Healthy
Conditions
Brief summary
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 706321 in healthy male and female subjects following oral administration of multiple rising doses for 14 days.
Interventions
DRUGBI 703621
BI 703621
DRUGPlacebo
Placebo
DRUGMidazolam
Midazolam
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 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female 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), temperature), 12-lead electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 55 years (inclusive, at screening) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive, at screening) * Signed and dated written informed consent prior to admission to the study, in accordance with GCP and local legislation
Exclusion criteria
* Any finding in the medical examination (including BP, PR, temperature or 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 45 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 30 days (or 5 half-lives (whichever longer)) of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered * Smoker of more than 10 cigarettes or 3 cigars or 3 pipes per day * Inability to refrain from smoking while in-house stay * Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males), and unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior to the trial medication administration and until Day 7 post trial medication administration. * 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 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 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 * ALT (alanine transaminase), AST (aspartate transaminase), or creatinine exceed upper limit of normal range at screening, confirmed by a repeat test * hemoglobin (Hb), platelets and neutrophils below lower limit of normal range at screening, confirmed by a repeat test * Positive result for human immunoinsufficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection at screening. * History of tuberculosis (TB) or positive finding in interferon-gamma release assay (IGRA). Female subjects will not be allowed to participate, if any of the following apply: * Not surgically sterilised or not postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with simultaneous levels of FSH above 30 U/L and estradiol below 20 ng/L is confirmatory) * Positive pregnancy test * Lactation Male subjects will not be allowed to participate, if any of the following apply: \- Male subjects with women of childbearing potential (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from time point of administration of trial medication until 30 days thereafter. Sperm donation is not allowed from the time point of drug administration until 30 days thereafter.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Drug-related Adverse Events | From first administration of study drug until 8 days after the last dosing, up to 27 days. | Number of subjects with drug-related adverse events is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h, 456h after dosing on Day 1. | Area under the concentration-time curve of BI 706321 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose. |
| Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1. | Maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose. |
| Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1. | Minimum concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmin,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose. |
| Accumulation Ratio Based on Cmax,ss (RA,Cmax) | Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1. | Accumulation ratio (RA) based on maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss), (RA,Cmax) is presented. RA,cmax = Cmax,ss \[nmol/L\]/ Cmax,1 \[nmol/l\], and the unit of measure is hence unitless. |
| Accumulation Ratio Based on AUC0-τ (RA,AUC) | Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1. | Accumulation ratio (RA) based on area under the concentration-time curve of BI 706321 in plasma after repeated doses over the time interval from τ (AUC0-τ), (RA,AUC) is presented with a dosing interval τ of 24 hours. RA, AUC= AUC tau, ss \[h\*nmol/L\]/ AUC tau,1 \[h\*nmol/L\]; hence the unit of measure is unitless. |
Countries
Belgium
Participant flow
Recruitment details
This is a double-blind, randomised, placebo-controlled, parallel group design trial in order to investigate safety, tolerability, and pharmacokinetics of BI 706321 in healthy male and female subjects following oral administration of multiple rising doses for 14 days.
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 |
|---|---|
| Placebo Subjects were orally administered a single daily dose of matching placebo to BI 706321 capsules on Day 1 and from Day 6 to 19. Three out of the seven subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h). | 7 |
| 2 mg BI 706321 Subjects were orally administered a single daily dose of 2 x 1 capsule of 1 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| 5 mg BI 706321 Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| 8 mg BI 706321 + 75 ug Midazolam Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) and 3 capsules of 1 mg of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h). | 8 |
| 10 mg BI 706321+ 75 ug Midazolam Subjects were orally administered a single daily dose of 2 capsules of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h). | 8 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 5 mg BI 706321 | 8 mg BI 706321 + 75 ug Midazolam | 10 mg BI 706321+ 75 ug Midazolam | Placebo | 2 mg BI 706321 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 46.4 Years STANDARD_DEVIATION 8.9 | 42.5 Years STANDARD_DEVIATION 7.4 | 44.8 Years STANDARD_DEVIATION 7.6 | 39.4 Years STANDARD_DEVIATION 8.7 | 49.1 Years STANDARD_DEVIATION 6.7 | 44.6 Years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 8 Participants | 6 Participants | 8 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 8 Participants | 6 Participants | 8 Participants | 38 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 8 Participants | 7 Participants | 6 Participants | 35 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 | 0 / 7 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 1 / 7 | 3 / 8 | 5 / 8 | 6 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Number of Subjects With Drug-related Adverse Events
Number of subjects with drug-related adverse events is presented.
Time frame: From first administration of study drug until 8 days after the last dosing, up to 27 days.
Population: Treated set (TS): The TS included all subjects who were randomised and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the subjects received. The TS was used for safety analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With Drug-related Adverse Events | 0 Participants |
| 2 mg BI 706321 | Number of Subjects With Drug-related Adverse Events | 1 Participants |
| 5 mg BI 706321 | Number of Subjects With Drug-related Adverse Events | 0 Participants |
| 8 mg BI 706321 + 75 ug Midazolam | Number of Subjects With Drug-related Adverse Events | 0 Participants |
| 10 mg BI 706321+ 75 ug Midazolam | Number of Subjects With Drug-related Adverse Events | 0 Participants |
Secondary
Accumulation Ratio Based on AUC0-τ (RA,AUC)
Accumulation ratio (RA) based on area under the concentration-time curve of BI 706321 in plasma after repeated doses over the time interval from τ (AUC0-τ), (RA,AUC) is presented with a dosing interval τ of 24 hours. RA, AUC= AUC tau, ss \[h\*nmol/L\]/ AUC tau,1 \[h\*nmol/L\]; hence the unit of measure is unitless.
Time frame: Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS):~This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Accumulation Ratio Based on AUC0-τ (RA,AUC) | 2.30 Untiless | Geometric Coefficient of Variation 33.3 |
| 2 mg BI 706321 | Accumulation Ratio Based on AUC0-τ (RA,AUC) | 2.76 Untiless | Geometric Coefficient of Variation 20.8 |
| 5 mg BI 706321 | Accumulation Ratio Based on AUC0-τ (RA,AUC) | 3.69 Untiless | Geometric Coefficient of Variation 23.9 |
| 8 mg BI 706321 + 75 ug Midazolam | Accumulation Ratio Based on AUC0-τ (RA,AUC) | 3.58 Untiless | Geometric Coefficient of Variation 19.8 |
Secondary
Accumulation Ratio Based on Cmax,ss (RA,Cmax)
Accumulation ratio (RA) based on maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss), (RA,Cmax) is presented. RA,cmax = Cmax,ss \[nmol/L\]/ Cmax,1 \[nmol/l\], and the unit of measure is hence unitless.
Time frame: Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS):~This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Accumulation Ratio Based on Cmax,ss (RA,Cmax) | 2.00 Unitless | Geometric Coefficient of Variation 27.7 |
| 2 mg BI 706321 | Accumulation Ratio Based on Cmax,ss (RA,Cmax) | 2.28 Unitless | Geometric Coefficient of Variation 23.1 |
| 5 mg BI 706321 | Accumulation Ratio Based on Cmax,ss (RA,Cmax) | 3.29 Unitless | Geometric Coefficient of Variation 24.5 |
| 8 mg BI 706321 + 75 ug Midazolam | Accumulation Ratio Based on Cmax,ss (RA,Cmax) | 3.34 Unitless | Geometric Coefficient of Variation 15.2 |
Secondary
Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)
Area under the concentration-time curve of BI 706321 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Time frame: From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h, 456h after dosing on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS):~This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 88.1 hour(h)*nanomole(nmol)/Litre (L) | Geometric Coefficient of Variation 34.5 |
| 2 mg BI 706321 | Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 235 hour(h)*nanomole(nmol)/Litre (L) | Geometric Coefficient of Variation 34.8 |
| 5 mg BI 706321 | Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 517 hour(h)*nanomole(nmol)/Litre (L) | Geometric Coefficient of Variation 30 |
| 8 mg BI 706321 + 75 ug Midazolam | Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 574 hour(h)*nanomole(nmol)/Litre (L) | Geometric Coefficient of Variation 35.6 |
Secondary
Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)
Maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Time frame: From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS):~This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 5.69 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 41.8 |
| 2 mg BI 706321 | Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 14.7 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 43.1 |
| 5 mg BI 706321 | Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 34.7 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 38.5 |
| 8 mg BI 706321 + 75 ug Midazolam | Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 39.9 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 35.7 |
Secondary
Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss)
Minimum concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmin,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Time frame: From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.
Population: Pharmacokinetic parameter analysis set (PKS):~This set included all subjects in the treated set (TS) who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 2.84 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 31 |
| 2 mg BI 706321 | Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 7.29 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 34.1 |
| 5 mg BI 706321 | Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 15.2 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 28.3 |
| 8 mg BI 706321 + 75 ug Midazolam | Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 17.3 nanomole(nmol)/Litre(L) | Geometric Coefficient of Variation 35.5 |