Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the absolute bioavailability of BI 1265162 following administration of oral solution and inhaled (with and without charcoal) via Respimat.
Interventions
DRUGBI 1265162 (T1)
oral solution
DRUGBI 1265162 (T2)
Solution for inhalation
DRUGBI 1265162 (R)
concentrate for i.v. solution
DRUGBI 1265162 (T3)
Solution for inhalation
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood pressure (BP), Pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory * Age of 18 to 50 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * 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 Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (ECG)) deviating from normal and assessed 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 45 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 assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or 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) * Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation) * Intake of an investigational drug in another clinical trial within 60 days of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered * 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 than 30 g per day) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trial * Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial * Inability to comply with the dietary regimen of the trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms) or any other relevant ECG finding at screening * A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome) * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered 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 * A history of chronic kidney disease * Cannot use Respimat® appropriately
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm) | Up to 24 hours following administration of the trial drug, see detailed time frame in the endpoint description. | Area under the concentration-time curve of BI 1265162 in plasma over the time interval from 0 extrapolated to infinity, dose-normalized to 1 µg BI 1265162, (AUC0-∞, norm). Time frame for treatment T1: Within 3 hours before and 30 and 45 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours following administration of the trial drug. Time frame for treatment T2 and T3: Within 3 hours before and 2, 5, 10, 15 and 40 minutes, 1, 2, 4, 8, 10, 12 and 24 hours following administration of the trial drug. Time frame for treatment R: Within 3 hours (h) before and 5, 30 and 59 minutes (min), 1 h 5 min, 1 h 10 min, 1 h 20 min, 1 h 40 min, 2, 2 h 30 min, 3, 3 h 30 min, 4, 5, 7, 9, 11, 13 and 24 hours following administration of the trial drug. |
Countries
Germany
Participant flow
Recruitment details
The trial was performed as a randomized, open-label, 3-way crossover trial followed by a fixed treatment in healthy male subjects in order to compare BI 1265162 given as oral solution (T1) and BI 1265162 inhaled via Respimat® with activated charcoal (T2) and without activated charcoal (fixed treatment, T3) compared with BI 1265162 given intravenously (R).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| (T1-T2-R-T3) Treatment Sequence In this randomized, 3-way crossover trial followed by a fixed treatment participants were randomized to one of 3 possible treatment sequences. Treatments administered were 1.25 milligram (mg) of BI 1265162 as oral solution (5 milliliter (mL) of 0.25 mg/mL) administered orally with 240 mL of water after an overnight fast of at least 8 hours (h) (Test treatment 1, T1), 200 microgram (μg) of BI 1265162 as solution for inhalation (2 actuations of 100 μg) inhaled by Respimat® after an overnight fast of at least 8 h in combination with activated charcoal (Test treatment 2, T2) and without activated charcoal (Fixed treatment, Test treatment 3, T3), 50 μg of BI 1265162 concentrate for infusion (2 mL of 25 μg/mL) administered intravenously over 1 h after an overnight fast of at least 8 h (Reference treatment, R). Each treatment was administered as a single dose and a washout period of at least 6 days was adhered to between drug administrations. | 4 |
| (R-T1-T2-T3) Treatment Sequence In this randomized, 3-way crossover trial followed by a fixed treatment participants were randomized to one of 3 possible treatment sequences. Treatments administered were 1.25 milligram (mg) of BI 1265162 as oral solution (5 milliliter (mL) of 0.25 mg/mL) administered orally with 240 mL of water after an overnight fast of at least 8 hours (h) (Test treatment 1, T1), 200 microgram (μg) of BI 1265162 as solution for inhalation (2 actuations of 100 μg) inhaled by Respimat® after an overnight fast of at least 8 h in combination with activated charcoal (Test treatment 2, T2) and without activated charcoal (Fixed treatment, Test treatment 3, T3), 50 μg of BI 1265162 concentrate for infusion (2 mL of 25 μg/mL) administered intravenously over 1 h after an overnight fast of at least 8 h (Reference treatment, R). Each treatment was administered as a single dose and a washout period of at least 6 days was adhered to between drug administrations. | 4 |
| (T2-R-T1-T3) Treatment Sequence In this randomized, 3-way crossover trial followed by a fixed treatment participants were randomized to one of 3 possible treatment sequences. Treatments administered were 1.25 milligram (mg) of BI 1265162 as oral solution (5 milliliter (mL) of 0.25 mg/mL) administered orally with 240 mL of water after an overnight fast of at least 8 hours (h) (Test treatment 1, T1), 200 microgram (μg) of BI 1265162 as solution for inhalation (2 actuations of 100 μg) inhaled by Respimat® after an overnight fast of at least 8 h in combination with activated charcoal (Test treatment 2, T2) and without activated charcoal (Fixed treatment, Test treatment 3, T3), 50 μg of BI 1265162 concentrate for infusion (2 mL of 25 μg/mL) administered intravenously over 1 h after an overnight fast of at least 8 h (Reference treatment, R). Each treatment was administered as a single dose and a washout period of at least 6 days was adhered to between drug administrations. | 4 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Period 3 + Washout Period 3 | Not treated with BI 1265162 because of Serious Adverse Event in Treatment Period 2 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | (T1-T2-R-T3) Treatment Sequence | (R-T1-T2-T3) Treatment Sequence | (T2-R-T1-T3) Treatment Sequence | Total |
|---|---|---|---|---|
| Age, Continuous | 29.3 years STANDARD_DEVIATION 6.9 | 41.3 years STANDARD_DEVIATION 7.9 | 39.8 years STANDARD_DEVIATION 10.2 | 36.8 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 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 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 1 / 12 | 2 / 12 | 0 / 11 | 1 / 12 |
| serious Total, serious adverse events | 0 / 12 | 1 / 12 | 0 / 11 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm)
Area under the concentration-time curve of BI 1265162 in plasma over the time interval from 0 extrapolated to infinity, dose-normalized to 1 µg BI 1265162, (AUC0-∞, norm). Time frame for treatment T1: Within 3 hours before and 30 and 45 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours following administration of the trial drug. Time frame for treatment T2 and T3: Within 3 hours before and 2, 5, 10, 15 and 40 minutes, 1, 2, 4, 8, 10, 12 and 24 hours following administration of the trial drug. Time frame for treatment R: Within 3 hours (h) before and 5, 30 and 59 minutes (min), 1 h 5 min, 1 h 10 min, 1 h 20 min, 1 h 40 min, 2, 2 h 30 min, 3, 3 h 30 min, 4, 5, 7, 9, 11, 13 and 24 hours following administration of the trial drug.
Time frame: Up to 24 hours following administration of the trial drug, see detailed time frame in the endpoint description.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): All participants who were randomized and treated with at least 1 dose of any trial drug and who provided at least 1 PK endpoint being defined as primary or further and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1265162 as Infusion (R) | Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm) | 44.63 ((hour * millimole) / liter) / kilogram |
| BI 1265162 as Oral Solution (T1) | Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm) | 0.22 ((hour * millimole) / liter) / kilogram |
| BI 1265162 for Inhalation With Activated Charcoal (T2) | Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm) | 17.97 ((hour * millimole) / liter) / kilogram |
| BI 1265162 for Inhalation Without Activated Charcoal (T3) | Area Under the Concentration-time Curve of BI 1265162 in Plasma Over the Time Interval From 0 Extrapolated to Infinity, Dose-normalized, (AUC0-∞, Norm) | 17.96 ((hour * millimole) / liter) / kilogram |
Comparison: Exploratory trial, no formal hypotheses were tested. Analysis of variance (ANOVA) on the logarithmic scale including effects for treatment sequence ('fixed effect'), subjects nested within treatment sequences ('random effect'), and treatment ('fixed effect').90% CI: [0.39, 0.63]Mixed Models Analysis
Comparison: Exploratory trial, no formal hypotheses were tested. Analysis of variance (ANOVA) on the logarithmic scale including effects for treatment sequence ('fixed effect'), subjects nested within treatment sequences ('random effect'), and treatment ('fixed effect').90% CI: [31.68, 51.15]Mixed Models Analysis
Comparison: Exploratory trial, no formal hypotheses were tested. Analysis of variance (ANOVA) on the logarithmic scale including effects for treatment sequence ('fixed effect'), subjects nested within treatment sequences ('random effect'), and treatment ('fixed effect').90% CI: [31.86, 50.83]Mixed Models Analysis