Healthy
Conditions
Brief summary
To investigate safety, tolerability and pharmacokinetics, following single doses of BI 443651
Interventions
DRUGBI 443651
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male according to the investigators assessment, based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 50 years (incl.) * BMI of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) * Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication * Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Alcohol abuse (consumption of more 30 g per day for males) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study * The subject has a diagnosis history of pulmonary hyperreactivity. * Estimated glomerular filtration rate (eGFR) below 80 mL/min
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Drug-related Adverse Events (AEs) | Up to 216 hours. | This outcome measure presents percentage of the subjects with drug-related AEs. The doses ranged from 10 μg to 3600 μg for the outcome measure \[Percentage of subjects with drug-related Adverse Events (AEs)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 1.30 (hours: minutes) hours (h) before drug administration and 0:05h, 0:10h, 0:15h, 0:20h, 0:30h, 0:40h, 0:50h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, 72:00h, 96:00h after drug administration. | This outcome measure presents area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz). Time frame note: The time points 72:00h, 96:00h below was only applicable for highest dose (and corresponding placebo subjects). Two blood sample for stability testing were taken at 3:00h time point from the Treatment C dose group only. The doses ranged from 10 μg to 3600 μg for the outcome measure \[AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point)\]. |
| Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 1.30 (hours: minutes) hours (h) before drug administration and 0:05h, 0:10h, 0:15h, 0:20h, 0:30h, 0:40h, 0:50h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, 72:00h, 96:00h after drug administration. | This outcome measure presents maximum concentration of analyte in plasma (Cmax). Time frame note: The time points 72:00h, 96:00h below was only applicable for highest dose (and corresponding placebo subjects). Two blood sample for stability testing were taken at 3:00h time point from the Treatment C dose group only. The doses ranged from 10 μg to 3600 μg for the outcome measure \[Cmax (maximum measured concentration of the analyte in plasma)\]. |
Countries
Germany
Participant flow
Recruitment details
This trial was performed as a partially randomised, placebo-controlled within parallel dose groups, single-blind trial.
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 randomised to trial drug if any of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects were administered single dose of matching placebo to BI 443651 solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 16 |
| BI 443651 10 μg Subjects were administered single dose of BI 443651 10 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 30 μg Subjects were administered single dose of BI 443651 30 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 100 μg Subjects were administered single dose of BI 443651 100 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 300 μg Subjects were administered single dose of BI 443651 300 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 900 μg Subjects were administered single dose of BI 443651 900 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 5 |
| BI 443651 1800 μg Subjects were administered single dose of BI 443651 1800 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 2700 μg Subjects were administered single dose of BI 443651 2700 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| BI 443651 3600 μg Subjects were administered single dose of BI 443651 3600 μg solution for inhalation per actuation via the RESPIMAT® inhaler orally. | 6 |
| Total | 63 |
Baseline characteristics
| Characteristic | Placebo | BI 443651 10 μg | BI 443651 30 μg | BI 443651 100 μg | BI 443651 300 μg | BI 443651 900 μg | BI 443651 1800 μg | BI 443651 2700 μg | BI 443651 3600 μg | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 33.6 Years STANDARD_DEVIATION 9.3 | 31.0 Years STANDARD_DEVIATION 7.5 | 40.5 Years STANDARD_DEVIATION 7.2 | 26.8 Years STANDARD_DEVIATION 1.9 | 30.3 Years STANDARD_DEVIATION 5.1 | 37.6 Years STANDARD_DEVIATION 8.3 | 31.5 Years STANDARD_DEVIATION 7.8 | 31.7 Years STANDARD_DEVIATION 10 | 31.8 Years STANDARD_DEVIATION 9.7 | 32.8 Years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 63 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 16 | 1 / 6 | 0 / 6 | 0 / 6 | 2 / 6 | 2 / 5 | 3 / 6 | 4 / 6 | 4 / 6 |
| serious Total, serious adverse events | 0 / 16 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Percentage of Subjects With Drug-related Adverse Events (AEs)
This outcome measure presents percentage of the subjects with drug-related AEs. The doses ranged from 10 μg to 3600 μg for the outcome measure \[Percentage of subjects with drug-related Adverse Events (AEs)\].
Time frame: Up to 216 hours.
Population: Treated Set (TS): This subject set includes all subjects from the Randomised Set (RS) who were documented to have taken at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0.0 Percentage of subjects |
| BI 443651 10 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0.0 Percentage of subjects |
| BI 443651 30 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0.0 Percentage of subjects |
| BI 443651 100 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0.0 Percentage of subjects |
| BI 443651 300 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 16.7 Percentage of subjects |
| BI 443651 900 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0.0 Percentage of subjects |
| BI 443651 1800 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 16.7 Percentage of subjects |
| BI 443651 2700 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 66.7 Percentage of subjects |
| BI 443651 3600 μg | Percentage of Subjects With Drug-related Adverse Events (AEs) | 66.7 Percentage of subjects |
Secondary
AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point)
This outcome measure presents area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz). Time frame note: The time points 72:00h, 96:00h below was only applicable for highest dose (and corresponding placebo subjects). Two blood sample for stability testing were taken at 3:00h time point from the Treatment C dose group only. The doses ranged from 10 μg to 3600 μg for the outcome measure \[AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point)\].
Time frame: 1.30 (hours: minutes) hours (h) before drug administration and 0:05h, 0:10h, 0:15h, 0:20h, 0:30h, 0:40h, 0:50h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, 72:00h, 96:00h after drug administration.
Population: Pharmacokinetic Analysis Set (PKS): This subject set includes all subjects from the TS on who received Boehringer Ingelheim (BI) 443651 and who provided at least 1 PK endpoint value that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 24.2 pmol*h/L | Geometric Coefficient of Variation 54.7 |
| BI 443651 10 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 146 pmol*h/L | Geometric Coefficient of Variation 69.4 |
| BI 443651 30 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 506 pmol*h/L | Geometric Coefficient of Variation 42.5 |
| BI 443651 100 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 1860 pmol*h/L | Geometric Coefficient of Variation 54.8 |
| BI 443651 300 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 5680 pmol*h/L | Geometric Coefficient of Variation 57.3 |
| BI 443651 900 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 26400 pmol*h/L | Geometric Coefficient of Variation 49.8 |
| BI 443651 1800 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 39300 pmol*h/L | Geometric Coefficient of Variation 34.3 |
| BI 443651 2700 μg | AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point) | 60700 pmol*h/L | Geometric Coefficient of Variation 43.9 |
95% CI: [1.2242, 1.366]
95% CI: [0.9128, 1.2633]
95% CI: [0.4791, 1.89]
Secondary
Cmax (Maximum Measured Concentration of the Analyte in Plasma)
This outcome measure presents maximum concentration of analyte in plasma (Cmax). Time frame note: The time points 72:00h, 96:00h below was only applicable for highest dose (and corresponding placebo subjects). Two blood sample for stability testing were taken at 3:00h time point from the Treatment C dose group only. The doses ranged from 10 μg to 3600 μg for the outcome measure \[Cmax (maximum measured concentration of the analyte in plasma)\].
Time frame: 1.30 (hours: minutes) hours (h) before drug administration and 0:05h, 0:10h, 0:15h, 0:20h, 0:30h, 0:40h, 0:50h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, 72:00h, 96:00h after drug administration.
Population: Pharmacokinetic Analysis Set (PKS): This subject set includes all subjects from the TS on who received BI 443651 and who provided at least 1 PK endpoint value that was judged as PK evaluable and not affected by protocol violations relevant to the evaluation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 14.1 pmol/L | Geometric Coefficient of Variation 20.7 |
| BI 443651 10 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 58.7 pmol/L | Geometric Coefficient of Variation 81.6 |
| BI 443651 30 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 198 pmol/L | Geometric Coefficient of Variation 35.5 |
| BI 443651 100 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 725 pmol/L | Geometric Coefficient of Variation 41.1 |
| BI 443651 300 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 1700 pmol/L | Geometric Coefficient of Variation 43 |
| BI 443651 900 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 7590 pmol/L | Geometric Coefficient of Variation 60.2 |
| BI 443651 1800 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 14400 pmol/L | Geometric Coefficient of Variation 39.2 |
| BI 443651 2700 μg | Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 19800 pmol/L | Geometric Coefficient of Variation 56.2 |
95% CI: [1.1409, 1.2818]
95% CI: [0.9696, 1.1845]
95% CI: [0.5563, 2.2375]