Healthy
Conditions
Brief summary
The primary objectives of this trial are to investigate safety and tolerability of BI 1595043 in healthy male subjects following administration of multiple rising doses over 14 days. Secondary objectives are the exploration of pharmacokinetics (PK) of BI 1595043 after single and multiple dosing.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
As this is a Multiple Rising Dose (MRD) trial, blinded individuals will be aware of the current dose level. All individuals are unblinded regarding the midazolam administration.
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), body temperature), 12-lead electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 50 years (inclusive) * 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 * Male subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication until 30 days after trial completion: * Use of adequate contraception, i.e. use of condom (male subjects) plus any of the following methods (female partners): intrauterine device, hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first drug administration to the male subject, or barrier method (e.g. diaphragm with spermicide), or surgically sterilised (including bilateral tubal occlusion, hysterectomy or bilateral oophorectomy), or postmenopausal, defined as at least 1 year of spontaneous amenorrhea * Sexually abstinent * Vasectomised (vasectomy at least 1 year prior to enrolment) in combination with a barrier method (i.e. condom) Unprotected sexual intercourse (i.e. without use of condom) with a pregnant female partner and sperm donation is not allowed throughout the study and until 30 days after trial completion
Exclusion criteria
* Any finding in the medical examination (including BP, PR 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 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (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 * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Drug-related Adverse Events (AEs) | From first drug administration until end of trial examination, up to 30 days. | Percentage of participants with drug-related adverse events (AEs). The causal relationship of AEs to the investigational product was judged by the investigator. The investigator was asked to record a 'yes' if there was, in his/her judgement, a reasonable causal relationship between the investigational product administered and the AE or a 'no' if there was, in his/her judgement, no reasonable causal relationship between the investigational product administered and the AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) | 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043. | Area under the concentration-time curve of BI 1595043 in plasma at steady state over a uniform dosing interval τ (AUC0-τ,ss) after the last dose of BI 1595043. |
| Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043. | Maximum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) after the last dose of BI 1595043. |
| Minimum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043. | Minimum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmin,ss) after the last dose of BI 1595043. |
| Accumulation Ratio Based on Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) (RA, Cmax) | 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043. | Accumulation ratio based on maximum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) (RA, Cmax), after the last dose. RA,Cmax = Cmax after last dose / Cmax after first dose. |
| Accumulation Ratio Based on Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) (RA, AUC) | 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043. | Accumulation ratio based on area under the concentration-time curve of BI 1595043 in plasma at steady state over a uniform dosing interval τ (AUC0-τ,ss) (RA, AUC). RA,AUC = AUC0-\\tau after last dose / AUC0-\\tau after first dose. |
Countries
Belgium
Participant flow
Recruitment details
A double-blind, randomised, placebo-controlled, parallel group trial to investigate the safety and tolerability of BI 1595043 in healthy male subjects after oral administration of multiple rising doses of 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 strictly met all inclusion and none of the exclusion criteria. All subjects were informed that they were free to withdraw their consent at any time during the trial without penalty or prejudice. Subjects were recruited to a dose group according to their temporal availability and randomised within each dose group in a 4:1 ratio (trial drug to placebo).
Participants by arm
| Arm | Count |
|---|---|
| Placebo / Placebo + Midazolam Film-coated tablets of Placebo, matching to 5 milligram (mg) and 25 mg BI 1595043,were administered orally once daily with 240 milliliter (mL) of water to the corresponding dose group.
Patients included in the placebo arm corresponding to dose group 3, also received a single oral dose of 75 µg (5 mg/5 mL diluted to 50 µg/mL·1.5 mL) solution for injection of midazolam on Day - 1, Day 1 and Day 18. | 6 |
| 15 mg BI 1595043 qd 3 film-coated tablets of 5 milligram (mg) (total dose: 15 mg) BI 1595043 were administered orally once daily (qd), with 240 mL of water after an overnight fast of at least 10 hours (h) on Day 1, followed by a washout of 4 days and from Day 5 to Day 18. Dose group 1. | 8 |
| 30 mg BI 1595043 qd 1 film-coated tablet of 5 mg and 1 film-coated tablet of 25 mg (total dose: 30 mg) of BI 1595043 were administered orally once daily (qd), with 240 mL of water after an overnight fast of at least 10 hours (h) on Day 1, followed by a washout of 4 days and from Day 5 to Day 18. Dose group 2. | 8 |
| 60 mg BI 1595043 qd + Midazolam 2 film-coated tablets of 5 mg and 2 film-coated tablets of 25 mg (total dose: 60 mg) of BI 1595043 were administered orally once daily (qd), with 240 mL of water after an overnight fast of at least 10 hours (h) on Day 1, followed by a washout of 4 days and from Day 5 to Day 18. On Day - 1, Day 1 and Day 18, 75 µg (5 mg/5 mL diluted to 50 µg/mL·1.5 mL) solution for injection of midazolam was administered as single oral dose. Dose group 3. | 8 |
| Total | 30 |
Baseline characteristics
| Characteristic | Placebo / Placebo + Midazolam | 15 mg BI 1595043 qd | 30 mg BI 1595043 qd | 60 mg BI 1595043 qd + Midazolam | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.8 Years STANDARD_DEVIATION 11.7 | 30.5 Years STANDARD_DEVIATION 7.8 | 30.6 Years STANDARD_DEVIATION 7.8 | 40.8 Years STANDARD_DEVIATION 5.8 | 35.1 Years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 8 Participants | 8 Participants | 8 Participants | 30 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 8 Participants | 7 Participants | 29 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 8 Participants | 8 Participants | 30 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 / 6 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 3 / 6 | 8 / 8 | 4 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Percentage of Participants With Drug-related Adverse Events (AEs)
Percentage of participants with drug-related adverse events (AEs). The causal relationship of AEs to the investigational product was judged by the investigator. The investigator was asked to record a 'yes' if there was, in his/her judgement, a reasonable causal relationship between the investigational product administered and the AE or a 'no' if there was, in his/her judgement, no reasonable causal relationship between the investigational product administered and the AE.
Time frame: From first drug administration until end of trial examination, up to 30 days.
Population: Treated Set (TS): The TS included all subjects who were randomised and treated with at least one dose of trial drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo / Placebo + Midazolam | Percentage of Participants With Drug-related Adverse Events (AEs) | 0 Percentage of participants |
| 15 mg BI 1595043 qd | Percentage of Participants With Drug-related Adverse Events (AEs) | 12.5 Percentage of participants |
| 30 mg BI 1595043 qd | Percentage of Participants With Drug-related Adverse Events (AEs) | 25.0 Percentage of participants |
| 60 mg BI 1595043 qd + Midazolam | Percentage of Participants With Drug-related Adverse Events (AEs) | 37.5 Percentage of participants |
Secondary
Accumulation Ratio Based on Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) (RA, AUC)
Accumulation ratio based on area under the concentration-time curve of BI 1595043 in plasma at steady state over a uniform dosing interval τ (AUC0-τ,ss) (RA, AUC). RA,AUC = AUC0-\\tau after last dose / AUC0-\\tau after first dose.
Time frame: 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Placebo + Midazolam | Accumulation Ratio Based on Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) (RA, AUC) | 1.04 Ratio | Geometric Coefficient of Variation 4.93 |
| 15 mg BI 1595043 qd | Accumulation Ratio Based on Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) (RA, AUC) | 1.06 Ratio | Geometric Coefficient of Variation 11.4 |
| 30 mg BI 1595043 qd | Accumulation Ratio Based on Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) (RA, AUC) | 1.11 Ratio | Geometric Coefficient of Variation 4.97 |
Secondary
Accumulation Ratio Based on Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) (RA, Cmax)
Accumulation ratio based on maximum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) (RA, Cmax), after the last dose. RA,Cmax = Cmax after last dose / Cmax after first dose.
Time frame: 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Placebo + Midazolam | Accumulation Ratio Based on Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) (RA, Cmax) | 0.894 Ratio | Geometric Coefficient of Variation 19.9 |
| 15 mg BI 1595043 qd | Accumulation Ratio Based on Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) (RA, Cmax) | 1.12 Ratio | Geometric Coefficient of Variation 30.3 |
| 30 mg BI 1595043 qd | Accumulation Ratio Based on Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) (RA, Cmax) | 1.09 Ratio | Geometric Coefficient of Variation 31.4 |
Secondary
Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss)
Area under the concentration-time curve of BI 1595043 in plasma at steady state over a uniform dosing interval τ (AUC0-τ,ss) after the last dose of BI 1595043.
Time frame: 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Placebo + Midazolam | Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) | 1970 Hours*nanomol per Liter | Geometric Coefficient of Variation 22.1 |
| 15 mg BI 1595043 qd | Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) | 3630 Hours*nanomol per Liter | Geometric Coefficient of Variation 10.2 |
| 30 mg BI 1595043 qd | Area Under the Concentration-time Curve of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUC0-τ,ss) | 8170 Hours*nanomol per Liter | Geometric Coefficient of Variation 18.5 |
Secondary
Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)
Maximum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) after the last dose of BI 1595043.
Time frame: 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Placebo + Midazolam | Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 333 Nanomol per Liter | Geometric Coefficient of Variation 22.1 |
| 15 mg BI 1595043 qd | Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 797 Nanomol per Liter | Geometric Coefficient of Variation 23.3 |
| 30 mg BI 1595043 qd | Maximum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 1630 Nanomol per Liter | Geometric Coefficient of Variation 36.8 |
Secondary
Minimum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss)
Minimum measured concentration of BI 1595043 in plasma at steady state over a uniform dosing interval τ (Cmin,ss) after the last dose of BI 1595043.
Time frame: 0.25 hours before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 34, 48, 72, 96, 120 and 144 hours after the last dose of BI 1595043.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he/she contributed only one PK parameter value for one period to the statistical assessment. Only participants with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo / Placebo + Midazolam | Minimum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 12.7 Nanomole per Liter | Geometric Coefficient of Variation 58.6 |
| 15 mg BI 1595043 qd | Minimum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 17.7 Nanomole per Liter | Geometric Coefficient of Variation 13.6 |
| 30 mg BI 1595043 qd | Minimum Measured Concentration of BI 1595043 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss) | 36.4 Nanomole per Liter | Geometric Coefficient of Variation 33.4 |