Healthy
Conditions
Brief summary
Safety, tolerability, and pharmacokinetics of BI 474121 will be assessed in healthy Japanese male using single rising oral doses in order to provide the basis for an ongoing clinical development of BI 474121 for the treatment of cognitive impairment in patients with Alzheimer's Disease and schizophrenia.
Interventions
DRUGPlacebo
Healthy subjects were given a single dose of placebo tablet(s) matched to the active treatment, subjects receiving placebo were equally distributed across dose groups. Tablet(s) were taken orally with 240 milliliter of water after an overnight fast of at least 10 hours.
DRUGBI 474121
Healthy subjects were given a single dose of BI 474121 as a uncoated tablet(s) taken orally with 240 milliliter of water after an overnight fast of at least 10 hours.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 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)) including body temperature, 12-lead electrocardiogram (ECG), and clinical laboratory tests at screening visit * Japanese ethnicity, according to the following criteria: * born in Japan, have lived outside of Japan \<10 years, * have parents and grandparents who are Japanese * Age of 20 to 45 years (inclusive) at screening visit * Body mass index (BMI) of 18.5 to 25.0 kilogram per square meter (kg/m2) (inclusive) at screening visit * Signed and dated written informed consent prior to admission to the study, 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 by 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.
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator at screening visit * Repeated measurement of systolic blood pressure outside the range of 100 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 millimetre of mercury (mmHg), or pulse rate outside the range of 50 to 90 beats per minute (bpm) at screening visit * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance at screening visit * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * Chronic or relevant acute infections including viral hepatitis, human immunodeficiency virus (HIV) and/or syphilis. * 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) * further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Drug-related Adverse Events (AEs) | From the time of first administration of study medication until 168 hours (7 days) after time of administration, up to 8 days. | Percentage of subjects with investigator-defined drug-related adverse events (AEs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following drug administration. | Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). |
| Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following drug administration. | Maximum measured concentration of BI 474121 in plasma (Cmax). |
Countries
Japan
Participant flow
Recruitment details
This was a trial with a randomised within dose groups, placebo-controlled, double-blind, parallel group design to investigate safety, tolerability, and pharmacokinetics following single rising doses of BI 474121.
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 Healthy subjects were given a single dose of placebo tablet(s) matched to the active treatment, subjects receiving placebo were equally distributed across dose groups. Tablet(s) were taken orally with 240 milliliter of water after an overnight fast of at least 10 hours. | 8 |
| 2.5 mg BI 474121 Healthy subjects were given a single dose of 2.5 milligram (mg) of BI 474121 as a single (2.5 mg) uncoated tablet taken orally with 240 milliliter of water after an overnight fast of at least 10 hours. | 6 |
| 5 mg BI 474121 Healthy subjects were given a single dose of 5 milligram (mg) of BI 474121 as two (2.5 mg) uncoated tablets taken orally with 240 milliliter of water after an overnight fast of at least 10 hours. | 6 |
| 10 mg BI 474121 Healthy subjects were given a single dose of 10 milligram (mg) of BI 474121 as a single (10 mg) uncoated tablet taken orally with 240 milliliter of water after an overnight fast of at least 10 hours. | 6 |
| 20 mg BI 474121 Healthy subjects were given a single dose of 20 milligram (mg) of BI 474121 as two (10 mg) uncoated tablets taken orally with 240 milliliter of water after an overnight fast of at least 10 hours. | 6 |
| Total | 32 |
Baseline characteristics
| Characteristic | Placebo | 2.5 mg BI 474121 | 5 mg BI 474121 | 10 mg BI 474121 | 20 mg BI 474121 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 28.5 years STANDARD_DEVIATION 8.6 | 36.0 years STANDARD_DEVIATION 8.4 | 27.0 years STANDARD_DEVIATION 5.8 | 32.3 years STANDARD_DEVIATION 9 | 36.5 years STANDARD_DEVIATION 9.4 | 31.8 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 32 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 | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 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 | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 32 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 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 8 | 1 / 6 | 1 / 6 | 2 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Percentage of Subjects With Drug-related Adverse Events (AEs)
Percentage of subjects with investigator-defined drug-related adverse events (AEs).
Time frame: From the time of first administration of study medication until 168 hours (7 days) after time of administration, up to 8 days.
Population: Treated set (TS): all subjects who were randomised and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With Drug-related Adverse Events (AEs) | 25 Percentage of participants |
| 2.5 mg BI 474121 | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0 Percentage of participants |
| 5 mg BI 474121 | Percentage of Subjects With Drug-related Adverse Events (AEs) | 16.7 Percentage of participants |
| 10 mg BI 474121 | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0 Percentage of participants |
| 20 mg BI 474121 | Percentage of Subjects With Drug-related Adverse Events (AEs) | 0 Percentage of participants |
Secondary
Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).
Time frame: Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects who were randomised and treated with at least one dose of study drug and who provided at least one pharmacokinetic (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 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 289 hour*nanomole/liter | Geometric Coefficient of Variation 25.6 |
| 2.5 mg BI 474121 | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 658 hour*nanomole/liter | Geometric Coefficient of Variation 21.2 |
| 5 mg BI 474121 | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1440 hour*nanomole/liter | Geometric Coefficient of Variation 15.4 |
| 10 mg BI 474121 | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2330 hour*nanomole/liter | Geometric Coefficient of Variation 25.4 |
Secondary
Maximum Measured Concentration of BI 474121 in Plasma (Cmax)
Maximum measured concentration of BI 474121 in plasma (Cmax).
Time frame: Within 3 hours before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following drug administration.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects who were randomised and treated with at least one dose of study drug and 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | 27.0 nanomole/liter | Geometric Coefficient of Variation 20.6 |
| 2.5 mg BI 474121 | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | 54.3 nanomole/liter | Geometric Coefficient of Variation 13.5 |
| 5 mg BI 474121 | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | 113 nanomole/liter | Geometric Coefficient of Variation 11.2 |
| 10 mg BI 474121 | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | 193 nanomole/liter | Geometric Coefficient of Variation 16.7 |