A Study in Healthy Japanese Men to Test How Different Doses of BI 1323495 Are Tolerated and How Itraconazole Influences the Amount of BI 1323495 in the Blood

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: BI 1323495
Drug: Placebo
Drug: Itraconazole

Registration Number: NCT04619251

Lead Sponsor: Boehringer Ingelheim

Brief Summary: The main objective of the single-rising dose (SRD) part and the multiple rising dose (MD) part is to investigate safety, tolerability, pharmacokinetics and pharmacodynamics (for MD part only) following single rising doses and multiple oral doses of BI 1323495 in healthy male Japanese subjects genotyped as poor metabolizers (PM) and extensive metabolizers (EM) of UGT2B17.

The main objective of the drug-drug interaction (DDI) part is to investigate the relative bioavailability of a single oral dose of BI 1323495 when given alone (treatment R) or in combination with itraconazole (treatment T) in healthy male subjects genotyped as PM of UGT2B17.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 74

Inclusion Criteria

Healthy male subjects according to the assessment of the investigator, as based on a complete medical history, including a medical examination, vital signs (BP, PR), 12- lead ECG, and clinical laboratory tests
Japanese ethnicity, according to the following criteria:

--born in Japan, have lived outside of Japan <10 years, and have parents and grandparents who are Japanese
Age of 20 to 45 years (inclusive) at screening
BMI of 18.5 to 25.0 kg/m2 (inclusive) at screening
Signed and dated written informed consent prior to admission to the trial, in accordance with Good Clinical Practice (GCP) and local legislation
Subjects who agree to minimize the risk of making their partner pregnant by fulfilling any of the following criteria starting from the first administration of trial medication until 90 days after last administration of trial medication
Use of adequate contraception, any of the following methods plus condom: intrauterine device, combined oral contraceptives that started at least 2 months prior to the first drug administration.
Vasectomized (vasectomy at least 1 year prior to enrolment)
Surgical sterilization (including bilateral tubal occlusion, hysterectomy or bilateral oophorectomy) of the subject's female partner
Subjects genotyped as UGT2B17 poor metabolizers, i.e. carrying allele of UGT2B17 gene (*2/*2) (DDI part only)

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 mmHg, diastolic blood pressure outside the range of 40 to 90 mmHg, or pulse rate outside the range of 40 to 99 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 exclusion criteria apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
SRD part: PM Subjects, BI1323495 30mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
MD part: PM Subjects, BI1323495 30mg BID	BI 1323495	Participants were administered from Day 1 to Day 10 two times per day (bid) an oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water, At Day 11 participants were administered only a single dose in the morning. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. Morning and evening dose were taken with a 12 h time interval approximately at the same time each day during the treatment phase. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: EM Subjects, BI1323495 150mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 150 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: Placebo	Placebo	This arm comprises all placebo treated participants in trial part SRD, regardless of the dose group in which they were treated. Participants were randomized within each dose group in a 3:1 ratio (test treatment to placebo). Participants were administered on Day 1 a single oral dose of placebo film-coated tablet(s) together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
MD part: Placebo	Placebo	This arm comprises all placebo treated participants in trial part MD, regardless of the dose group in which they were treated. Participants were randomized within each dose group in a 3:1 ratio (test treatment to placebo). Participants were administered from Day 1 to Day 11 one time per day (qd) an oral dose of placebo film-coated tablets or two times per day (bid) an oral dose of placebo together with about 240 milliliter (mL) of water. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: PM Subjects, BI1323495 10mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 10 milligram (mg) of BI 1323495 film-coated tablet together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: EM Subjects, BI1323495 70mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 70 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
MD part: PM Subjects, BI1323495 60mg QD	BI 1323495	Participants were administered from Day 1 to Day 11 one time per day (qd) an oral dose of 60 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. Participants took a normal caloric meal 30 minutes (min) before drug administration. Subjects fasted for 4 hours (h) after intake of morning dose. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: PM Subjects, BI1323495 100mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 100 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
SRD part: EM Subjects, BI1323495 30mg	BI 1323495	Participants were administered on Day 1 a single oral dose of 30 milligram (mg) of BI 1323495 film-coated tablets together with about 240 milliliter (mL) of water. A standardized meal was served 30 minutes (min) before drug administration. One authorized employee of the trial site was witness of the administration of the trial medication.
DDI part: PM Subjects, BI1323495 / BI1323495+ Itraconazole	BI 1323495	* Period 1: Participants were administered the reference treatment (R) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 together with about 240 milliliter (mL) of water on Day 1 of Period 1. One authorized employee of the trial site was witness of the administration of the trial medication. * Period 2: Participants were administered the test treatment (T) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 with about 240 milliliter (mL) of water on Day 1 of Period 2, together with multiple oral doses of 200 mg itraconazole from Day -3 to Day 7, in total 10 doses, as oral solution formulation. One authorized employee of the trial site was witness of the administration of the trial medication. Administration of BI 1323495 in treatment R and T were separated by at least 11 days.
DDI part: PM Subjects, BI1323495 / BI1323495+ Itraconazole	Itraconazole	* Period 1: Participants were administered the reference treatment (R) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 together with about 240 milliliter (mL) of water on Day 1 of Period 1. One authorized employee of the trial site was witness of the administration of the trial medication. * Period 2: Participants were administered the test treatment (T) which consisted of a single oral dose of 10 milligram (mg) film-coated tablet of BI 1323495 with about 240 milliliter (mL) of water on Day 1 of Period 2, together with multiple oral doses of 200 mg itraconazole from Day -3 to Day 7, in total 10 doses, as oral solution formulation. One authorized employee of the trial site was witness of the administration of the trial medication. Administration of BI 1323495 in treatment R and T were separated by at least 11 days.

Primary Outcome Measures

Name	Time	Method
SRD and MD Part: Number of Participants With Drug-related Adverse Events (AEs)	Up to 7 days (for SRD part), up to 17 days (for MD part).	Number of participants with drug-related adverse events (AEs) is reported for Single rising dose (SRD) and Multiple dose (MD) parts is reported.
DDI Part: Maximum Measured Concentration of BI 1323495 in Plasma (Cmax)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h, 34h, 47h, 71h, 95h, 119h, 143h, and 167h after start of BI 1323495 administration on both periods (1 and 2).	Maximum measured concentration of BI 1323495 in plasma is reported. The statistical model used for the analysis of this endpoint was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: subject and treatment. The effect 'subject' was considered as random, whereas the effect 'treatment' was considered as fixed. These quantities were then back-transformed to the original scale.
DDI Part: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h, 34h, 47h, 71h, 95h, 119h, 143h, and 167h after start of BI 1323495 administration on both periods (1 and 2).	The area under the concentration-time curve of BI 1323495 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. The statistical model used for the analysis of this endpoint was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: subject and treatment. The effect 'subject' was considered as random, whereas the effect 'treatment' was considered as fixed. These quantities were then back-transformed to the original scale.

Secondary Outcome Measures

Name	Time	Method
DDI Part: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h, 34h, 47h, 71h, 95h, 119h, 143h, and 167h after start of BI 1323495 administration on both periods (1 and 2).	The area under the concentration-time curve BI 1323495 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. The statistical model used for the analysis of this endpoint was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: subject and treatment. The effect 'subject' was considered as random, whereas the effect 'treatment' was considered as fixed. These quantities were then back-transformed to the original scale.
MD Part: Area Under the Concentration-time Curve of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After Last Dose Administration.	Within 15 minutes (min) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h (only for the 60mg qd administration) after last dose administration.	Area under the concentration-time curve of BI 1323495 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) after last dose administration is reported. T for 30 mg bid is 12h, for 60 mg qd is 24h.
SRD Part: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h, 34h, 48h, 72h, 96h after start of BI 1323495 administration. Additionally only in the PM group: at 120h, 144h, and 168h.	The area under the concentration-time curve of BI 1323495 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported.
SRD Part: Maximum Measured Concentration of BI 1323495 in Plasma (Cmax)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 24h, 34h, 48h, 72h, 96h after start of BI 1323495 administration. Additionally only in the PM group: at 120h, 144h, and 168h.	Maximum measured concentration of BI 1323495 in plasma (Cmax) is reported.
MD Part: Maximum Measured Concentration of BI 1323495 in Plasma (Cmax) After First Dose	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, after start of first dose BI 1323495 administration.	Maximum measured concentration of BI 1323495 in plasma (Cmax) after first dose is reported.
MD Part: Area Under the Concentration-time Curve of BI 1323495 in Plasma Over the Time Interval of 12 h After Administration of the First Dose (AUC0-12)	Within 3 hours (h) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, after start of first dose BI 1323495 administration.	The area under the concentration-time curve of BI 1323495 in plasma over the time interval of 12 h after administration of the first dose (AUC0-12) is reported.
MD Part: Maximum Measured Concentration of BI 1323495 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)	Within 15 minutes (min) before and 20min, 40min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h and 24h (only for the 60mg qd administration) after last dose administration.	Maximum measured concentration of BI 1323495 in plasma (Cmax,ss) at steady state over a uniform dosing interval τ is reported. T for 30 mg bid is 12h, for 60 mg qd is 24h.