Asthma
Conditions
Brief summary
The primary objective of this study is to assess the efficacy (bronchoprotection) and safety of single doses of BI 1744 CL inhalation solution (2, 5, 10 and 20 mcg) delivered via the Respimat® inhaler, in patients with intermittent asthma.
Interventions
DRUGPlacebo
Placebo device for comparison
DRUGOlodaterol (BI1744CL)
Olodaterol comparison of low, medium low, medium high and high doses
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of intermittent asthma according to Global Initiative for Asthma criteria 2. Non-smokers or ex-smokers who have not smoked for at least 1 year and have a smoking history of less than 5 pack-years 3. Forced Expiratory Volume in 1second greater than or equal to 80% predicted normal (Visit 1). 4. Bronchial hyperresponsiveness to inhaled methacholine with a provocative concentration of a methacholine causing a 20% fall in Forced Expiratory Volume in one second less than or equal to 8 mg/mL (Visit 1). 5. Be able to perform technically acceptable pulmonary function tests 6. Be able to inhale medication in a competent manner from the Respimat® inhaler 7. Must sign and date an informed consent consistent with International Conference on Harmonisation-Good Clinical Practice guidelines prior to participation in the trial, which includes medication washout and restrictions.
Exclusion criteria
1. Patients with a significant disease other than asthma 2. Patients with seasonal asthma or allergies whose participation in the trial will occur during the season for which they are allergic. 3. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with a serum glutamic oxaloacetic transaminase \> 80 IU/L, serum glutamic pyruvic transaminase \> 80 IU/L, bilirubin \>2.0 mg/dL or creatinine \> 2.0 mg/dL will be excluded regardless of clinical condition 4. Patients with any of the following conditions: a diagnosis of hyperthyrosis or paroxysmal tachycardia (\>100 beats per minute), a marked baseline prolongation of QT/QTc interval, a history of additional risk factors for Torsade de Pointes, a history of myocardial infarction, a diagnosis of clinically relevant cardiac arrhythmia, a history of cor pulmonale, known active tuberculosis, a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the 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, or a history of significant alcohol or drug abuse. 5. Patients who have undergone thoracotomy with pulmonary resection 6. Patients who are being treated with any of the following concomitant medications: medications that prolong the QT/QTc interval, oral beta-adrenergics, beta-blockers or monoamine oxidase inhibitors or tricyclic antidepressants. 7. Patients who have been treated with any respiratory medications (excluding short-acting beta-agonists) for control of their asthma symptoms within 3 months of the Screening Visit (Visit 1). 8. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to Screening Visit (Visit 1). 9. Pregnant or nursing women, or women of childbearing potential not using a highly effective method of birth control.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 24 hours post dose | Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 30 minutes post dose | Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 30 minutes |
| Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 4 hours post dose | Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 4 hours |
| Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 8 hours post dose | Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 8 hours |
| Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 32 hours post dose | Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 32 hours |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | 5 days | 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 (cardiac disorders and investigations). |
| Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Baseline to Visit 6 | Laboratory testing: Average change from baseline of potassium and calcium measured on test-days |
Countries
Canada
Participant flow
Recruitment details
This was a randomised, double-blind, placebo-controlled, 5-way crossover trial. The duration of each treatment period was 1 day with a 14 day washout period between treatments.
Pre-assignment details
One patient was randomized, but the trial was put on hold so that the patient had to be discontinued and re-randomized. This causes a discrepancy between the 32 patients enrolled and the 31 patients reported for the participant flow.
Participants by arm
| Arm | Count |
|---|---|
| Study Total Total number of patients treated in the study. This was a randomised, double-blind, placebo-controlled, 5-way crossover trial. 31 patients were assigned randomly to one of 5 treatment sequences in which they received each of 5 treatments. The duration of each treatment period was 1 day with a 14 day washout period between treatments. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other reasons not listed above | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Study Total |
|---|---|
| Age, Continuous | 28.9 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 29 | 1 / 28 | 1 / 28 | 1 / 30 | 4 / 29 |
| serious Total, serious adverse events | 0 / 29 | 0 / 28 | 0 / 28 | 0 / 30 | 0 / 29 |
Outcome results
Primary
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 24 hours
Time frame: 24 hours post dose
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and post-dose data for at least two periods for the same endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 0.793 Log base 2 (mg/ml) | Standard Error 0.182 |
| Olodaterol (Olo) 2 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 1.950 Log base 2 (mg/ml) | Standard Error 0.186 |
| Olodaterol (Olo) 5 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 2.504 Log base 2 (mg/ml) | Standard Error 0.19 |
| Olodaterol (Olo) 10 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 3.236 Log base 2 (mg/ml) | Standard Error 0.179 |
| Olodaterol (Olo) 20 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 24 Hours | 3.777 Log base 2 (mg/ml) | Standard Error 0.183 |
p-value: <0.000195% CI: [0.657, 1.657]Mixed Models Analysis
p-value: <0.000195% CI: [1.205, 2.217]Mixed Models Analysis
p-value: <0.000195% CI: [1.952, 2.935]Mixed Models Analysis
p-value: <0.000195% CI: [2.486, 3.483]Mixed Models Analysis
Secondary
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 30 minutes
Time frame: 30 minutes post dose
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and post-dose data for at least two periods for the same endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 0.393 Log base 2 (mg/ml) | Standard Error 0.18 |
| Olodaterol (Olo) 2 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 2.532 Log base 2 (mg/ml) | Standard Error 0.184 |
| Olodaterol (Olo) 5 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 3.029 Log base 2 (mg/ml) | Standard Error 0.187 |
| Olodaterol (Olo) 10 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 3.953 Log base 2 (mg/ml) | Standard Error 0.177 |
| Olodaterol (Olo) 20 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 30 Minutes | 4.617 Log base 2 (mg/ml) | Standard Error 0.181 |
p-value: <0.000195% CI: [1.645, 2.633]Mixed Models Analysis
p-value: <0.000195% CI: [2.135, 3.136]Mixed Models Analysis
p-value: <0.000195% CI: [3.074, 4.046]Mixed Models Analysis
p-value: <0.000195% CI: [3.731, 4.717]Mixed Models Analysis
Secondary
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 32 hours
Time frame: 32 hours post dose
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and post-dose data for at least two periods for the same endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 0.960 Log base 2 (mg/ml) | Standard Error 0.2 |
| Olodaterol (Olo) 2 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 2.189 Log base 2 (mg/ml) | Standard Error 0.2 |
| Olodaterol (Olo) 5 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 2.785 Log base 2 (mg/ml) | Standard Error 0.203 |
| Olodaterol (Olo) 10 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 3.074 Log base 2 (mg/ml) | Standard Error 0.192 |
| Olodaterol (Olo) 20 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 32 Hours | 3.605 Log base 2 (mg/ml) | Standard Error 0.197 |
p-value: <0.000195% CI: [0.692, 1.766]Mixed Models Analysis
p-value: <0.000195% CI: [1.281, 2.369]Mixed Models Analysis
p-value: <0.000195% CI: [1.578, 2.65]Mixed Models Analysis
p-value: <0.000195% CI: [2.11, 3.181]Mixed Models Analysis
Secondary
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 4 hours
Time frame: 4 hours post dose
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and post-dose data for at least two periods for the same endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 0.577 Log base 2 (mg/ml) | Standard Error 0.214 |
| Olodaterol (Olo) 2 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 2.602 Log base 2 (mg/ml) | Standard Error 0.219 |
| Olodaterol (Olo) 5 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 2.957 Log base 2 (mg/ml) | Standard Error 0.223 |
| Olodaterol (Olo) 10 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 4.126 Log base 2 (mg/ml) | Standard Error 0.211 |
| Olodaterol (Olo) 20 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 4 Hours | 4.786 Log base 2 (mg/ml) | Standard Error 0.215 |
p-value: <0.000195% CI: [1.437, 2.613]Mixed Models Analysis
p-value: <0.000195% CI: [1.785, 2.975]Mixed Models Analysis
p-value: <0.000195% CI: [2.971, 4.127]Mixed Models Analysis
p-value: <0.000195% CI: [3.622, 4.794]Mixed Models Analysis
Secondary
Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours
Provocative concentration of methacholine required to produce a 20% decrease in FEV1 (PC20FEV1) at 8 hours
Time frame: 8 hours post dose
Population: Full analysis set (FAS). FAS is defined as all patients that were randomised, received treatment and had baseline data and post-dose data for at least two periods for the same endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 0.576 Log base 2 (mg/ml) | Standard Error 0.213 |
| Olodaterol (Olo) 2 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 2.484 Log base 2 (mg/ml) | Standard Error 0.218 |
| Olodaterol (Olo) 5 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 3.050 Log base 2 (mg/ml) | Standard Error 0.222 |
| Olodaterol (Olo) 10 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 3.903 Log base 2 (mg/ml) | Standard Error 0.21 |
| Olodaterol (Olo) 20 mcg qd | Adjusted Mean of Provocative Concentration of Methacholine Required to Produce a 20% Decrease in FEV1 (PC20FEV1) at 8 Hours | 4.796 Log base 2 (mg/ml) | Standard Error 0.214 |
p-value: <0.000195% CI: [1.322, 2.492]Mixed Models Analysis
p-value: <0.000195% CI: [1.822, 3.066]Mixed Models Analysis
p-value: <0.000195% CI: [2.752, 3.902]Mixed Models Analysis
p-value: <0.000195% CI: [3.637, 4.803]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 (cardiac disorders and investigations).
Time frame: 5 days
Population: The safety set included all patients who received any study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Cardiac disorders | 0 percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0 percentage of participants |
| Olodaterol (Olo) 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Cardiac disorders | 0 percentage of participants |
| Olodaterol (Olo) 2 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0 percentage of participants |
| Olodaterol (Olo) 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Cardiac disorders | 0 percentage of participants |
| Olodaterol (Olo) 5 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0 percentage of participants |
| Olodaterol (Olo) 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0 percentage of participants |
| Olodaterol (Olo) 10 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Cardiac disorders | 0 percentage of participants |
| Olodaterol (Olo) 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Cardiac disorders | 0 percentage of participants |
| Olodaterol (Olo) 20 mcg qd | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG | Investigations | 0 percentage of participants |
Secondary
Laboratory Testing: Average Change From Baseline of Potassium and Calcium
Laboratory testing: Average change from baseline of potassium and calcium measured on test-days
Time frame: Baseline to Visit 6
Population: All patients in the Safety set who have a baseline value and post dose values for each planned time.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Potassium | 1.01 mmol/L |
| Placebo | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Calcium | 1.00 mmol/L |
| Olodaterol (Olo) 2 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Potassium | 1.04 mmol/L |
| Olodaterol (Olo) 2 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Calcium | 1.01 mmol/L |
| Olodaterol (Olo) 5 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Potassium | 1.02 mmol/L |
| Olodaterol (Olo) 5 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Calcium | 1.00 mmol/L |
| Olodaterol (Olo) 10 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Calcium | 1.00 mmol/L |
| Olodaterol (Olo) 10 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Potassium | 1.00 mmol/L |
| Olodaterol (Olo) 20 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Potassium | 0.98 mmol/L |
| Olodaterol (Olo) 20 mcg qd | Laboratory Testing: Average Change From Baseline of Potassium and Calcium | Calcium | 1.01 mmol/L |