Healthy
Conditions
Brief summary
The main objective of Part 1of this trial is to investigate the effect of co-administration of multiple doses of donepezil on the single-dose pharmacokinetics of BI 425809 in healthy subjects. In Part 2 the main objective is the investigation of the effect of co-administration of multiple doses of BI 425809 on the single-dose pharmacokinetics of donepezil in healthy subjects.
Interventions
DRUGBI 425809
Film coated tablet
DRUGDonepezil
Film coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 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, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12- lead Electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 50 years (inclusive) * Body Mass Index (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, or female subjects who meet any of the following criteria from the first administration of trial medication until 30 days after trial completion: * Use of adequate contraception that does not contain hormones, i.e. non-hormonal intrauterine device plus condom * Sexually abstinent * A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * Surgically sterilised (including hysterectomy) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate (PR) or Electrocardiogram (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 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 * 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 * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) * 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 of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) * 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 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) or any other relevant Electrocardiogram (ECG) finding at screening * A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome) * 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 * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Detailed time frame is in the description section | Area under the concentration-time curve of BI 425809 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) plasma concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil. |
| Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Detailed time frame is in the description section | Area under the concentration-time curve of donepezil in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured within 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809. |
| Maximum Measured Concentration of BI 425809 in Plasma (Cmax) | Detailed time frame is in the description section | Maximum measured concentration of BI 425809 in plasma (Cmax). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil. |
| Maximum Measured Concentration of Donepezil in Plasma (Cmax) | Detailed time frame is in the description section | Maximum measured concentration of donepezil in plasma (Cmax). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured withing 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Detailed time frame is in the description section | Area under the concentration-time curve of BI 425809 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil. |
| Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Detailed time frame is in the description section | Area under the concentration-time curve of donepezil in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured within 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809. |
Countries
Germany
Participant flow
Recruitment details
This is an open-label, two-treatment, two-period, one fixed sequence cross-over design study in order to investigate the effects of donepezil (Don) on the pharmacokinetics (PK) of BI 425809 (trial part 1) and vice versa (trial part 2) in healthy male and female subjects over a period up to 57 days in part 1 and up to 55 days in part 2.
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 |
|---|---|
| Trial Part 1: BI 425809 / Donepezil + BI 425809 All participants were orally administered a single dose of BI 425809, 25 milligrams (mg) film-coated tablet on day 1 of visit 2 (Treatment A, Reference 1) and on day 22 of visit 3, together with multiple doses of donepezil, film-coated tablets, 5 mg once a day (qd) (1 tablet) on day 1 to 7 of visit 3 and 10 mg qd (2 tablets) on day 8 to 28 of visit 3 (Treatment B, Test 1) in the fasted state with about 240 milliliters (ml) of fluid. | 18 |
| Trial Part 2: Donepezil / BI 425809 + Donepezil All participants were orally administered a single dose of donepezil, 10 mg film-coated tablet on day 1 of visit 2 (Treatment C, Reference 2) and on day 10 of visit 3, together with multiple doses of BI 425809, film-coated tablets, 25 mg qd (1 tablet) on day 1 to 24 of visit 3 (Treatment D, Test 2) in the fasted state with about 240 milliliters (ml) of fluid. | 14 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 for Trial Part 1 and 2 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Trial Part 2: Donepezil / BI 425809 + Donepezil | Total | Trial Part 1: BI 425809 / Donepezil + BI 425809 |
|---|---|---|---|
| Age, Continuous | 35.9 Years STANDARD_DEVIATION 8.6 | 37.7 Years STANDARD_DEVIATION 8.3 | 39.1 Years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 32 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 32 Participants | 18 Participants |
| Sex: Female, Male Female | 5 Participants | 21 Participants | 16 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 2 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 5 / 18 | 15 / 18 | 13 / 18 | 7 / 14 | 4 / 14 | 10 / 14 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of BI 425809 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) plasma concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 11815.37 nanomoles * hours per liter | Standard Error 1.1 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 10944.06 nanomoles * hours per liter | Standard Error 1.1 |
90% CI: [85.34, 100.53]ANOVA
Primary
Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of donepezil in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured within 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 647.16 nanograms * hours per milliliter | Standard Error 1.09 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 638.38 nanograms * hours per milliliter | Standard Error 1.09 |
90% CI: [93.21, 104.39]ANOVA
Primary
Maximum Measured Concentration of BI 425809 in Plasma (Cmax)
Maximum measured concentration of BI 425809 in plasma (Cmax). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Maximum Measured Concentration of BI 425809 in Plasma (Cmax) | 293.97 nanomoles per liter | Standard Error 1.07 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Maximum Measured Concentration of BI 425809 in Plasma (Cmax) | 289.51 nanomoles per liter | Standard Error 1.08 |
90% CI: [90.74, 106.88]ANOVA
Primary
Maximum Measured Concentration of Donepezil in Plasma (Cmax)
Maximum measured concentration of donepezil in plasma (Cmax). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured withing 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Maximum Measured Concentration of Donepezil in Plasma (Cmax) | 15.94 nanograms per milliliter | Standard Error 1.12 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Maximum Measured Concentration of Donepezil in Plasma (Cmax) | 15.96 nanograms per milliliter | Standard Error 1.12 |
90% CI: [89.01, 112.68]ANOVA
Secondary
Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 425809 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For BI 425809 alone (Part 1: Treatment A, Reference 1) and BI 425809 + donepezil (Part 1: Treatment B, Test 1) concentrations of BI 425809 were measured within 2 hours (h) before and at 30 minutes (min), 1 h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, 96h, 120h, 144h, 168h after administration of BI 425809 alone or in combination with donepezil.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 10638.64 nanomoles * hours per liter | Standard Error 1.08 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 10082.12 nanomoles * hours per liter | Standard Error 1.08 |
90% CI: [88.36, 101.64]ANOVA
Secondary
Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of donepezil in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For donepezil alone (Part 2: Treatment C, Reference 2) and donepezil + BI 425809 (Part 2: Treatment D, Test 2) concentrations of donepezil were measured within 2 hours (h) before and at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h, 336h, after administration of donepezil alone or in combination with BI 425809.
Time frame: Detailed time frame is in the description section
Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and 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 |
|---|---|---|---|
| BI 425809 Alone Group (Part 1: Treatment A, Reference 1) | Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 600.86 nanograms * hours per milliliter | Standard Error 1.1 |
| BI 425809 + Don Group (Part 1: Treatment B, Test 1) | Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 601.20 nanograms * hours per milliliter | Standard Error 1.1 |
90% CI: [94.56, 105.87]ANOVA