Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the safety and tolerability of BI 1467335 in healthy male and female subjects following oral administration of multiple rising doses over 28 days. Secondary objectives are the exploration of the pharmacokinetics (PK) and target engagement biomarkers of BI 1467335 after multiple dosing.
Interventions
DRUGBI 1467335
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the investigator's assessment, 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 (incl.) * Body mass index (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 * Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion: * Surgically sterilised (including hysterectomy) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of Follicle Stimulating Hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including Blood pressure(BP),Pulse rate (PR) or Electrocardiogram (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 * Used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks before screening and unable to abstain from using these products until study completion * Alcohol abuse (consumption of more than 20 g per day for females and 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/corrected QT (QTc) interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) 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 * Detection of cataract in slit lamp examination * GFR according to CKD-EPI-Formula \< 90 mL/min at screening * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Investigator Defined Drug-related Adverse Events | From first day of study drug administration until 20 days after last dose of study drug administration, up to 48 days. | Number of subjects with investigator defined drug-related adverse events (AEs) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 0:00 hour (h) (within 30 minutes prior to dosing) and 0:15 h, 0:30 h, 0:45 h, 1:00 h, 1:30 h, 2:00 h, 3:00 h, 4:00 h, 6:00 h, 8:00 h, 10:00 h, 12:00 h and 24:00 h after drug administration on Day 1. | Cmax is the maximum measured concentration of BI 1467335 in plasma after administration of the first dose. |
| AUC0-24 | 0:00 hour (h) (within 30 minutes prior to dosing) and 0:15 h, 0:30 h, 0:45 h, 1:00 h, 1:30 h, 2:00 h, 3:00 h, 4:00 h, 6:00 h, 8:00 h, 10:00 h, 12:00 h and 24:00 h after drug administration on Day 1. | AUC0-24 is the area under the concentration-time curve of BI 1467335 in plasma over the time interval from 0 to 24 hours after administration of the first dose. |
| Cmax,28 | 648:00 hours (h) (within 30 minutes prior to dosing) and 648:15 h, 648:30 h, 648:45 h, 649:00h, 649:30 h, 650:00 h, 651:00 h, 652:00 h, 654:00 h, 656:00 h, 658:00 h, 660:00 h, 672:00 h after first drug administration on Day 1. | Cmax,28 is the maximum measured concentration of BI 1467335 in plasma following administration of the 28th dose. |
| AUC0-24,28 | 648:00 hours (h) (within 30 minutes prior to dosing) and 648:15 h, 648:30 h, 648:45 h, 649:00 h, 649:30 h, 650:00 h, 651:00 h, 652:00 h, 654:00 h, 656:00 h, 658:00 h, 660:00 h and 672:00 h after first drug administration on Day 1. | AUC0-24,28 is the area under the concentration-time curve of BI 1467335 in plasma over the time interval from 0 to 24 hours after administration of the 28th dose. |
Countries
Germany
Participant flow
Recruitment details
This was a double-blind, randomised, placebo-controlled within parallel dose groups, multiple dose trial.Only male subjects & postmenopausal or surgically sterilised female subjects were included into trial because at time of trial start-up no data on reproductive toxicology were available.
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 |
|---|---|
| BI 1467335 10 mg (Low Dose) Participants were orally administered 20 ml solution containing 10 mg of BI 1467335: (0.5 mg/ml) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 9 |
| BI 1467335 15 mg (Medium Dose) Participants were orally administered 30 ml solution containing 15 mg of BI 1467335: (0.5 mg/ml) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 9 |
| BI 1467335 20 mg (High Dose) Participants were orally administered 40 ml solution containing 20 mg of BI 1467335: (0.5 mg/ml) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 9 |
| Placebo Participants were orally administered 40 ml solution containing 20 mg of BI 1467335: (0.5 mg/ml) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 9 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawn due laboratory reason concerning neutrophils in agreement with the sponsor | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | BI 1467335 10 mg (Low Dose) | BI 1467335 15 mg (Medium Dose) | BI 1467335 20 mg (High Dose) |
|---|---|---|---|---|---|
| Age, Continuous | 38.7 Years STANDARD_DEVIATION 9.8 | 36.8 Years STANDARD_DEVIATION 8.5 | 39.7 Years STANDARD_DEVIATION 7.9 | 33.8 Years STANDARD_DEVIATION 8 | 35.2 Years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 36 Participants | 9 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 34 Participants | 9 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 28 Participants | 6 Participants | 8 Participants | 8 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 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 7 / 9 | 4 / 9 | 8 / 9 | 7 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Number of Subjects With Investigator Defined Drug-related Adverse Events
Number of subjects with investigator defined drug-related adverse events (AEs) is reported.
Time frame: From first day of study drug administration until 20 days after last dose of study drug administration, up to 48 days.
Population: Treated set (TS): All participants who received at least 1 dose of trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BI 1467335 10 mg (Low Dose) | Number of Subjects With Investigator Defined Drug-related Adverse Events | 3 Participants |
| BI 1467335 15 mg (Medium Dose) | Number of Subjects With Investigator Defined Drug-related Adverse Events | 4 Participants |
| BI 1467335 20 mg (High Dose) | Number of Subjects With Investigator Defined Drug-related Adverse Events | 6 Participants |
| Placebo | Number of Subjects With Investigator Defined Drug-related Adverse Events | 4 Participants |
Secondary
AUC0-24
AUC0-24 is the area under the concentration-time curve of BI 1467335 in plasma over the time interval from 0 to 24 hours after administration of the first dose.
Time frame: 0:00 hour (h) (within 30 minutes prior to dosing) and 0:15 h, 0:30 h, 0:45 h, 1:00 h, 1:30 h, 2:00 h, 3:00 h, 4:00 h, 6:00 h, 8:00 h, 10:00 h, 12:00 h and 24:00 h after drug administration on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS): All participants of the TS who provided at least 1 pharmacokinetic (PK) parameter that was not excluded due to relevant protocol violations or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 mg (Low Dose) | AUC0-24 | 2.34 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 61.2 |
| BI 1467335 15 mg (Medium Dose) | AUC0-24 | 17.0 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 40.6 |
| BI 1467335 20 mg (High Dose) | AUC0-24 | 41.6 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 39.7 |
Comparison: The basic model for the investigation of dose proportionality was a power model. The model consisted of a regression model applied to log-transformed data. The corresponding ANCOVA model included the logarithm of the dose as a covariate. The assumption of a linear relationship between the log-transformed pharmacokinetic endpoint and the log-transformed dose was checked.95% CI: [3.5094, 4.8527]
Secondary
AUC0-24,28
AUC0-24,28 is the area under the concentration-time curve of BI 1467335 in plasma over the time interval from 0 to 24 hours after administration of the 28th dose.
Time frame: 648:00 hours (h) (within 30 minutes prior to dosing) and 648:15 h, 648:30 h, 648:45 h, 649:00 h, 649:30 h, 650:00 h, 651:00 h, 652:00 h, 654:00 h, 656:00 h, 658:00 h, 660:00 h and 672:00 h after first drug administration on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS): All participants of the TS who provided at least 1 pharmacokinetic (PK) parameter that was not excluded due to relevant protocol violations or due to PK non-evaluability. Participants of the Placebo arm were excluded from the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 mg (Low Dose) | AUC0-24,28 | 373 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 143 |
| BI 1467335 15 mg (Medium Dose) | AUC0-24,28 | 1720 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 12.8 |
| BI 1467335 20 mg (High Dose) | AUC0-24,28 | 2940 nanomol*hour/Liter (nmol*h/L) | Geometric Coefficient of Variation 29.5 |
Comparison: The basic model for the investigation of dose proportionality was a power model. The model consisted of a regression model applied to log-transformed data. The corresponding ANCOVA model included the logarithm of the dose as a covariate. The assumption of a linear relationship between the log-transformed pharmacokinetic endpoint and the log-transformed dose was checked.95% CI: [2.0631, 4.0723]
Secondary
Cmax
Cmax is the maximum measured concentration of BI 1467335 in plasma after administration of the first dose.
Time frame: 0:00 hour (h) (within 30 minutes prior to dosing) and 0:15 h, 0:30 h, 0:45 h, 1:00 h, 1:30 h, 2:00 h, 3:00 h, 4:00 h, 6:00 h, 8:00 h, 10:00 h, 12:00 h and 24:00 h after drug administration on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS): All participants of the TS who provided at least 1 pharmacokinetic (PK) parameter that was not excluded due to relevant protocol violations or due to PK non-evaluability. Participants of the Placebo arm were not included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 mg (Low Dose) | Cmax | 1.79 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 45.9 |
| BI 1467335 15 mg (Medium Dose) | Cmax | 9.74 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 30.6 |
| BI 1467335 20 mg (High Dose) | Cmax | 25.0 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 59.5 |
Comparison: The basic model for the investigation of dose proportionality was a power model. The model consisted of a regression model applied to log-transformed data. The corresponding ANCOVA model included the logarithm of the dose as a covariate. The assumption of a linear relationship between the log-transformed pharmacokinetic endpoint and the log-transformed dose was checked.95% CI: [3.2155, 4.4376]
Secondary
Cmax,28
Cmax,28 is the maximum measured concentration of BI 1467335 in plasma following administration of the 28th dose.
Time frame: 648:00 hours (h) (within 30 minutes prior to dosing) and 648:15 h, 648:30 h, 648:45 h, 649:00h, 649:30 h, 650:00 h, 651:00 h, 652:00 h, 654:00 h, 656:00 h, 658:00 h, 660:00 h, 672:00 h after first drug administration on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS): All participants of the TS who provided at least 1 pharmacokinetic (PK) parameter that was not excluded due to relevant protocol violations or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 mg (Low Dose) | Cmax,28 | 72.1 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 71 |
| BI 1467335 15 mg (Medium Dose) | Cmax,28 | 189 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 15.3 |
| BI 1467335 20 mg (High Dose) | Cmax,28 | 255 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 24.6 |
Comparison: The basic model for the investigation of dose proportionality was a power model. The model consisted of a regression model applied to log-transformed data. The corresponding ANCOVA model included the logarithm of the dose as a covariate. The assumption of a linear relationship between the log-transformed pharmacokinetic endpoint and the log-transformed dose was checked.95% CI: [1.2503, 2.5234]