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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03988803
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 3.4
• Patients Per Site Per Month: 4.6

Study Details

Study Description

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.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study to Investigate the Effects of Memantine on the Pharmacokinetics of BI 425809 and Vice Versa in Healthy Male and Female Subjects (Non-randomized, Single-arm, Open-label, Three-period, One Fixed Sequence Cross-over Study)
• Actual Study Start Date: Jul 17, 2019
• Actual Primary Completion Date: Oct 30, 2019
• Actual Study Completion Date: Oct 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All subjects	Drug: BI 425809; Film coated tablet; Drug: Memantine; Film coated tablet

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

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.

4. 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.

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 (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 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)

• Statistical Analysis Plan - Nov 22, 2019
• Study Protocol - Jul 19, 2019

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03988803
• Other Study ID Numbers: 1346-0039; 2019-000468-36
• First Posted: Jun 17, 2019
• Last Update Posted: Apr 13, 2021
• Last Verified: Mar 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: Memantine; BI 425809

Study Results

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 Detail	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.

Arm/Group Title	BI 425809/Memantine/BI 425809+Memantine
Arm/Group Description	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.
Period Title: Screening
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Screening
STARTED	16
COMPLETED	16
NOT COMPLETED	0
Period Title: Screening
STARTED	16
Treated	15
Started Days 1 - 7: Multiple Doses of 5 mg Memantine qd	15
Started Days 8 - 14: Multiple Doses of 10 mg Memantine qd	14
Started Days 15 - 21: Multiple Doses of 15 mg Memantine qd	13
Started Days 22 - 35: Multiple Doses of 20 mg Memantine qd	13
COMPLETED	13
NOT COMPLETED	3
Period Title: Screening
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	BI 425809/Memantine/BI 425809+Memantine
Arm/Group Description	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.
Overall Participants	16
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	32.1 (7.5)
Sex: Female, Male (Count of Participants)
Female	6 37.5%
Male	10 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 425809	Memantine + BI 425809
Arm/Group Description	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.	Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) in combination with oral administration of 1 tablet of 20 mg Memantine with 240 milliliter (mL) of water after an overnight fast of at least 10 hours for days 1 - 10 of period 3.
Measure Participants	16	13
Geometric Mean (Standard Error) [nanomol * hours per liter]	9029.04 (1.09)	8559.78 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809, Memantine + BI 425809
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R1)
	Estimated Value	94.80
	Confidence Interval	(2-Sided) 90%; 87.14 to 103.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.2
	Estimation Comments	Standard error of the mean is the geometric coefficient of variation

2. Primary Outcome

Title	Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : BI 425809)
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.
Time Frame	Detailed time frame can be found in the measure description.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 425809	Memantine + BI 425809
Arm/Group Description	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.	Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) in combination with oral administration of 1 tablet of 20 mg Memantine with 240 milliliter (mL) of water after an overnight fast of at least 10 hours for days 1 - 10 of period 3.
Measure Participants	16	13
Geometric Mean (Standard Error) [nanomol per liter]	535.03 (1.07)	531.49 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809, Memantine + BI 425809
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R1)
	Estimated Value	99.34
	Confidence Interval	(2-Sided) 90%; 91.22 to 108.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.3
	Estimation Comments	Standard error fo the mean is the geometric coefficient of variation

3. Primary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Memantine	Memantine + BI 425809
Arm/Group Description	Treatment period 2 (Reference 2 (R2)): Oral administration of 1 film-coated tablet of Memantine alone with 240 milliliter (mL) of water after an overnight fast of at least 10 hours once daily. Memantine was up-titrated starting with one tablet of 5 mg for days 1-7 of period 2, for days 8 -14 of period 2 one tablet of 10 mg Memantine daily, for days 15-21 one tablet of 15 mg Memantine daily, for days 22 - 28 of period 2 one tablet of 20 mg daily, and from days 29 - 35 of period 2 one tablet of 20 mg daily.	Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) in combination with oral administration of 1 tablet of 20 mg Memantine with 240 milliliter (mL) of water after an overnight fast of at least 10 hours for days 1 - 10 of period 3.
Measure Participants	13	13
Geometric Mean (Standard Error) [nanomol * hours per liter]	1800.36 (1.09)	1866.76 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 425809, Memantine + BI 425809
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R2)
	Estimated Value	103.69
	Confidence Interval	(2-Sided) 90%; 99.99 to 107.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.2
	Estimation Comments	Standard error fo the mean is the geometric coefficient of variation

4. Primary Outcome

Title	Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ (BI 425809 + Memantine : Memantine)
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.
Time Frame	Detailed time frame can be found in the measure description.

Outcome Measure Data

Analysis Population Description

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/Group Title	Memantine	Memantine + BI 425809
Arm/Group Description	Treatment period 2 (Reference 2 (R2)): Oral administration of 1 film-coated tablet of Memantine alone with 240 milliliter (mL) of water after an overnight fast of at least 10 hours once daily. Memantine was up-titrated starting with one tablet of 5 mg for days 1-7 of period 2, for days 8 -14 of period 2 one tablet of 10 mg Memantine daily, for days 15-21 one tablet of 15 mg Memantine daily, for days 22 - 28 of period 2 one tablet of 20 mg daily, and from days 29 - 35 of period 2 one tablet of 20 mg daily.	Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) in combination with oral administration of 1 tablet of 20 mg Memantine with 240 milliliter (mL) of water after an overnight fast of at least 10 hours for days 1 - 10 of period 3.
Measure Participants	13	13
Geometric Mean (Standard Error) [nanomol per liter]	87.06 (1.08)	93.54 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine + BI 425809
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the geometric means (T/R2)
	Estimated Value	107.45
	Confidence Interval	(2-Sided) 90%; 102.66 to 112.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.5
	Estimation Comments	Standard error fo the mean is the geometric coefficient of variation

Adverse Events

Time Frame	Adverse events of BI 425809: up to 17 days. Adverse events of Memantine: up to 41 days. Adverse events of Memantine + BI 425809: up to 25 days. All-Cause Mortality was collected for up to 91 days.
Adverse Event Reporting Description	Treated set (TS): The treated set included all subjects who were treated with at least one dose of study drug. The treated set was used for safety analyses
Arm/Group Title	BI 425809		Memantine		Memantine + BI 425809
Arm/Group Description	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 milliliter (mL) of water after an overnight fast of at least 10 hours once daily. Memantine was up-titrated starting with one tablet of 5 mg for days 1-7 of period 2, for days 8 -14 of period 2 one tablet of 10 mg Memantine daily, for days 15-21 one tablet of 15 mg Memantine daily, for days 22 - 28 of period 2 one tablet of 20 mg daily, and from days 29 - 35 of period 2 one tablet of 20 mg daily.		Oral administration of 25 milligram (mg) BI 425809 (1 tablet of 25 mg) in combination with oral administration of 1 tablet of 20 mg Memantine with 240 milliliter (mL) of water after an overnight fast of at least 10 hours for days 1 - 10 of period 3.
All Cause Mortality
	BI 425809		Memantine		Memantine + BI 425809
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	BI 425809		Memantine		Memantine + BI 425809
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	BI 425809		Memantine		Memantine + BI 425809
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/16 (62.5%)		10/15 (66.7%)		10/15 (66.7%)
Eye disorders
Vision blurred	1/16 (6.3%)		0/15 (0%)		1/15 (6.7%)
Photophobia	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Gastrointestinal disorders
Diarrhoea	2/16 (12.5%)		1/15 (6.7%)		1/15 (6.7%)
Abdominal pain	0/16 (0%)		1/15 (6.7%)		0/15 (0%)
Aphthous ulcer	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Nausea	1/16 (6.3%)		1/15 (6.7%)		0/15 (0%)
Abdominal pain lower	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Abdominal pain upper	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Gastrooesophageal reflux disease	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Vomiting	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
General disorders
Fatigue	5/16 (31.3%)		2/15 (13.3%)		2/15 (13.3%)
Vessel puncture site reaction	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Infections and infestations
Gastroenteritis	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Hordeolum	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Nasopharyngitis	0/16 (0%)		1/15 (6.7%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Post lumbar puncture syndrome	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Investigations
Eosinophil percentage increased	0/16 (0%)		1/15 (6.7%)		0/15 (0%)
Nervous system disorders
Headache	5/16 (31.3%)		4/15 (26.7%)		2/15 (13.3%)
Dizziness	2/16 (12.5%)		2/15 (13.3%)		1/15 (6.7%)
Tension headache	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Head discomfort	1/16 (6.3%)		0/15 (0%)		0/15 (0%)
Psychiatric disorders
Change in sustained attention	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Emotional disorder	0/16 (0%)		1/15 (6.7%)		0/15 (0%)
Libido decreased	0/16 (0%)		1/15 (6.7%)		0/15 (0%)
Listless	1/16 (6.3%)		1/15 (6.7%)		0/15 (0%)
Sleep disorder	0/16 (0%)		0/15 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/16 (0%)		2/15 (13.3%)		1/15 (6.7%)
Cough	0/16 (0%)		0/15 (0%)		1/15 (6.7%)

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.