Healthy
Conditions
Brief summary
Investigate the effect of steady state exposures of memantine on the steady-state pharmacokinetics of BI 425809 and vice versa in healthy subjects.
Interventions
DRUGBI 425809
Film coated tablet
DRUGMemantine
Film coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
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 (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 50 years (inclusive) * 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 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. nonhormonal 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 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 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 * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | Detailed time frame is described in the measure description section. | Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). Comparison of BI 425809 + Memantine versus BI 425809. Period 1 (BI 425809): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h (10 minutes (min) before the next dosing ) after first administration of BI 425809 on day 10 of Period 1. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 min before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after first administration of BI 425809 + Memantine on day 10 of Period 3. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | Detailed time frame can be found in the measure description. | Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmax,ss). Comparison of BI 425809 + Memantine versus BI 425809. Period 1 (BI 425809): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h (10 minutes (min) before the next dosing ) after first administration of BI 425809 on day 10 of Period 1. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 min before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after first administration of BI 425809 + Memantine on day 10 of Period 3. |
| Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | Detailed time frame is described in the measure description section. | Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). Comparison of BI 425809 + Memantine versus BI 425809. Treatment Period 2 (Memantine): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12 h after administration of Memantine on day 35 of Period 2. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after administration of BI 425809 + Memantine on day 10 of Period 3. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | Detailed time frame can be found in the measure description. | Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmax,ss). Comparison of BI 425809 + Memantine versus BI Memantine. Treatment Period 2 (Memantine): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12 h after administration of Memantine on day 35 of Period 2. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after administration of BI 425809 + Memantine on day 10 of Period 3. |
Countries
Germany
Participant flow
Recruitment details
Non-randomised, single-arm, open-Label, three-period, one fixed sequence cross-over Study to investigate the effects of memantine in steady state on the pharmacokinetics of BI 425809 in steady state and vice versa in healthy male and female subjects.
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects visited specialist site to ensure that they met all implemented inclusion criteria. Subjects meeting the exclusion criteria were excluded.
Participants by arm
| Arm | Count |
|---|---|
| BI 425809/Memantine/BI 425809+Memantine Treatment period 1 (Reference 1 (R1)): Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours once daily for days 1 - 10 of period 1. Treatment period 2 (Reference 2 (R2)): Oral administration of 1 film-coated tablet of Memantine alone with 240 mL of water after an overnight fast of at least 10 hours once daily. Dose was up-titrated starting with one tablet of 5 mg for days 1-7, for days 8 -14 one tablet of 10 mg, for days 15-21 one tablet of 15 mg, for days 22 - 28 one tablet of 20 mg, and from days 29 - 35 of period 2 one tablet of 20 mg for period 2. Treatment Period 3 (Test (T)): Oral administration of 25 mg BI 425809 in combination with oral administration one tablet of 20 mg memantine with 240 mL of water after an overnight fast of at least 10 hours once daily for days 1 - 10 of period 3. Periods 1 and 2 with a washout period of at least 7 days. Period 3 followed directly after Period 2. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2 | Adverse Event | 1 |
| Period 2 | Prematurely discontinued from medication | 2 |
Baseline characteristics
| Characteristic | BI 425809/Memantine/BI 425809+Memantine |
|---|---|
| Age, Continuous | 32.1 Years STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 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 | 16 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 10 / 16 | 10 / 15 | 10 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809)
Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). Comparison of BI 425809 + Memantine versus BI 425809. Period 1 (BI 425809): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h (10 minutes (min) before the next dosing ) after first administration of BI 425809 on day 10 of Period 1. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 min before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after first administration of BI 425809 + Memantine on day 10 of Period 3.
Time frame: Detailed time frame is described in the measure description section.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least one pharmacokinetic (PK) endpoint that was defined as Primary and was not excluded due to protocol deviations relevant to the evaluation of PK or due to PK non-evaluability
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 425809 | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | 9029.04 nanomol * hours per liter | Standard Error 1.09 |
| Memantine + BI 425809 | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | 8559.78 nanomol * hours per liter | Standard Error 1.09 |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That was, the PK endpoints were logtransformed (natural logarithm) prior to fitting the ANOVA model. The model used included effects accounting for the following sources of variation: subjects and treatment. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [87.14, 103.14]ANOVA
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine)
Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). Comparison of BI 425809 + Memantine versus BI 425809. Treatment Period 2 (Memantine): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12 h after administration of Memantine on day 35 of Period 2. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after administration of BI 425809 + Memantine on day 10 of Period 3.
Time frame: Detailed time frame is described in the measure description section.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least one pharmacokinetic (PK) endpoint that was defined as Primary and was not excluded due to protocol deviations relevant to the evaluation of PK or due to PK non-evaluability
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 425809 | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | 1800.36 nanomol * hours per liter | Standard Error 1.09 |
| Memantine + BI 425809 | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | 1866.76 nanomol * hours per liter | Standard Error 1.09 |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That was, the PK endpoints were logtransformed (natural logarithm) prior to fitting the ANOVA model. The model used included effects accounting for the following sources of variation: subjects and treatment. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [99.99, 107.52]ANOVA
Primary
Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809)
Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmax,ss). Comparison of BI 425809 + Memantine versus BI 425809. Period 1 (BI 425809): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h (10 minutes (min) before the next dosing ) after first administration of BI 425809 on day 10 of Period 1. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 min before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after first administration of BI 425809 + Memantine on day 10 of Period 3.
Time frame: Detailed time frame can be found in the measure description.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least one pharmacokinetic (PK) endpoint that was defined as Primary and was not excluded due to protocol deviations relevant to the evaluation of PK or due to PK non-evaluability
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 425809 | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | 535.03 nanomol per liter | Standard Error 1.07 |
| Memantine + BI 425809 | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809) | 531.49 nanomol per liter | Standard Error 1.07 |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That was, the PK endpoints were logtransformed (natural logarithm) prior to fitting the ANOVA model. The model used included effects accounting for the following sources of variation: subjects and treatment. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [91.22, 108.18]ANOVA
Primary
Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine)
Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmax,ss). Comparison of BI 425809 + Memantine versus BI Memantine. Treatment Period 2 (Memantine): Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12 h after administration of Memantine on day 35 of Period 2. Treatment Period 3 (Memantine + BI 425809) Measurements of steady state concentration where taken 10 minutes (min) before the next dosing of BI 425809 + Memantine and 30 min, 1h, 2h, 3h, 3h 30min, 4h, 4h 30min, 5h, 6h, 7h, 8h, 10h, 12h, 24h after administration of BI 425809 + Memantine on day 10 of Period 3.
Time frame: Detailed time frame can be found in the measure description.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided at least one PK endpoint that was defined as Primary and was not excluded due to protocol deviations relevant to the evaluation of PK or due to PK non-evaluability
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 425809 | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | 87.06 nanomol per liter | Standard Error 1.08 |
| Memantine + BI 425809 | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine) | 93.54 nanomol per liter | Standard Error 1.08 |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That was, the PK endpoints were logtransformed (natural logarithm) prior to fitting the ANOVA model. The model used included effects accounting for the following sources of variation: subjects and treatment. The effect 'subjects' was considered as random, whereas the effect 'treatment' was considered as fixed.90% CI: [102.66, 112.45]ANOVA