A Study in Healthy Men and Women to Test Which Effects Donepezil and BI 425809 Have on Each Other

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03905096
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 2
• Actual Duration (Months): 4.6
• Patients Per Site Per Month: 7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 425809; Drug: Donepezil	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study to Investigate the Effects of Donepezil on the Pharmacokinetics of BI 425809 and Vice Versa in Healthy Male and Female Subjects (Open-label, Two-treatment, Two-period, One Fixed Sequence Cross-over Design)
• Actual Study Start Date: Apr 12, 2019
• Actual Primary Completion Date: Aug 30, 2019
• Actual Study Completion Date: Aug 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1	Drug: BI 425809; Film coated tablet; Drug: Donepezil; Film coated tablet
Experimental: Part 2	Drug: BI 425809; Film coated tablet; Drug: Donepezil; Film coated tablet

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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 Outcome Measures

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) [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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CRS Clinical Research Services Mannheim GmbH	Mannheim		Germany	68167

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 29, 2019
• Statistical Analysis Plan - Sep 20, 2019

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03905096
• Other Study ID Numbers: 1346.29; 2018-004806-24
• First Posted: Apr 5, 2019
• Last Update Posted: Feb 17, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Donepezil; BI 425809

Study Results

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 Detail	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.

Arm/Group Title	Trial Part 1: BI 425809 / Donepezil + BI 425809	Trial Part 2: Donepezil / BI 425809 + Donepezil
Arm/Group Description	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.	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.
Period Title: Period 1 for Trial Part 1 and 2
STARTED	18	14
COMPLETED	18	14
NOT COMPLETED	0	0
Period Title: Period 1 for Trial Part 1 and 2
STARTED	18	14
COMPLETED	17	14
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Trial Part 1: BI 425809 / Donepezil + BI 425809	Trial Part 2: Donepezil / BI 425809 + Donepezil	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	18	14	32
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.1 (8.0)	35.9 (8.6)	37.7 (8.3)
Sex: Female, Male (Count of Participants)
Female	16 88.9%	5 35.7%	21 65.6%
Male	2 11.1%	9 64.3%	11 34.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	18 100%	14 100%	32 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	18 100%	14 100%	32 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of BI 425809 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)	BI 425809 + Don Group (Part 1: Treatment B, Test 1)
Arm/Group Description	All participants were orally administered a single dose of BI 425809, 25 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment A, Reference 1).	All participants were orally administered a single dose of BI 425809, 25 mg, film-coated tablet, on day 22 of visit 3, together with multiple doses of donepezil, film-coated tablets, 5 mg (1 tablet) once a day (qd) on day 1 to 7 and 10 mg (2 tablets) qd on day 8 to 29 of visit 3 in the fasted state with about 240 ml of fluid (Treatment B, Test 1).
Measure Participants	17	15
Geometric Mean (Standard Error) [nanomoles * hours per liter]	11815.37 (1.10)	10944.06 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	92.63
	Confidence Interval	(2-Sided) 90%; 85.34 to 100.53
	Parameter Dispersion	Type: Standard Deviation; Value: 12.4
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

2. Primary Outcome

Title	Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Don Alone Group (Part 2: Treatment C, Reference 2)	Don + BI 425809 Group (Part 2: Treatment D, Test 2)
Arm/Group Description	All participants were orally administered a single dose of donepezil, 10 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment C, Reference 2).	All participants were orally administered a single dose of donepezil, 10 mg, film-coated tablet, on day 10 of visit 3, together with multiple doses of BI 425809, film-coated tablets, 25 mg qd on day 1 to 24 of visit 3 in the fasted state with about 240 ml of fluid (Treatment D, Test 2).
Measure Participants	10	12
Geometric Mean (Standard Error) [nanograms * hours per milliliter]	647.16 (1.09)	638.38 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	98.64
	Confidence Interval	(2-Sided) 90%; 93.21 to 104.39
	Parameter Dispersion	Type: Standard Deviation; Value: 6.9
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

3. Primary Outcome

Title	Maximum Measured Concentration of BI 425809 in Plasma (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)	BI 425809 + Don Group (Part 1: Treatment B, Test 1)
Arm/Group Description	All participants were orally administered a single dose of BI 425809, 25 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment A, Reference 1).	All participants were orally administered a single dose of BI 425809, 25 mg, film-coated tablet, on day 22 of visit 3, together with multiple doses of donepezil, film-coated tablets, 5 mg (1 tablet) qd on day 1 to 7 and 10 mg (2 tablets) qd on day 8 to 29 of visit 3 in the fasted state with about 240 ml of fluid (Treatment B, Test 1).
Measure Participants	17	15
Geometric Mean (Standard Error) [nanomoles per liter]	293.97 (1.07)	289.51 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	98.48
	Confidence Interval	(2-Sided) 90%; 90.74 to 106.88
	Parameter Dispersion	Type: Standard Deviation; Value: 12.4
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

4. Primary Outcome

Title	Maximum Measured Concentration of Donepezil in Plasma (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Don Alone Group (Part 2: Treatment C, Reference 2)	Don + BI 425809 Group (Part 2: Treatment D, Test 2)
Arm/Group Description	All participants were orally administered a single dose of donepezil, 10 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment C, Reference 2).	All participants were orally administered a single dose of donepezil, 10 mg, film-coated tablet, on day 10 of visit 3, together with multiple doses of BI 425809, film-coated tablets, 25 mg qd on day 1 to 24 of visit 3 in the fasted state with about 240 ml of fluid (Treatment D, Test 2).
Measure Participants	10	12
Geometric Mean (Standard Error) [nanograms per milliliter]	15.94 (1.12)	15.96 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	100.15
	Confidence Interval	(2-Sided) 90%; 89.01 to 112.68
	Parameter Dispersion	Type: Standard Deviation; Value: 14.4
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

5. Secondary Outcome

Title	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)
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). 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

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)	BI 425809 + Don Group (Part 1: Treatment B, Test 1)
Arm/Group Description	All participants were orally administered a single dose of BI 425809, 25 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment A, Reference 1).	All participants were orally administered a single dose of BI 425809, 25 mg, film-coated tablet, on day 22 of visit 3, together with multiple doses of donepezil, film-coated tablets, 5 mg (1 tablet) qd on day 1 to 7 and 10 mg (2 tablets) qd on day 8 to 29 of visit 3 in the fasted state with about 240 ml of fluid (Treatment B, Test 1).
Measure Participants	17	15
Geometric Mean (Standard Error) [nanomoles * hours per liter]	10638.64 (1.08)	10082.12 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	94.77
	Confidence Interval	(2-Sided) 90%; 88.36 to 101.64
	Parameter Dispersion	Type: Standard Deviation; Value: 10.6
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

6. Secondary Outcome

Title	Area Under the Concentration-time Curve of Donepezil in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Don Alone Group (Part 2: Treatment C, Reference 2)	Don + BI 425809 Group (Part 2: Treatment D, Test 2)
Arm/Group Description	All participants were orally administered a single dose of donepezil, 10 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment C, Reference 2).	All participants were orally administered a single dose of donepezil, 10 mg, film-coated tablet, on day 10 of visit 3, together with multiple doses of BI 425809, film-coated tablets, 25 mg qd on day 1 to 24 of visit 3 in the fasted state with about 240 ml of fluid (Treatment D, Test 2).
Measure Participants	10	12
Geometric Mean (Standard Error) [nanograms * hours per milliliter]	600.86 (1.10)	601.20 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809 Alone Group (Part 1: Treatment A, Reference 1), BI 425809 + Don Group (Part 1: Treatment B, Test 1)
	Comments
	Type of Statistical Test	Other
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R) %
	Estimated Value	100.06
	Confidence Interval	(2-Sided) 90%; 94.56 to 105.87
	Parameter Dispersion	Type: Standard Deviation; Value: 6.9
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference

Adverse Events

Time Frame	The adverse events collection time frame for BI 425809 part 1 is 8 days, for donepezil part 1 it is 28 days, and for donepezil + BI 425809 part 1 it is 14 days. The adverse events collection time frame for donepezil part 2 is 15 days, for BI 425809 part 2 it is 19 days, and for BI 425809 + donepezil part 2 it is 15 days.
Adverse Event Reporting Description	Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.
Arm/Group Title	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)		Donepezil Group (Part 1: Treatment B, Test 1)		BI 425809 + Donepezil Group (Part 1: Treatment B, Test 1)		Donepezil Alone Group (Part 2: Treatment C, Reference 2)		BI 425809 Group (Part 2: Treatment D, Test 2)		Donepezil + BI 425809 Group (Part 2: Treatment D, Test 2)
Arm/Group Description	All participants were orally administered a single dose of BI 425809, 25 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment A, Reference 1).		All participants were orally administered multiple doses of donepezil, film-coated tablets, 5 mg (1 tablet) qd on day 1 to 7 and 10 mg (2 tablets) qd on day 8 to 29 of visit 3 in the fasted state with about 240 ml of fluid (Treatment B, Test 1).		All participants were orally administered a single dose of BI 425809, 25 mg, film-coated tablet, on day 22 of visit 3, together with multiple doses of donepezil, film-coated tablets, 5 mg (1 tablet) qd on day 1 to 7 and 10 mg (2 tablets) qd on day 8 to 29 of visit 3 in the fasted state with about 240 ml of fluid (Treatment B, Test 1).		All participants were orally administered a single dose of donepezil, 10 milligrams (mg) film-coated tablet on day 1 of visit 2 in the fasted state with about 240 milliliters (ml) of fluid (Treatment C, Reference 2).		All participants were orally administered multiple doses of BI 425809, film-coated tablets, 25 mg qd on day 1 to 24 of visit 3 in the fasted state with about 240 ml of fluid (Treatment D, Test 2).		All participants were orally administered a single dose of donepezil, 10 mg, film-coated tablet, on day 10 of visit 3, together with multiple doses of BI 425809, film-coated tablets, 25 mg qd on day 1 to 24 of visit 3 in the fasted state with about 240 ml of fluid (Treatment D, Test 2).
All Cause Mortality
	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)		Donepezil Group (Part 1: Treatment B, Test 1)		BI 425809 + Donepezil Group (Part 1: Treatment B, Test 1)		Donepezil Alone Group (Part 2: Treatment C, Reference 2)		BI 425809 Group (Part 2: Treatment D, Test 2)		Donepezil + BI 425809 Group (Part 2: Treatment D, Test 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)		Donepezil Group (Part 1: Treatment B, Test 1)		BI 425809 + Donepezil Group (Part 1: Treatment B, Test 1)		Donepezil Alone Group (Part 2: Treatment C, Reference 2)		BI 425809 Group (Part 2: Treatment D, Test 2)		Donepezil + BI 425809 Group (Part 2: Treatment D, Test 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	BI 425809 Alone Group (Part 1: Treatment A, Reference 1)		Donepezil Group (Part 1: Treatment B, Test 1)		BI 425809 + Donepezil Group (Part 1: Treatment B, Test 1)		Donepezil Alone Group (Part 2: Treatment C, Reference 2)		BI 425809 Group (Part 2: Treatment D, Test 2)		Donepezil + BI 425809 Group (Part 2: Treatment D, Test 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/18 (27.8%)		15/18 (83.3%)		13/18 (72.2%)		7/14 (50%)		4/14 (28.6%)		10/14 (71.4%)
Eye disorders
Vision blurred	0/18 (0%)		5/18 (27.8%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Gastrointestinal disorders
Nausea	1/18 (5.6%)		9/18 (50%)		5/18 (27.8%)		3/14 (21.4%)		0/14 (0%)		5/14 (35.7%)
Vomiting	1/18 (5.6%)		1/18 (5.6%)		2/18 (11.1%)		4/14 (28.6%)		0/14 (0%)		2/14 (14.3%)
Diarrhoea	0/18 (0%)		2/18 (11.1%)		0/18 (0%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)
Abdominal discomfort	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)
Abdominal pain upper	0/18 (0%)		0/18 (0%)		0/18 (0%)		1/14 (7.1%)		0/14 (0%)		1/14 (7.1%)
Dry mouth	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		1/14 (7.1%)
Flatulence	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)
General disorders
Fatigue	0/18 (0%)		3/18 (16.7%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Feeling hot	0/18 (0%)		0/18 (0%)		0/18 (0%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)
Malaise	0/18 (0%)		1/18 (5.6%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Infections and infestations
Nasopharyngitis	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)
Injury, poisoning and procedural complications
Muscle strain	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/18 (5.6%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Bone pain	0/18 (0%)		1/18 (5.6%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Nervous system disorders
Dizziness	2/18 (11.1%)		6/18 (33.3%)		5/18 (27.8%)		2/14 (14.3%)		1/14 (7.1%)		6/14 (42.9%)
Headache	3/18 (16.7%)		5/18 (27.8%)		4/18 (22.2%)		2/14 (14.3%)		1/14 (7.1%)		3/14 (21.4%)
Syncope	0/18 (0%)		0/18 (0%)		0/18 (0%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)
Migraine	0/18 (0%)		0/18 (0%)		1/18 (5.6%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Psychiatric disorders
Sleep disorder	1/18 (5.6%)		0/18 (0%)		3/18 (16.7%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Abnormal dreams	2/18 (11.1%)		1/18 (5.6%)		2/18 (11.1%)		1/14 (7.1%)		0/14 (0%)		0/14 (0%)
Insomnia	0/18 (0%)		1/18 (5.6%)		0/18 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/18 (0%)		0/18 (0%)		0/18 (0%)		0/14 (0%)		1/14 (7.1%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.