Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the effect of multiple oral doses of BI 1569912 on the pharmacokinetics of a single oral dose of repaglinide, midazolam and bupropion (i.e. sensitive CYP2C8, CYP3A4 and CYP2B6 substrates).
Interventions
DRUGBI 1569912
Intended dose of BI 1569912
DRUGRepaglinide
0.5 mg tablet
DRUGMidazolam
2 mg solution for injection
DRUGBupropion
150 mg extended-release tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients cross over from test treatment (T) to reference treatment (R) (two periods, fixed sequence).
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, standardized mental and neurological assessment, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests without clinically significant abnormalities * Age of 18 to 55 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial * Either male subjects or female subjects who meet the following criteria requiring highly effective contraception 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 or male partners of female subjects) plus any of the following methods (female subjects or female partners of male subjects): intrauterine device, hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives), , surgically sterilised (including bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy) or postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of Follicle stimulating hormone (FSH) above 40 U/L is confirmatory) * Sexually abstinent (considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) * Vasectomised male subjects or male partners of female subjects (vasectomy at least 1 year prior to enrolment) in combination with a barrier method (i.e. use of condom) and provided that the partner is the sole sexual partner of the trial participant Unprotected sexual intercourse (i.e. without use of condom) of a male subject with a pregnant female partner and sperm donation is not allowed throughout the study and until 30 days after trial completion. Female subjects should not participate in egg donation from the first trial medication administration, for the duration of the study and for at least 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(s) of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm) * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance, in particular hepatic parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin) or renal parameters (creatinine) exceeding the Upper limit of normal (ULN) after repeated measurements * 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, bulimia or anorexia, or bipolar mood disorder), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before repaglinide administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured the area under the concentration-time curve of repaglinide in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before midazolam administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured the area under the concentration-time curve of midazolam in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under the Concentration-time Curve of S-bupropion in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured the area under the concentration-time curve of chiral form S-bupropion in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞), when bupropion was administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under the Concentration-time Curve of Total Bupropion in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured the area under the concentration-time curve of total bupropion in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞), when bupropion was administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Repaglinide in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before repaglinide administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured the area under the concentration-time curve of repaglinide in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Maximum Measured Concentration of Repaglinide in Plasma (Cmax) | Within 3 hours (h) before repaglinide administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured maximum measured concentration of repaglinide in plasma (Cmax), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before midazolam administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured the area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz), when administered alone or co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) | Within 3 hours (h) before midazolam administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h thereafter. | This outcome measured maximum measured concentration of midazolam in plasma (Cmax), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under the Concentration-time Curve of S-bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured the area under the concentration-time curve of the chiral form S-bupropion in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz), when bupropion was administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Maximum Measured Concentration of S-bupropion in Plasma (Cmax) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured maximum measured concentration of the chiral form S-bupropion in plasma (Cmax), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Area Under the Concentration-time Curve of Total Bupropion in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured the area under the concentration-time curve of total bupropion in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz), when bupropion was administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
| Maximum Measured Concentration of Total Bupropion in Plasma (Cmax) | Within 3 hours (h) before bupropion administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120 h thereafter. | This outcome measured maximum measured concentration of total bupropion in plasma (Cmax), when administered alone and when co-administered at BI 1569912 steady-state. The statistical model used was an analysis of variance (ANOVA) accounting for the following sources of variation: participant and treatment. The effect 'participant' was considered as random, whereas the effect 'treatment' was considered as fixed. |
Countries
Belgium
Participant flow
Recruitment details
This was a non-randomized, open-label, 2-period trial in healthy male and female participants in order to test the influence of multiple doses of BI 1569912 on the pharmacokinetics of repaglinide, midazolam, and bupropion (sensitive CYP2C8, CYP3A4 and CYP2B6 substrates).
Pre-assignment details
All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 35.4 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 8 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 1 / 18 | 5 / 17 | 3 / 17 | 12 / 17 | 0 / 17 | 2 / 17 | 6 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 |
Outcome results
None listed