Healthy
Conditions
Brief summary
Part I: To investigate whether and to what extent donepezil affects single dose pharmacokinetics of BI 409306 Part II: To investigate whether and to what extent BI 409306 affects the single dose pharmacokinetics of donepezil
Interventions
DRUGBI 409306
DRUGDonepezil
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male/female subjects, * age of 18 to 55 years, * body mass index (BMI) of 18.5 to 29.9 kg/m2 * Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation * Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion: * Use of adequate contraception, e.g. any of the following methods plus condom: intrauterine device (non-hormonal) * 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 simultaneous levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged 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 60 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 judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication (except appendectomy and 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) * Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication * Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication * Smoker * Alcohol abuse Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: AUC0-tz of BI 409306 | Within 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours thereafter. | Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 to the last quantifiable data point. |
| Part 1: Cmax of BI 409306 | Within 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14,16 hours thereafter. | Maximum measured concentration of the BI 409306 in plasma. |
| Part 2: AUC0-tz of Donepezil | At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter. | Area under the concentration-time curve of donepezil in plasma over the time interval from 0 to the last quantifiable data point. |
| Part 2: Cmax of Donepezil | At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter. | Maximum measured concentration of the donepezil in plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: AUC 0-infinity of BI 409306 | At approximate 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14,16 hours thereafter. | Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity. |
| Part 2: AUC0-infinity of Donepezil | At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter. | This outcome measure presents the area under the concentration-time curve of donepezil in plasma over the time interval from 0 extrapolated to infinity. |
Countries
Germany
Participant flow
Recruitment details
Part I (18 subjects entered) of this trial was performed as a one fixed sequence, open-label trial; single doses of BI 409306 and multiple doses of donepezil were administered. Part II (14 subjects entered) was performed as a randomised, open-label, 2-way crossover trial; single doses of donepezil and multiple doses of BI 409306 were administered.
Pre-assignment details
All subjects were screened for eligibility to participate in the trial. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated. Removal of individual subjects if the subject withdrew consent for trial treatment or trial participation, without the need to justify the decision.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: 25 mg BI 409306 (R1) / 25 mg BI 409306 + 10 mg Donepezil (T1) This arm is used in part 1 of this trial only. The subjects received the treatments in a fixed sequence: Reference treatment (R1) / test treatment (T1). The test treatment (T1) was administered after preceding treatment with donepezil for 21 days.
On day 1 of period 1, one film-coated tablet of 25 milligram (mg) BI 409306 was administered as single oral dose with 240 milliliter (mL) of water after a standardized dinner (R1).
In period 2, day 1 to 7, subjects received one film-coated tablet of 5 mg donepezil administered orally once daily, followed by 2 film-coated tablets of 5 mg (total: 10 mg) donepezil once daily on day 8 to 21 (up-titration regime).
On day 1 of period 3, one film-coated tablet of 25 mg BI 409306 was administered as single oral dose together with 2 film-coated tablets of 5 mg (total: 10 mg) donepezil with 240 mL of water after a standardized dinner (T1). There was no washout periods between the visits. | 18 |
| Part 2: 5 mg Donepezil (R2) / 5 mg Donepezil + 100 mg BI 409306 (T2) This arm is used in part 2 of this trial only. Each subject received first the reference treatment (R2) followed by a washout period of at least 25 days, followed by the test treatment (T2). On day 1 of period 1, one film-coated tablet of 5 mg donepezil (R2) was administered as single oral dose with 240 mL of water in the morning in fasted state, followed by a washout period of at least 25 days. On day 1 of period 2, one film-coated tablet of 5 mg donepezil together with 4 film-coated tablets of 25 mg (total: 100 mg) BI 409306 (T2) were administered orally with 240 ml of water in the morning in fasted state. From day 2 to day 7 in period 2, subjects were administered 4 film-coated tablets of 25 mg (total: 100 mg) BI 409306 orally once daily. | 7 |
| Part 2: 5 mg Donepezil + 100 mg BI 409306 (T2) / 5mg Donepezil (R2) This arm is used in part 2 of this trial only. Each subject received first the test treatment (T2) followed by a washout period of at least 25 days, followed by the reference treatment (R2).
On day 1 of period 1, one film-coated tablet of 5 mg donepezil together with 4 film-coated tablets of 25 mg (total: 100 mg) BI 409306 (T2) were administered orally with 240 ml of water in the morning in fasted state. From day 2 to day 7 in period 1, subjects were administered 4 film-coated tablets of 25 mg (total: 100 mg) BI 409306 orally once daily, followed by a washout period of 25 days. On day 1 of period 2, one film-coated tablet of 5 mg donepezil (R2) was administered as single oral dose with 240 mL of water in the morning in fasted state. | 7 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1, Period 2 | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: 25 mg BI 409306 (R1) / 25 mg BI 409306 + 10 mg Donepezil (T1) | Part 2: 5 mg Donepezil (R2) / 5 mg Donepezil + 100 mg BI 409306 (T2) | Part 2: 5 mg Donepezil + 100 mg BI 409306 (T2) / 5mg Donepezil (R2) | Total |
|---|---|---|---|---|
| Age, Continuous | 43.7 Years STANDARD_DEVIATION 8.9 | 45.1 Years STANDARD_DEVIATION 8.8 | 36.9 Years STANDARD_DEVIATION 6.3 | 42.5 Years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 5 Participants | 17 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 | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 18 | 15 / 18 | 5 / 17 | 4 / 14 | 12 / 14 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 17 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Part 1: AUC0-tz of BI 409306
Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 to the last quantifiable data point.
Time frame: Within 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14, 16 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations. Only participants with non-missing results are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 1: AUC0-tz of BI 409306 | 603 nanomol (nmol)*hour (h)/Litre (L) | Geometric Coefficient of Variation 95.4 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 1: AUC0-tz of BI 409306 | 643 nanomol (nmol)*hour (h)/Litre (L) | Geometric Coefficient of Variation 86.2 |
Comparison: The statistical model used for the analysis of those endpoints was an analysis of variance (ANOVA) model on the logarithmic scale (natural logarithm). This model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the other effect was considered as fixed.~Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [89.502, 111.62]
Primary
Part 1: Cmax of BI 409306
Maximum measured concentration of the BI 409306 in plasma.
Time frame: Within 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14,16 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations. Only participants with non-missing results are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 1: Cmax of BI 409306 | 268 nmol/L | Geometric Coefficient of Variation 86.2 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 1: Cmax of BI 409306 | 286 nmol/L | Geometric Coefficient of Variation 47.8 |
Comparison: The statistical model used for the analysis of those endpoints was an analysis of variance (ANOVA) model on the logarithmic scale (natural logarithm). This model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the other effect was considered as fixed.~Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [81.861, 124.17]
Primary
Part 2: AUC0-tz of Donepezil
Area under the concentration-time curve of donepezil in plasma over the time interval from 0 to the last quantifiable data point.
Time frame: At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 2: AUC0-tz of Donepezil | 299 nanogram (ng)*h/ millilitre (mL) | Geometric Coefficient of Variation 20.4 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 2: AUC0-tz of Donepezil | 301 nanogram (ng)*h/ millilitre (mL) | Geometric Coefficient of Variation 20.6 |
Comparison: 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: 'sequence', 'subjects within sequences', 'periods' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [97.584, 104.19]
Primary
Part 2: Cmax of Donepezil
Maximum measured concentration of the donepezil in plasma.
Time frame: At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 2: Cmax of Donepezil | 6.23 ng/mL | Geometric Coefficient of Variation 27.5 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 2: Cmax of Donepezil | 7.04 ng/mL | Geometric Coefficient of Variation 30 |
Comparison: 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: 'sequence', 'subjects within sequences', 'periods' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.~Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [106.41, 120.15]
Secondary
Part 1: AUC 0-infinity of BI 409306
Area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity.
Time frame: At approximate 3 hours (h) prior to administration of BI 409306 and 10, 20, 30, 45 minutes (min) and 1, 1:30, 2:00, 2:30, 3, 4, 5, 6, 8, 10, 12, 14,16 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations. Only participants with non-missing results are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 1: AUC 0-infinity of BI 409306 | 604 nmol*h/L | Geometric Coefficient of Variation 95.5 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 1: AUC 0-infinity of BI 409306 | 644 nmol*h/L | Geometric Coefficient of Variation 86.4 |
Comparison: The statistical model used for the analysis of those endpoints was an analysis of variance (ANOVA) model on the logarithmic scale (natural logarithm). This model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas the other effect was considered as fixed. Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [89.549, 111.68]
Secondary
Part 2: AUC0-infinity of Donepezil
This outcome measure presents the area under the concentration-time curve of donepezil in plasma over the time interval from 0 extrapolated to infinity.
Time frame: At approximate 2 hours (h) prior to first administration of donepezil and 1, 2, 2:30, 3, 3:30, 4, 6, 8, 10, 12, 15, 24:30, 48:30, 72:30, 96:30, 120:30, 144:30, 168:30 hours thereafter.
Population: Pharmacokinetic analysis set (PKS) included all subjects who were documented to have taken at least one dose of trial drug and provided at least one pharmacokinetic (PK) parameter that was defined as primary or secondary endpoint and was judged as PK evaluable and not affected by protocol violations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 25 mg BI 409306 | Part 2: AUC0-infinity of Donepezil | 386 ng*h/mL | Geometric Coefficient of Variation 29.9 |
| 25 mg BI 409306 + 10 mg Donepezil | Part 2: AUC0-infinity of Donepezil | 380 ng*h/mL | Geometric Coefficient of Variation 23.4 |
Comparison: 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: 'sequence', 'subjects within sequences', 'periods' and 'treatment'. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.~Abbreviations used: geometric mean (gMean), donepezil (don)90% CI: [93.413, 103.6]