Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in healthy subjects following bid oral administration of multiple rising doses, each over an 11 day treatment period. Secondary objectives are the exploration of the pharmacokinetics (PK) including dose proportionality (only for Part 1) as well as attainment of steady state. This includes exploration of a therapeutic exposure range, a range not adequately achieved in the single-rising dose trial 1405-0001.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), PR), 12-lead Electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 70 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 * For Part I: Subjects genotyped as UGT2B17 extensive metabolizers, i.e., carrying at least one functional allele of the UGT2B17 gene (\*1/\*1 or \*1/\*2). For Part II: Subjects genotyped as UGT2B17 poor metabolizers, i.e., carrying no functional allele of the UGT2B17 gene (\*2/\*2) -Male or female subjects: * For 'female subjects not of childbearing potential' at least one of the following criteria must be fulfilled: * Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory) * Female subjects of childbearing potential must use a highly effective contraception method from at least 30 days before the first administration of trial medication until 14 days after trial completion
Exclusion criteria
* Any finding in the medical examination (including Blood Pressure (BP), PR, or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator. In particular 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) at screening * 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; safety laboratory screening evaluation can be repeated a maximum of two times * Any evidence of a concomitant disease assessed as clinically relevant by the investigator or at risk of requiring concomitant drug therapy, e.g., gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorder, 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 cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * History of relevant orthostatic hypotension, fainting spells, or blackouts * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients); mild seasonal allergy adequately managed by topic administration of drugs to eyes or nose is not excluded * Subjects with a documented active malignancy, or malignancy for which the subject has undergone resection, radiation therapy, or drug therapy (e.g., cytostatic, protein kinase inhibitor, or immune checkpoint inhibitor therapy), within the last 5 years. * Subjects who have been previously randomised in this study. * 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, or within 5 half-lives of the investigational drug (whichever is longer), of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered * Major surgery (major according to the investigator's assessment) performed within 6 weeks prior to randomisation or planned within 3 months after screening, e.g. hip replacement. * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day), also inability to refrain from smoking during in-house confinement * Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) or any other 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 history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome) * Subjects with veins unsuited for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator. * 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 * Male subjects with 'women of childbearing potential' (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from the first administration of trial medication until 30 days after the last administration of trial medication * Known relevant immunodeficiency, as judged by the investigator * Chronic or relevant acute infections * History and/or presence of tuberculosis; positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), or history of pneumococcal infection * Positive results for Hepatitis B antigen, Hepatitis C antibodies, and/or human immunodeficiency virus (HIV) 1 antigen or HIV1/2 antibodies, at screening * Aural body temperature of more than 37.7°C on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing. * Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosing * C-reactive protein above upper limit of laboratory reference range at screening and/or on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing. * Subjects with signs of current gingivitis/periodontitis. Inspection of the oral cavity will be performed by the investigator. * Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure), according to investigator. * Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula \< 80 mL/min at screening. * Known clinically relevant impairment of liver function or clinically relevant laboratory abnormality at the screening visit (V1) regarding liver aminotransferases, alkaline phosphatase, gamma glutamyl transferase, bilirubin, serum albumin, as judged by the investigator. * Subjects with a known coagulopathy or abnormal coagulation laboratory parameters at screening, or subjects who, within 10 days prior to administration of trial medication, used any drug that could reasonably inhibit coagulation * Females with a positive pregnancy test or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | Midazolam alone: From administration of midazolam on Day -1 until first administration of BI 1323495 on Day 1, up to 24 hours. All others: From first administration until 7 days after the last administration of BI 1323495, up to 18 days. | Percentage of participants with treatment-emergent drug-related Adverse Events (AEs) is reported. Percentages are calculated using total number of subjects per treatment as the denominator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, and 12h after the first administration of BI 1323495 on Day 1. | Area under the concentration-time curve of BI 1323495 in plasma over a time interval of 12 h after administration of the first dose (AUC0-12) is reported. |
| Only for Once Daily (qd) Dosing Group: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Uniform Dosing Interval of 24 h After Administration of the First Dose (AUC0-24) | Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24 h after administration of BI 1323495 on Day 1. | Area under the concentration-time curve of BI 1323495 in plasma over a uniform dosing interval of 24 h after administration of the first dose (AUC0-24) for the once daily (qd) dosing group is reported. |
| Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the first administration of BI 1323495 on Day 1. * Applicable only for the 120 mg BI 1323495 qd EM arm. | Maximum measured concentration of BI 1323495 in plasma after the first dose (Cmax) is reported. |
| Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | Within 3 hours before and 20 minutes (min), 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm. | Area under the concentration-time curve of BI 1323495 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is reported. The dosing interval τ is not the same for all groups. The dosing interval is 12 hours (h) for the dose groups with a twice daily (bid) BI 1323495 administration and 24 h for the dose group with a once daily (qd) BI 1323495 administration. |
| Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | Within 3 hours before and 20 min, 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last drug administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm. | Maximum measured concentration of BI 1323495 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is reported. The dosing interval τ is not the same for all groups. The dosing interval is 12 hours (h) for the dose groups with a twice daily (bid) BI 1323495 administration and 24 h for the dose group with a once daily (qd) BI 1323495 administration. |
Countries
Germany
Participant flow
Recruitment details
This was a trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising oral doses of BI 1323495 versus placebo in healthy subjects, including an investigation of drug-drug interaction with microdose midazolam (double-blind, randomised, placebo-controlled \[within dose groups\] trial).
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/Placebo + Midazolam This arm comprises placebo only treated participants and those participants who received placebo + midazolam. Placebo only treated participants were administered film-coated tablets of placebo matching BI 1323495 dosage and participants who received placebo + midazolam were administered film-coated tablets of placebo matching BI 1323495 dosage + a single daily dose of 1.5 milliliter (mL) of solution for injection of midazolam concentrated 50 microgram (ug)/mL (total dosage=75 ug) orally with 240 mL of water within 30 minutes after a standard breakfast on Day -1 and on Day 11. | 22 |
| 10 mg BI 1323495 Bid EM Participants carrying at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) one film-coated tablet of 10 milligram (mg) of BI 1323495 orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. | 9 |
| 10 mg BI 1323495 Bid PM Participants carrying no functional allele of the UGT2B17 gene (poor metabolisers (PM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) one film-coated tablet of 10 milligram (mg) of BI 1323495 orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. | 5 |
| 30 mg BI 1323495 Bid EM Participants carrying at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) three film-coated tablets of 10 milligram (mg) of BI 1323495 (total dosage=30 mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. | 9 |
| 30 mg BI 1323495 Bid PM Participants carrying no functional allele of the UGT2B17 gene (poor metabolisers (PM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) three film-coated tablets of 10 milligram (mg) of BI 1323495 (total dosage = 30 mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. | 6 |
| 70 mg BI 1323495 Bid + Midazolam EM Participants carrying at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) two film-coated tablets of 10 milligram (mg) and one film-coated tablet of 50 mg of BI 1323495 (total dosage=70 mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. On Day -1 and on Day 11 participants were also administered a single daily dose of 1.5 mL of solution for injection of midazolam concentrated 50 microgram (ug)/mL (total dosage=75 ug) orally with 240 mL of water within 30 minutes after a standard breakfast. | 9 |
| 120 mg BI 1323495 Bid + Midazolam EM Participants with at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) two film-coated tablets of 10 milligram (mg) and two film-coated tablets of 50 mg of BI 1323495 (total dosage=120 mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. On Day -1 and on Day 11 participants were also administered a single daily dose of 1.5 mL of solution for injection of midazolam concentrated 50 microgram (ug)/mL (total dosage=75 ug) orally with 240 mL of water within 30 minutes after a standard breakfast. | 9 |
| 120 mg BI 1323495 qd EM Participants carrying at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 11 once daily (qd) two film-coated tablets of 10 milligram (mg) and two film-coated tablets of 50 mg of BI 1323495 (total dosage=120 mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. | 9 |
| 150 mg BI 1323495 Bid + Midazolam EM Participants carrying at least one functional allele of the UGT2B17 gene (extensive metabolisers (EM)) were administered from Day 1 to Day 10 twice daily (bid) and on Day 11 once daily (qd) one film-coated tablet of 150 milligram (mg) orally with 240 milliliter (mL) of water within 30 minutes (min) of a meal. On Day -1 and on Day 11 participants were also administered a single daily dose of 1.5 mL of solution for injection of midazolam concentrated 50 microgram (ug)/mL (total dosage=75 ug) orally with 240 mL of water within 30 minutes after a standard breakfast. | 9 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo/Placebo + Midazolam | 10 mg BI 1323495 Bid EM | 10 mg BI 1323495 Bid PM | 30 mg BI 1323495 Bid EM | 30 mg BI 1323495 Bid PM | 70 mg BI 1323495 Bid + Midazolam EM | 120 mg BI 1323495 Bid + Midazolam EM | 120 mg BI 1323495 qd EM | 150 mg BI 1323495 Bid + Midazolam EM | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 34.1 Years STANDARD_DEVIATION 11.1 | 44.3 Years STANDARD_DEVIATION 15.8 | 36.4 Years STANDARD_DEVIATION 14.2 | 43.3 Years STANDARD_DEVIATION 15.4 | 41.2 Years STANDARD_DEVIATION 15.1 | 44.4 Years STANDARD_DEVIATION 13.1 | 33.7 Years STANDARD_DEVIATION 10.3 | 29.9 Years STANDARD_DEVIATION 9.4 | 35.3 Years STANDARD_DEVIATION 15.5 | 37.4 Years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 9 Participants | 5 Participants | 9 Participants | 6 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 87 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 9 Participants | 4 Participants | 9 Participants | 6 Participants | 8 Participants | 9 Participants | 9 Participants | 9 Participants | 83 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 4 Participants | 5 Participants | 3 Participants | 3 Participants | 32 Participants |
| Sex: Female, Male Male | 16 Participants | 6 Participants | 1 Participants | 6 Participants | 5 Participants | 5 Participants | 4 Participants | 6 Participants | 6 Participants | 55 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 | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 36 | 0 / 9 | 0 / 5 | 0 / 9 | 0 / 6 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 9 / 22 | 2 / 36 | 6 / 9 | 3 / 5 | 8 / 9 | 4 / 6 | 6 / 9 | 4 / 9 | 6 / 9 | 6 / 9 |
| serious Total, serious adverse events | 0 / 22 | 0 / 36 | 0 / 9 | 0 / 5 | 0 / 9 | 0 / 6 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs)
Percentage of participants with treatment-emergent drug-related Adverse Events (AEs) is reported. Percentages are calculated using total number of subjects per treatment as the denominator.
Time frame: Midazolam alone: From administration of midazolam on Day -1 until first administration of BI 1323495 on Day 1, up to 24 hours. All others: From first administration until 7 days after the last administration of BI 1323495, up to 18 days.
Population: Treated Set (TS): The treated set 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. Midazolam alone arm consisted of all subjects of the arms 70 mg BI 1323495 bid+Midazolam EM, 120 mg BI 1323495 bid+Midazolam EM, 150 mg BI 1323495 bid+ Midazolam EM and 9 subjects of the arm Placebo/Placebo+Midazolam which were treated with midazolam on Day -1 of the trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/Placebo+ Midazolam | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 4.5 percentage of participants |
| Midazolam Alone | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 0 percentage of participants |
| 10 mg BI 1323495 Bid EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 22.2 percentage of participants |
| 10 mg BI 1323495 Bid PM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 0 percentage of participants |
| 30 mg BI 1323495 Bid EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 33.3 percentage of participants |
| 30 mg BI 1323495 Bid PM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 16.7 percentage of participants |
| 70 mg BI 1323495 Bid + Midazolam EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 11.1 percentage of participants |
| 120 mg BI 1323495 Bid + Midazolam EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 22.2 percentage of participants |
| 120 mg BI 1323495 qd EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 0 percentage of participants |
| 150 mg BI 1323495 Bid + Midazolam EM | Percentage of Participants With Treatment-emergent Drug-related Adverse Events (AEs) | 44.4 percentage of participants |
Secondary
Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)
Area under the concentration-time curve of BI 1323495 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is reported. The dosing interval τ is not the same for all groups. The dosing interval is 12 hours (h) for the dose groups with a twice daily (bid) BI 1323495 administration and 24 h for the dose group with a once daily (qd) BI 1323495 administration.
Time frame: Within 3 hours before and 20 minutes (min), 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm.
Population: Pharmacokinetic (PK) 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. Thus, a subject was included in the PKS, even if he/she contributed to only 1 PK parameter value for 1 period to the statistical assessment. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo+ Midazolam | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 237 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 60.8 |
| Midazolam Alone | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 738 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 22.8 |
| 10 mg BI 1323495 Bid EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 475 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 86.2 |
| 10 mg BI 1323495 Bid PM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 2370 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 28.1 |
| 30 mg BI 1323495 Bid EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 2490 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 59.4 |
| 30 mg BI 1323495 Bid PM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 2850 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 69.4 |
| 70 mg BI 1323495 Bid + Midazolam EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 1960 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 55.9 |
| 120 mg BI 1323495 Bid + Midazolam EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 2070 hours *nanomol/Liter (hnmol/L) | Geometric Coefficient of Variation 41.5 |
Secondary
Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12)
Area under the concentration-time curve of BI 1323495 in plasma over a time interval of 12 h after administration of the first dose (AUC0-12) is reported.
Time frame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, and 12h after the first administration of BI 1323495 on Day 1.
Population: Pharmacokinetic (PK) 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. Thus, a subject was included in the PKS, even if he/she contributed to only 1 PK parameter value for 1 period to the statistical assessment. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo+ Midazolam | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 118 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 56.1 |
| Midazolam Alone | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 430 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 27.2 |
| 10 mg BI 1323495 Bid EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 282 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 66.2 |
| 10 mg BI 1323495 Bid PM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 1310 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 29.1 |
| 30 mg BI 1323495 Bid EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 702 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 48.6 |
| 30 mg BI 1323495 Bid PM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 982 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 76.2 |
| 70 mg BI 1323495 Bid + Midazolam EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | 784 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 81.7 |
| 120 mg BI 1323495 Bid + Midazolam EM | Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Time Interval of 12 h After Administration of the First Dose (AUC0-12) | NA hours *nanomol/Liter (h*nmol/L) | — |
Secondary
Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax)
Maximum measured concentration of BI 1323495 in plasma after the first dose (Cmax) is reported.
Time frame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the first administration of BI 1323495 on Day 1. * Applicable only for the 120 mg BI 1323495 qd EM arm.
Population: Pharmacokinetic (PK) 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. Thus, a subject was included in the PKS, even if he/she contributed to only 1 PK parameter value for 1 period to the statistical assessment. Only participants with evaluable results of this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo+ Midazolam | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 23.5 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 31.4 |
| Midazolam Alone | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 85.3 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 30.1 |
| 10 mg BI 1323495 Bid EM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 62.0 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 57.1 |
| 10 mg BI 1323495 Bid PM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 216 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 39.7 |
| 30 mg BI 1323495 Bid EM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 123 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 50 |
| 30 mg BI 1323495 Bid PM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 152 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 67.5 |
| 70 mg BI 1323495 Bid + Midazolam EM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 125 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 98.1 |
| 120 mg BI 1323495 Bid + Midazolam EM | Maximum Measured Concentration of BI 1323495 in Plasma After the First Dose (Cmax) | 109 nanomol/Liter (nmol/L) | Geometric Coefficient of Variation 77.8 |
Secondary
Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)
Maximum measured concentration of BI 1323495 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is reported. The dosing interval τ is not the same for all groups. The dosing interval is 12 hours (h) for the dose groups with a twice daily (bid) BI 1323495 administration and 24 h for the dose group with a once daily (qd) BI 1323495 administration.
Time frame: Within 3 hours before and 20 min, 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24h* after the last drug administration of BI 1323495 on Day 11. * Applicable only for the 120 mg BI 1323495 qd EM arm.
Population: Pharmacokinetic (PK) 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. Thus, a subject was included in the PKS, even if he/she contributed to only 1 PK parameter value for 1 period to the statistical assessment. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo+ Midazolam | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 37.5 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 49.6 |
| Midazolam Alone | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 109 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 27.7 |
| 10 mg BI 1323495 Bid EM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 64.4 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 78.7 |
| 10 mg BI 1323495 Bid PM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 300 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 32.6 |
| 30 mg BI 1323495 Bid EM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 281 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 48 |
| 30 mg BI 1323495 Bid PM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 362 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 77.7 |
| 70 mg BI 1323495 Bid + Midazolam EM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 164 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 48.7 |
| 120 mg BI 1323495 Bid + Midazolam EM | Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 265 nanomol/liter (nmol/L) | Geometric Coefficient of Variation 46 |
Secondary
Only for Once Daily (qd) Dosing Group: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Uniform Dosing Interval of 24 h After Administration of the First Dose (AUC0-24)
Area under the concentration-time curve of BI 1323495 in plasma over a uniform dosing interval of 24 h after administration of the first dose (AUC0-24) for the once daily (qd) dosing group is reported.
Time frame: Within 3 hours before and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h and 24 h after administration of BI 1323495 on Day 1.
Population: Pharmacokinetic (PK) parameter analysis set (PKS) of 120 mg BI qd EM arm: This set included all treated subjects of 120 mg BI 1323495 qd EM arm 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. Thus, a subject was included in the PKS of arm, even if he/she contributed to only 1 PK parameter value for 1 period to the statistical assessment. Only participants with evaluable results are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo+ Midazolam | Only for Once Daily (qd) Dosing Group: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over a Uniform Dosing Interval of 24 h After Administration of the First Dose (AUC0-24) | 1550 hours *nanomol/Liter (h*nmol/L) | Geometric Coefficient of Variation 75.6 |