|---|
| Trough FEV1 Response | Baseline, 3 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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . |
| FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose | Response was defined as change from baseline. Baseline FVC AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. |
| FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose | Response was defined as change from baseline. Baseline FVC AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. |
| FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1, 0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose | Response was defined as change from baseline. Baseline FVC AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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. |
| Peak FVC (0-3h) Response After 3 Weeks | Baseline, 3 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. Peak FVC (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. |
| Trough FVC Response | Baseline, 3 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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment . |
| FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1,0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose | Response was defined as change from baseline. Baseline FEV1 AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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. |
| Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State | 3 weeks | Steady state concentration of the analyte in plasma measured at 0.167 hours post dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range. |
| Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | 3 weeks | Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range. |
| Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours | 3 weeks | Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range. |
| Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | 3 weeks | Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range. |
| Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours | 3 weeks | Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | 3 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). |
| Peak FEV1 (0-3h) Response After 3 Weeks | Baseline, 3 weeks | 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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment. |
Countries
Belgium, Netherlands
Participant flow
Pre-assignment details
This was a multi-centre, randomised, double-blind, 4-way crossover trial. The duration of each treatment period was 3 weeks with no 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, active-controlled, 4 way crossover trial. 47 patients were assigned randomly to one of 4 treatment sequences in which they received each of the 4 treatments. The duration of each treatment period was 3 weeks with no washout period between treatments. | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 65.57 years STANDARD_DEVIATION 7.96 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 36 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 | 1 / 47 | 4 / 47 | 4 / 46 | 3 / 46 |
| serious Total, serious adverse events | 1 / 47 | 0 / 47 | 0 / 46 | 0 / 46 |
Outcome results
Primary
FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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: Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.155 Liter | Standard Error 0.024 |
| Olo 5 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.209 Liter | Standard Error 0.024 |
| Olo 5 mcg Bid | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.189 Liter | Standard Error 0.024 |
| Olo 10 mcg qd | FEV1 Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.204 Liter | Standard Error 0.024 |
p-value: 0.000395% CI: [0.025, 0.083]Mixed Models Analysis
p-value: 0.158295% CI: [-0.008, 0.05]Mixed Models Analysis
p-value: 0.301195% CI: [-0.014, 0.044]Mixed Models Analysis
p-value: 0.704695% CI: [-0.034, 0.023]Mixed Models Analysis
p-value: 0.024895% CI: [0.004, 0.063]Mixed Models Analysis
Primary
FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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: Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.167 Liter | Standard Error 0.022 |
| Olo 5 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.155 Liter | Standard Error 0.022 |
| Olo 5 mcg Bid | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.201 Liter | Standard Error 0.022 |
| Olo 10 mcg qd | FEV1 Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.149 Liter | Standard Error 0.022 |
p-value: 0.000695% CI: [-0.081, -0.023]Mixed Models Analysis
p-value: 0.001995% CI: [-0.076, -0.017]Mixed Models Analysis
p-value: 0.411195% CI: [-0.041, 0.017]Mixed Models Analysis
p-value: 0.70995% CI: [-0.035, 0.024]Mixed Models Analysis
p-value: 0.021195% CI: [0.005, 0.064]Mixed Models Analysis
Secondary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination
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: 3 weeks
Population: Treated set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olo 2 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Cardiac disorders | 0.0 percentage of participants |
| Olo 2 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Investigations | 0.0 percentage of participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Investigations | 0.0 percentage of participants |
| Olo 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Cardiac disorders | 0.0 percentage of participants |
| Olo 5 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Cardiac disorders | 0.0 percentage of participants |
| Olo 5 mcg Bid | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Investigations | 0.0 percentage of participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Cardiac disorders | 0.0 percentage of participants |
| Olo 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination | Investigations | 0.0 percentage of participants |
Secondary
FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FEV1 AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. 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: Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1,0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.160 Liter | Standard Error 0.022 |
| Olo 5 mcg qd | FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.182 Liter | Standard Error 0.022 |
| Olo 5 mcg Bid | FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.195 Liter | Standard Error 0.022 |
| Olo 10 mcg qd | FEV1 Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.176 Liter | Standard Error 0.022 |
p-value: 0.175395% CI: [-0.045, 0.008]Mixed Models Analysis
p-value: 0.344495% CI: [-0.04, 0.014]Mixed Models Analysis
p-value: 0.116195% CI: [-0.005, 0.049]Mixed Models Analysis
p-value: 0.678995% CI: [-0.033, 0.021]Mixed Models Analysis
p-value: 0.012995% CI: [0.007, 0.062]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (0-12) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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: Day 0: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to planned morning dose on day 1; Day 21: -0:10, 0:30, 1, 2, 3, 4, 6, 8, 10, 11:50 h relative to morning dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.262 Liter | Standard Error 0.043 |
| Olo 5 mcg qd | FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.335 Liter | Standard Error 0.043 |
| Olo 5 mcg Bid | FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.294 Liter | Standard Error 0.043 |
| Olo 10 mcg qd | FVC Area Under Curve 0-12 h (AUC 0-12h) Response After 3 Weeks of Treatment | 0.340 Liter | Standard Error 0.043 |
p-value: 0.091795% CI: [-0.008, 0.099]Mixed Models Analysis
p-value: 0.127395% CI: [-0.012, 0.095]Mixed Models Analysis
p-value: 0.00895% CI: [0.019, 0.127]Mixed Models Analysis
p-value: 0.868395% CI: [-0.049, 0.058]Mixed Models Analysis
p-value: 0.244495% CI: [-0.022, 0.086]Mixed Models Analysis
Secondary
FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (0-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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: Day0:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to planned morning dose on day1, 0:30,1,2,10,11,11:50h relative to planned evening dose on day1; Day21:-0:10,0:30,1,2,3,4,6,8,10,11:50h relative to morning dose,0:30,1,2,10,11,11:50h relative to evening dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.249 Liter | Standard Error 0.041 |
| Olo 5 mcg qd | FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.275 Liter | Standard Error 0.041 |
| Olo 5 mcg Bid | FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.306 Liter | Standard Error 0.041 |
| Olo 10 mcg qd | FVC Area Under Curve 0-24 h (AUC 0-24h) Response After 3 Weeks of Treatment | 0.279 Liter | Standard Error 0.041 |
p-value: 0.329195% CI: [-0.08, 0.027]Mixed Models Analysis
p-value: 0.263895% CI: [-0.084, 0.023]Mixed Models Analysis
p-value: 0.338695% CI: [-0.028, 0.08]Mixed Models Analysis
p-value: 0.887795% CI: [-0.05, 0.057]Mixed Models Analysis
p-value: 0.040295% CI: [0.003, 0.111]Mixed Models Analysis
Secondary
FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment
Response was defined as change from baseline. Baseline FVC AUC (12-24) was defined as the AUC performed on the baseline visit, prior to the first dose of randomized treatment. FVC 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: Day 0: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to planned evening dose on day 1; Day 21: -0:10, 0:30, 1, 2, 10, 11, 11:50 h relative to evening dose
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.239 Liter | Standard Error 0.043 |
| Olo 5 mcg qd | FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.215 Liter | Standard Error 0.043 |
| Olo 5 mcg Bid | FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.318 Liter | Standard Error 0.043 |
| Olo 10 mcg qd | FVC Area Under Curve 12-24 h (AUC 12-24h) Response After 3 Weeks of Treatment | 0.219 Liter | Standard Error 0.043 |
p-value: 0.002395% CI: [-0.162, -0.036]Mixed Models Analysis
p-value: 0.001595% CI: [-0.165, -0.04]Mixed Models Analysis
p-value: 0.450895% CI: [-0.087, 0.039]Mixed Models Analysis
p-value: 0.908795% CI: [-0.059, 0.066]Mixed Models Analysis
p-value: 0.014695% CI: [0.016, 0.142]Mixed Models Analysis
Secondary
Peak FEV1 (0-3h) Response After 3 Weeks
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. Peak FEV1 (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment.
Time frame: Baseline, 3 weeks
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Peak FEV1 (0-3h) Response After 3 Weeks | 0.187 Liter | Standard Error 0.029 |
| Olo 5 mcg qd | Peak FEV1 (0-3h) Response After 3 Weeks | 0.249 Liter | Standard Error 0.029 |
| Olo 5 mcg Bid | Peak FEV1 (0-3h) Response After 3 Weeks | 0.230 Liter | Standard Error 0.029 |
| Olo 10 mcg qd | Peak FEV1 (0-3h) Response After 3 Weeks | 0.242 Liter | Standard Error 0.029 |
p-value: 0.493195% CI: [-0.023, 0.047]Mixed Models Analysis
p-value: 0.259795% CI: [-0.015, 0.054]Mixed Models Analysis
p-value: 0.000695% CI: [0.027, 0.097]Mixed Models Analysis
p-value: 0.657895% CI: [-0.042, 0.027]Mixed Models Analysis
p-value: 0.017595% CI: [0.008, 0.077]Mixed Models Analysis
Secondary
Peak FVC (0-3h) Response After 3 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. Peak FVC (0-3h) values were obtained within 0 - 3 hours after the last dose after three weeks of treatment.
Time frame: Baseline, 3 weeks
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Peak FVC (0-3h) Response After 3 Weeks | 0.325 Liter | Standard Error 0.049 |
| Olo 5 mcg qd | Peak FVC (0-3h) Response After 3 Weeks | 0.417 Liter | Standard Error 0.049 |
| Olo 5 mcg Bid | Peak FVC (0-3h) Response After 3 Weeks | 0.349 Liter | Standard Error 0.049 |
| Olo 10 mcg qd | Peak FVC (0-3h) Response After 3 Weeks | 0.433 Liter | Standard Error 0.049 |
p-value: 0.013395% CI: [0.018, 0.151]Mixed Models Analysis
p-value: 0.04595% CI: [0.002, 0.135]Mixed Models Analysis
p-value: 0.007895% CI: [0.025, 0.159]Mixed Models Analysis
p-value: 0.626895% CI: [-0.05, 0.083]Mixed Models Analysis
p-value: 0.489195% CI: [-0.044, 0.091]Mixed Models Analysis
Secondary
Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours
Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range.
Time frame: 3 weeks
Population: All evaluable subjects. A subject was considered to be not evaluable if the subject had a protocol violation relevant to the evaluation of PK parameters or had insufficient data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | 68.2 ng | Geometric Coefficient of Variation 67.5 |
| Olo 5 mcg qd | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | 115 ng | Geometric Coefficient of Variation 68.8 |
| Olo 5 mcg Bid | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | 177 ng | Geometric Coefficient of Variation 64.8 |
| Olo 10 mcg qd | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 12 Hours | 213 ng | Geometric Coefficient of Variation 70.6 |
Secondary
Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours
Amount of analyte that is eliminated in urine at steady state from the time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range.
Time frame: 3 weeks
Population: All evaluable subjects. A subject was considered to be not evaluable if the subject had a protocol violation relevant to the evaluation of PK parameters or had insufficient data.~This endpoint was only calculated for the two qd dose regimens, therefore the number of patients in the Olo 2 Mcg Bid Arm and the Olo 5 Mcg Bid Arm is 0.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olo 5 mcg qd | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours | 181 ng | Geometric Coefficient of Variation 66.8 |
| Olo 10 mcg qd | Pharmacokinetics (PK): Amount of Analyte That is Eliminated in Urine at Steady State From the Time Point 0 Hours to Time Point 24 Hours | 343 ng | Geometric Coefficient of Variation 65.9 |
Secondary
Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State
Steady state concentration of the analyte in plasma measured at 0.167 hours post dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range.
Time frame: 3 weeks
Population: All evaluable subjects. A subject was considered to be not evaluable if the subject had a protocol violation relevant to the evaluation of PK parameters or had insufficient data. In the Olo 2 mcg Bid Arm, there were only 14 patients with values within the validated concentration range.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olo 5 mcg qd | Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State | 3.52 pg/mL | Geometric Coefficient of Variation 35.9 |
| Olo 5 mcg Bid | Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State | 4.28 pg/mL | Geometric Coefficient of Variation 42 |
| Olo 10 mcg qd | Pharmacokinetics (PK): Concentration of the Analyte in Plasma Measured at 0.167 Hours Post Dosing at Steady State | 5.78 pg/mL | Geometric Coefficient of Variation 62.1 |
Secondary
Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours
Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 12 hours after dosing in week 3 (after the morning dose for the bid dose regimens). The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range.
Time frame: 3 weeks
Population: All evaluable subjects. A subject was considered to be not evaluable if the subject had a protocol violation relevant to the evaluation of PK parameters or had insufficient data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | 3.41 percent | Geometric Coefficient of Variation 67.5 |
| Olo 5 mcg qd | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | 2.29 percent | Geometric Coefficient of Variation 68.8 |
| Olo 5 mcg Bid | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | 3.55 percent | Geometric Coefficient of Variation 64.8 |
| Olo 10 mcg qd | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 12 Hours | 2.13 percent | Geometric Coefficient of Variation 70.6 |
Secondary
Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours
Fraction of analyte eliminated in urine at steady state from time point 0 hours to time point 24 hours after dosing in week 3. The start of inhalation was used as time point 0 for calculation of pharmacokinetic parameters. Descriptive statistics were calculated only if N\>=16 had concentrations within the validated concentration range.
Time frame: 3 weeks
Population: All evaluable subjects. A subject was considered to be not evaluable if the subject had a protocol violation relevant to the evaluation of PK parameters or had insufficient data.~This endpoint was only calculated for the two qd dose regimens, therefore the number of patients in the Olo 2 Mcg Bid Arm and the Olo 5 Mcg Bid Arm is 0.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Olo 5 mcg qd | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours | 3.61 percent | Geometric Coefficient of Variation 66.8 |
| Olo 10 mcg qd | Pharmacokinetics (PK): Fraction of Analyte Eliminated in Urine at Steady State From Time Point 0 Hours to Time Point 24 Hours | 3.43 percent | Geometric Coefficient of Variation 65.9 |
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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment .
Time frame: Baseline, 3 weeks
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Trough FEV1 Response | 0.093 Liter | Standard Error 0.028 |
| Olo 5 mcg qd | Trough FEV1 Response | 0.108 Liter | Standard Error 0.028 |
| Olo 5 mcg Bid | Trough FEV1 Response | 0.129 Liter | Standard Error 0.028 |
| Olo 10 mcg qd | Trough FEV1 Response | 0.087 Liter | Standard Error 0.028 |
p-value: 0.035395% CI: [-0.081, -0.003]Mixed Models Analysis
p-value: 0.287595% CI: [-0.06, 0.018]Mixed Models Analysis
p-value: 0.455395% CI: [-0.024, 0.054]Mixed Models Analysis
p-value: 0.290295% CI: [-0.06, 0.018]Mixed Models Analysis
p-value: 0.073195% CI: [-0.003, 0.075]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. Trough values were the mean of values obtained 23h and 23 h 50 min after the last dose of study drug after three weeks of treatment .
Time frame: Baseline, 3 weeks
Population: Full analysis set (FAS). FAS is defined as all randomised and treated patients with baseline (pre-dose) data and evaluable post-dose data for at least one period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Olo 2 mcg Bid | Trough FVC Response | 0.111 Liter | Standard Error 0.054 |
| Olo 5 mcg qd | Trough FVC Response | 0.177 Liter | Standard Error 0.054 |
| Olo 5 mcg Bid | Trough FVC Response | 0.181 Liter | Standard Error 0.054 |
| Olo 10 mcg qd | Trough FVC Response | 0.162 Liter | Standard Error 0.054 |
p-value: 0.625995% CI: [-0.097, 0.059]Mixed Models Analysis
p-value: 0.91995% CI: [-0.082, 0.074]Mixed Models Analysis
p-value: 0.098595% CI: [-0.012, 0.145]Mixed Models Analysis
p-value: 0.699195% CI: [-0.093, 0.063]Mixed Models Analysis
p-value: 0.080295% CI: [-0.009, 0.149]Mixed Models Analysis