Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The main objective of the current trial is to investigate safety, tolerability, pharmacokinetics and effect on inflammation of oral BI 1026706 administered twice daily for 4 weeks in patients with COPD.
Interventions
DRUGBI 1026706
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent consistent with ICH-Good Clinical Practice (GCP) guidelines and local legislation prior to participation in the trial. Medication washout and medication restrictions are allowed only after signed informed consent is obtained. * Males or females not of childbearing potential between 40 and 80 years (each inclusive) of age, on the day of patient´s signature of informed consent. * All patients must have a documented diagnosis of COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD). * Post-bronchodilator forced expiratory volume (FEV)1 of \>=40% and \<=90% of predicted normal at Visit 1 * Post-bronchodilator FEV1/forced vital capacity (FVC) \<70% at Visit 1 * Patients must be current or ex-smokers with a smoking history of more than 10 pack years * Patients on stable respiratory medications for at least 6 weeks prior to randomization (Visit 3). * Patients must be able to perform technically acceptable pulmonary function tests.
Exclusion criteria
* Significant pulmonary disease other than COPD or other medical conditions as determined by medical history, examination, and clinical investigations at screening that may, in the opinion of the investigator, result in the any of the following: 1. Put the patient at risk because of participation in the study 2. Influence the results of the study 3. Cast doubt on the patients ability to participate in the study * Patients with current asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. * Patients with clinically relevant abnormal hematology, blood chemistry, or urinalysis at the screening visit (Visit 1), if the abnormality indicates a relevant disease as defined in exclusion criterion number 1. Safety laboratory screening evaluation (Visit 1) can be repeated a maximum of two times. * Patients with a history of myocardial infarction or apoplexy within 6 months of the screening visit (Visit 1) or between the screening visit (Visit 1) and randomization. * Patients with a history of and/or active life-threatening cardiac arrhythmia, as assessed by the investigator. * Patients with a marked baseline prolongation of QT/QTcB interval (such as repeated demonstration of a QTcB interval \>450 ms), pulse/heart rate outside 50 to 90 bpm at Visit 1 (if confirmed by pulse rate measurement over 60 seconds), or any other relevant ECG finding. * Patients with a history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome). * Patients with known active tuberculosis. * Patients with clinically relevant bronchiectasis, as assessed by the investigator. * Patients with any respiratory infection (such as common cold, acute sinusitis, or similar illnesses) or COPD exacerbation within 6 weeks prior to the screening visit (Visit 1) or between the screening visit and randomization. * Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1). * Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed to participate. * Patients with a history of and/or active significant alcohol or drug abuse as assessed by the investigator. * Patients who are being treated with non-permitted concomitant medication. * Patients who have taken an investigational drug within 4 weeks prior to Visit 1 or if screening occurs within six half-lives of intake of another investigational drug (whichever is greater). * Patients with surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication as assessed by the investigator. * Patients with veins unsuited for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator. * Patients who are unable to comply with the dietary regimen. * Patients who have been previously randomized in this study. * Patients who have donated more than 100 mL blood in the 4 weeks prior to Visit 1 and between Visit 1 and Visit 3 or patients who have the intention to donate blood between Visit 3 and four weeks after the end of trial visit. * Patients who are pregnant or breastfeeding * Male patients who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until 3 months after the trial medication treatment has finished. * Patient is assessed as unsuitable for inclusion by the investigator; for instance, because he or she is not considered to comply with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period. | From first drug administration until 4 days after last drug administration, up to 32 days | Safety and tolerability of BI 1026706, as assessed by frequency (in percent) of patients with treatment-emergent adverse events (TEAEs) over the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 1026706 in Plasma (Cmax) After the First Dose (Morning of Day 1) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Maximum measured concentration of BI 1026706 in plasma (Cmax) after the first dose (morning of Day 1) |
| Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax) After the First Dose (Morning of Day 1) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Time from dosing to maximum concentration of BI 1026706 in plasma (Tmax) after the first dose (morning of Day 1) |
| Area Under the Concentration-time Curve of BI 1026706 in Plasma (AUC 0-12h) After the First Dose (Morning of Day 1) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Area under the concentration-time curve of BI 1026706 in plasma (AUC 0-12h) after the first dose (morning of Day 1) |
| Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period | 28 days | Change in Absolute Number of Neutrophil in Sputum at the end of the planned treatment period |
| Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax, ss) After the Last Dose (Morning of Day 28) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Time from dosing to maximum concentration of BI 1026706 in plasma (Tmax, ss) after the last dose (morning of Day 28) |
| Area Under the Concentration-time Curve of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUC Tau, ss) After the Last Dose (Morning of Day 28) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Area under the concentration-time curve of BI 1026706 in plasma at steady state over a uniform dosing interval tau (AUC tau, ss) after the last dose (morning of Day 28) |
| Maximum Measured Concentration of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (Cmax, ss) After the Last Dose (Morning of Day 28) | -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration. | Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval tau (Cmax, ss) after the last dose (morning of Day 28) |
Countries
Denmark, Germany, Sweden, United Kingdom
Participant flow
Recruitment details
Double dummy trial, 2 different type of medication were dispensed to the patient with the help of two different bottles: Bottle 1 - 5 mg OR 25 mg BI 1026706 tablets or placebo tablets matching 5 mg and 25 mg BI 1026706 tablets, Bottle 2 -100 mg tablets or Placebo tablets matching 100 mg BI 1026706 tablets.
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be entered in to the trial if any of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients received one placebo tablet (twice daily (BID) matching the 5 and 25 milligram (mg) tablets and one placebo tablet matching the 100 mg tablet orally with water with or without food (except on the morning of Days 1 and 28 when patients were to fast overnight for at least 8 hours before administration of trial medication) for 28 days, with end-of-trial visit 5 to 10 days after last administration of trial medication. In the twice daily (BID) dosing regimen, the patient had to take 2 tablets in the morning and 2 tablets in the evening. | 30 |
| 5 Milligram BI 1026706 Patients received BI 1026706 (5 milligram (mg) twice daily (BID) along with placebo matching the 100 mg tablet) film-coated tablet administered orally with water with or without food (except on the morning of Days 1 and 28 when patients were to fast overnight for at least 8 hours before administration of trial medication) for 28 days, with end-of-trial visit 5 to 10 days after last administration of trial medication. | 30 |
| 25 Milligram BI 1026706 Patients received BI 1026706 (25 milligram (mg) twice daily (BID) along with placebo matching the 100 mg tablet) film-coated tablet administered orally with water with or without food (except on the morning of Days 1 and 28 when patients were to fast overnight for at least 8 hours before administration of trial medication) for 28 days, with end-of-trial visit 5 to 10 days after last administration of trial medication. | 30 |
| 100 Milligram BI 1026706 Patients received BI 1026706 (100 milligram (mg) twice daily (BID) along with placebo matching the 5 and 25 mg tablets) film-coated tablet administered orally with water with or without food (except on the morning of Days 1 and 28 when patients were to fast overnight for at least 8 hours before administration of trial medication) for 28 days, with end-of-trial visit 5 to 10 days after last administration of trial medication. | 30 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | 5 Milligram BI 1026706 | 25 Milligram BI 1026706 | 100 Milligram BI 1026706 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 8.5 | 65.7 Years STANDARD_DEVIATION 7.2 | 65.3 Years STANDARD_DEVIATION 6.1 | 62.5 Years STANDARD_DEVIATION 7.1 | 64.3 Years STANDARD_DEVIATION 7.3 |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 11 Participants | 10 Participants | 41 Participants |
| Sex: Female, Male Male | 19 Participants | 21 Participants | 19 Participants | 20 Participants | 79 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 | 16 / 30 | 12 / 30 | 13 / 30 | 10 / 30 |
| serious Total, serious adverse events | 0 / 30 | 1 / 30 | 2 / 30 | 0 / 30 |
Outcome results
Primary
Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period.
Safety and tolerability of BI 1026706, as assessed by frequency (in percent) of patients with treatment-emergent adverse events (TEAEs) over the treatment period.
Time frame: From first drug administration until 4 days after last drug administration, up to 32 days
Population: Treated set (TS): The TS included all patients who were randomized and treated with at least 1 dose of trial medication. The treatment assignment was determined based on the first treatment the patient received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period. | 60.0 Percentage of Patients |
| 5 Milligram BI 1026706 | Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period. | 46.7 Percentage of Patients |
| 25 Milligram BI 1026706 | Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period. | 66.7 Percentage of Patients |
| 100 Milligram BI 1026706 | Safety and Tolerability of BI 1026706, as Assessed by Frequency (in Percent) of Patients With Treatment Emergent Adverse Events (TEAEs) Over the Treatment Period. | 53.3 Percentage of Patients |
Secondary
Area Under the Concentration-time Curve of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUC Tau, ss) After the Last Dose (Morning of Day 28)
Area under the concentration-time curve of BI 1026706 in plasma at steady state over a uniform dosing interval tau (AUC tau, ss) after the last dose (morning of Day 28)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: ePKS including participants with available data for this endpoint
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUC Tau, ss) After the Last Dose (Morning of Day 28) | 197 nmol*h/L | Geometric Coefficient of Variation 47.1 |
| 5 Milligram BI 1026706 | Area Under the Concentration-time Curve of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUC Tau, ss) After the Last Dose (Morning of Day 28) | 781 nmol*h/L | Geometric Coefficient of Variation 40.7 |
| 25 Milligram BI 1026706 | Area Under the Concentration-time Curve of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (AUC Tau, ss) After the Last Dose (Morning of Day 28) | 3850 nmol*h/L | Geometric Coefficient of Variation 34.3 |
Secondary
Area Under the Concentration-time Curve of BI 1026706 in Plasma (AUC 0-12h) After the First Dose (Morning of Day 1)
Area under the concentration-time curve of BI 1026706 in plasma (AUC 0-12h) after the first dose (morning of Day 1)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: ePKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve of BI 1026706 in Plasma (AUC 0-12h) After the First Dose (Morning of Day 1) | 138 nanomoles (nmol) * hour (h) / litre (L) | Geometric Coefficient of Variation 58.2 |
| 5 Milligram BI 1026706 | Area Under the Concentration-time Curve of BI 1026706 in Plasma (AUC 0-12h) After the First Dose (Morning of Day 1) | 489 nanomoles (nmol) * hour (h) / litre (L) | Geometric Coefficient of Variation 44.4 |
| 25 Milligram BI 1026706 | Area Under the Concentration-time Curve of BI 1026706 in Plasma (AUC 0-12h) After the First Dose (Morning of Day 1) | 1840 nanomoles (nmol) * hour (h) / litre (L) | Geometric Coefficient of Variation 42.7 |
Secondary
Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period
Change in Absolute Number of Neutrophil in Sputum at the end of the planned treatment period
Time frame: 28 days
Population: Treated set including participants with available data for the endpoint percent change in absolute number of neutrophil in sputum at the end of the planned treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period | 2.12 10^6 cells/ milliliter (mL) | Standard Error 0.47 |
| 5 Milligram BI 1026706 | Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period | 3.37 10^6 cells/ milliliter (mL) | Standard Error 0.79 |
| 25 Milligram BI 1026706 | Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period | 3.35 10^6 cells/ milliliter (mL) | Standard Error 0.73 |
| 100 Milligram BI 1026706 | Change in Absolute Number of Neutrophil in Sputum at the End of the Planned Treatment Period | 3.06 10^6 cells/ milliliter (mL) | Standard Error 0.66 |
Comparison: Adjusted means were calculated by exponentiating Least Square (LS) means of corresponding values obtained from fitting an ANCOVA model to the natural log transformed endpoint variable, including treatment effect and study baseline as covariates, and adjusting for stratification factors (extensive pharmacokinetic (PK) sub-study participation and Multiple-breath washout (MBW) sub-study participation)p-value: 0.15490% CI: [0.93, 2.72]ANCOVA
Comparison: The adjusted means were calculated by exponentiating the LS means of the corresponding values obtained from fitting an ANCOVA model to the natural log transformed endpoint variable, including treatment effect and study baseline as covariates, and adjusting for stratification factors (extensive PK sub-study participation and MBW sub-study participation)p-value: 0.14390% CI: [0.94, 2.65]ANCOVA
Comparison: The adjusted means were calculated by exponentiating the LS means of the corresponding values obtained from fitting an ANCOVA model to the natural log transformed endpoint variable, including treatment effect and study baseline as covariates, and adjusting for stratification factors (extensive PK sub-study participation and MBW sub-study participation)p-value: 0.239890% CI: [0.86, 2.41]ANCOVA
Secondary
Maximum Measured Concentration of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (Cmax, ss) After the Last Dose (Morning of Day 28)
Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval tau (Cmax, ss) after the last dose (morning of Day 28)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: ePKS including participants with available data for this endpoint
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (Cmax, ss) After the Last Dose (Morning of Day 28) | 51.2 nmol/L | Geometric Coefficient of Variation 26.4 |
| 5 Milligram BI 1026706 | Maximum Measured Concentration of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (Cmax, ss) After the Last Dose (Morning of Day 28) | 185 nmol/L | Geometric Coefficient of Variation 34.7 |
| 25 Milligram BI 1026706 | Maximum Measured Concentration of BI 1026706 in Plasma at Steady State Over a Uniform Dosing Interval Tau (Cmax, ss) After the Last Dose (Morning of Day 28) | 870 nmol/L | Geometric Coefficient of Variation 37.9 |
Secondary
Maximum Measured Concentration of BI 1026706 in Plasma (Cmax) After the First Dose (Morning of Day 1)
Maximum measured concentration of BI 1026706 in plasma (Cmax) after the first dose (morning of Day 1)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: Extensive pharmacokinetic set (ePKS): The ePKS included all patients in the PKS who signed the informed consent for participating in the extensive PK sub-study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration of BI 1026706 in Plasma (Cmax) After the First Dose (Morning of Day 1) | 39.0 nanomoles (nmol) / litre (L) | Geometric Coefficient of Variation 47.7 |
| 5 Milligram BI 1026706 | Maximum Measured Concentration of BI 1026706 in Plasma (Cmax) After the First Dose (Morning of Day 1) | 145 nanomoles (nmol) / litre (L) | Geometric Coefficient of Variation 37.8 |
| 25 Milligram BI 1026706 | Maximum Measured Concentration of BI 1026706 in Plasma (Cmax) After the First Dose (Morning of Day 1) | 524 nanomoles (nmol) / litre (L) | Geometric Coefficient of Variation 39 |
Secondary
Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax) After the First Dose (Morning of Day 1)
Time from dosing to maximum concentration of BI 1026706 in plasma (Tmax) after the first dose (morning of Day 1)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: ePKS
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax) After the First Dose (Morning of Day 1) | 1.00 hour | Full Range 47.7 |
| 5 Milligram BI 1026706 | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax) After the First Dose (Morning of Day 1) | 1.02 hour | Full Range 37.8 |
| 25 Milligram BI 1026706 | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax) After the First Dose (Morning of Day 1) | 1.00 hour | Full Range 39 |
Secondary
Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax, ss) After the Last Dose (Morning of Day 28)
Time from dosing to maximum concentration of BI 1026706 in plasma (Tmax, ss) after the last dose (morning of Day 28)
Time frame: -0:10 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, and 12:00h after drug administration.
Population: ePKS including participants with available data for this endpoint
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax, ss) After the Last Dose (Morning of Day 28) | 1.00 hour | Full Range 26.4 |
| 5 Milligram BI 1026706 | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax, ss) After the Last Dose (Morning of Day 28) | 1.50 hour | Full Range 34.7 |
| 25 Milligram BI 1026706 | Time From Dosing to Maximum Concentration of BI 1026706 in Plasma (Tmax, ss) After the Last Dose (Morning of Day 28) | 0.767 hour | Full Range 37.9 |