BI 409306 in Patients With Cognitive Impairment Due to Alzheimer's Disease.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02337907
• Collaborator: (none)
• Enrollment: 329
• Locations: 60
• Arms: 6
• Actual Duration (Months): 32.6
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study is designed to compare the effects of BI 409306 compared to placebo in patients with cognitive impairment due to Alzheimer's Disease

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: Placebo; Drug: Placebo; Drug: BI 409306; Drug: Donepezil	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 329 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Double-blind, Parallel-group, Randomised Controlled Study to Investigate Efficacy, Safety and Tolerability of Orally Administered BI 409306 During a 12-week Treatment Period Compared to Placebo in Patients With Cognitive Impairment Due to Alzheimer's Disease
• Actual Study Start Date: Jan 21, 2015
• Actual Primary Completion Date: Sep 15, 2017
• Actual Study Completion Date: Oct 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo comparator	Drug: Placebo; for blinding purposes; Drug: Placebo
Experimental: BI 409306 dose 1	Drug: Placebo; for blinding purposes; Drug: BI 409306
Experimental: BI 409306 dose 2	Drug: Placebo; for blinding purposes; Drug: BI 409306
Experimental: BI 409306 dose 3	Drug: Placebo; for blinding purposes; Drug: BI 409306
Active Comparator: Active Comparator Donepezil	Drug: Placebo; for blinding purposes; Drug: Donepezil
Experimental: BI 409306 dose 4	Drug: Placebo; for blinding purposes; Drug: BI 409306

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment. [Baseline and 12 weeks]

   Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Least Squares Mean is actually an adjusted mean change from baseline.

2. Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Sister Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907) [Baseline and 12 weeks]

   Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. The number of low test scores decreased with higher levels of intellectual abilities. Least Squares Mean is actually an adjusted mean change from baseline.

Secondary Outcome Measures

1. Change From Baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Total Score After 12-week Treatment [Baseline and 12 weeks]

   Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score can range from 0 to 78. Higher scores indicate better function. Least Squares Mean is actually an adjusted mean change from baseline.

2. Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment [Baseline and 12 weeks]

   The CDR-SB is obtained through semi-structured interviews of patients and informants, and cognitive functioning was rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Each domain was rated on a 5-point scale of functioning as follows: 0-no impairment; 0.5-questionable impairment; 1-mild impairment; 2-moderate impairment and 3-severe impairment. Only personal care was scored on a 4-point scale without a 0.5 rating available. The higher the score, the greater the severity of dementia. Least Squares Mean is actually an adjusted mean change from baseline.

3. Change From Baseline in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment [Baseline and 12 weeks]

   Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog11) is an 11-item cognitive subscale that objectively measures memory, language, orientation, and praxis with a total score range of 0 to 70. The greater the dysfunction, the greater the score. Least Squares Mean is actually an adjusted mean change from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patients with early signs of dementia of Alzheimer Type

• Male and female patients with an age of at least 55 years

• Previous use of Alzheimer's Disease (AD) medications (AChEIs, memantine) is allowed up 3 month prior to screening. Patients who are currently taking AChEIs are eligible as long as they have been using a stable dose for at least 3 months prior to screening and no change is foreseen for the duration of the study. This dose must be consistent with the product label in the concerned country. Patients currently taking memantine are excluded.

• Patients must have at least 6 years of formal education and fluency in the test language as verbally confirmed by the patient and documented by the study investigator.

• Patients must have a reliable study partner (per investigator judgement, for instance a family member, partner etc., guardian or, if applicable, a legal representative)

Exclusion criteria:

• Cognitive impairment or dementia with any etiology other than Alzheimer's Disease (AD)

• Substantial concomitant cerebrovascular disease (defined by a history of a stroke / intracranial haemorrhagia) temporally related to the onset of worsening of cognitive impairment per investigator judgement

• Medical history or diagnosis of any of symptomatic and unstable/uncontrolled conditions per investigator judgement

• Any other psychiatric disorders such as schizophrenia, or mental retardation

• Previous participation in investigational drug studies of mild cognitive impairment/Dementia of Alzheimer Type (DAT) within three months prior to screening. Having received active treatment in any other study targeting disease modification of AD like Aß immunization and tau therapies. Previous participation in studies with non-prescription medications, vitamins or other nutritional formulations is allowed.

• Clinically significant uncompensated hearing loss in the judgment of the investigator. Use of hearing aids is allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Neuroscience Research	Sherman Oaks	California	United States	91403
2	Bioclinica Research	Orlando	Florida	United States	32806
3	Premiere Research Institute	West Palm Beach	Florida	United States	33407
4	Indiana University	Indianapolis	Indiana	United States	46202
5	Memory Enhancement Center of America, Inc.	Eatontown	New Jersey	United States	07724
6	Psychiatry And Alzheimer's Care of Rochester, PLLC	Rochester	New York	United States	14623
7	Richmond Behavioral Associates	Staten Island	New York	United States	10312
8	ANI Neurology, PLLC, dba Alzheimer's Memory Center	Charlotte	North Carolina	United States	28270
9	Tulsa Clinical Research, LLC	Tulsa	Oklahoma	United States	74104
10	The Memory Clinic	Bennington	Vermont	United States	05201
11	Private Practice for Psychiatry and Neurology	Wien		Austria	1130
12	Brussels-UNIV Brugmann -Horta	Brussel		Belgium	1020
13	AZ Sint-Blasius	Dendermonde		Belgium	9200
14	UNIV UZ Gent	Gent		Belgium	9000
15	Mons - UNIV Ambroise Paré	Mons		Belgium	7000
16	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
17	Dr. Alexander McIntyre Inc.	Penticton	British Columbia	Canada	V2A 4M4
18	Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 1A5
19	Institut universitaire de geriatrie Sherbrooke	Quebec		Canada	J1J 3H5
20	HOP Pellegrin	Bordeaux		France	33076
21	HOP Bocage	Dijon		France	21079
22	HOP Timone	Marseille		France	13385
23	HOP Gui de Chauliac	Montpellier		France	34295
24	HOP Nord Laënnec	Nantes		France	44093
25	HOP La Pitié Salpêtrière	Paris		France	75651
26	HOP Jean Bernard, Géria, Poitiers	Poitiers		France	86021
27	Praxis Dr. med. Volker Schumann	Berlin		Germany	10245
28	emovis GmbH	Berlin		Germany	10629
29	St. Josef- und St. Elisabeth-Hospital gGmbH	Bochum		Germany	44791
30	Neuro Centrum Science GmbH	Erbach		Germany	64711
31	AFL Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04107
32	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
33	Zentralinstitut für seelische Gesundheit	Mannheim		Germany	68159
34	Universitätsklinikum Ulm	Ulm		Germany	89081
35	Neurologie und Psychiatrie / Psychotherapie	Westerstede		Germany	26655
36	P.O. Bellaria IRCCS Istituto delle scienze Neurologiche di Bologna	Bologna		Italy	40139
37	Azienda Ospedaliera Careggi	Firenze		Italy	50134
38	Azienda Ospedaliera di Parma	Parma		Italy	43126
39	Jeroen Bosch Ziekenhuis-Hertogenbosch	's-HERTOGENBOSCH		Netherlands	5223 GZ
40	Brain Research Center	Amsterdam		Netherlands	1081 GN
41	Podlassian Center of Psychogeriatry, Bialystok	Bialystok		Poland	15-756
42	Mental Health Center Biomed	Kielce		Poland	25-411
43	Non-Public Outpatient Clinic Neuromed M. i M. Nastaj	Lublin		Poland	20-064
44	Inst. of Rural Health, Spec. Outp. Clin. & Rural Occup. Dis.	Lublin		Poland	20-090
45	Non-Public Outpatient Clinic Neuro-Kard Ilkowski & Partners	Poznan		Poland	61-853
46	Medical Center Senior	Sopot		Poland	81-855
47	EUROMEDIS Sp. z o.o., Szczecin	Szczecin		Poland	70-111
48	Reg. Specialist Hospital Wroclaw, Research & Develop. Center	Wroclaw		Poland	51-124
49	Hospital Fernando Fonseca, EPE	Amadora		Portugal	2700-276
50	Hospital de Braga-Escala Braga	Braga		Portugal	4710-243
51	CHUC - Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra		Portugal	3000-075
52	Hospital Senhora Oliveira Guimarães,EPE	Guimarães		Portugal	4835-044
53	CHLO, EPE - Hospital Egas Moniz	Lisboa		Portugal	1349-019
54	Hospital Beatriz Ângelo	Loures		Portugal	2674-514
55	ULSM, EPE - Hospital Pedro Hispano	Matosinhos		Portugal	4454-509
56	Centro Hospitalar de Entre o Douro e Vouga, E.P.E. - Hospital de São Sebastião	Santa Maria da Feira		Portugal	4520-211
57	Royal United Hospital	Bath		United Kingdom	BA1 3NG
58	Ninewells Hospital & Medical School	Dundee, Scotland		United Kingdom	DD19SY
59	West Devon (Tavistock) CMHT & Memory Clinic (EDI)	Ivybridge		United Kingdom	PL219AB
60	Re-Cognition Health	Plymouth		United Kingdom	PL6 8BT

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 13, 2017
• Study Protocol - Feb 23, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02337907
• Other Study ID Numbers: 1289.7; 2013-005040-28
• First Posted: Jan 14, 2015
• Last Update Posted: Nov 14, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Alzheimer Disease; Cognitive Dysfunction; Donepezil; BI 409306

Study Results

Participant Flow

Recruitment Details	This was a Phase II, multi-centre, double-blind, parallel-group, randomised, placebo controlled trial with patients with mild Alzheimer's disease. The randomisation allocation ratio was 1:1:1:1:2 of 10 milligram (mg), 25 mg, 50 mg once daily (QD), 25 mg twice a day (BID) of BI 409306 and placebo respectively.
Pre-assignment Detail	All patients were screened for eligibility. All patients eligible after screening underwent a 2-week single-blind placebo run-in period before randomisation. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were not met.

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Placebo Matching BI 409306	Donepezil QD
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.	Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.
Period Title: Overall Study
STARTED	55	53	55	55	106	5
COMPLETED	51	49	54	51	96	4
NOT COMPLETED	4	4	1	4	10	1

Baseline Characteristics

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Placebo Matching BI 409306	Donepezil QD	Total
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.	Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.	Total of all reporting groups
Overall Participants	55	53	55	55	106	5	329
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.7 (8.4)	74.2 (7.8)	73.0 (6.5)	74.8 (9.1)	74.0 (7.7)	79.6 (7.0)	74.0 (7.9)
Sex: Female, Male (Count of Participants)
Female	26 47.3%	30 56.6%	26 47.3%	30 54.5%	48 45.3%	3 60%	163 49.5%
Male	29 52.7%	23 43.4%	29 52.7%	25 45.5%	58 54.7%	2 40%	166 50.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.6%	2 3.8%	4 7.3%	2 3.6%	2 1.9%	1 20%	13 4%
Not Hispanic or Latino	53 96.4%	51 96.2%	51 92.7%	53 96.4%	104 98.1%	4 80%	316 96%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 1.8%	0 0%	1 1.8%	0 0%	0 0%	0 0%	2 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	3 2.8%	0 0%	3 0.9%
White	54 98.2%	53 100%	54 98.2%	55 100%	103 97.2%	5 100%	324 98.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.
Description	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS): FAS includes all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one post-baseline on-treatment primary endpoint NTB or secondary endpoint assessment. Observed cases (OC)

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Pooled BI 409306	Placebo Matching BI 409306
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Measure Participants	54	50	55	55	214	101
Least Squares Mean (Standard Error) [Z-score]	0.13 (0.059)	0.17 (0.061)	0.16 (0.056)	0.01 (0.060)	0.12 (0.30)	0.15 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.7907
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.163 to 0.124
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.073
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg QD, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.7622
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.125 to 0.171
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.075
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg QD, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.8789
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.130 to 0.152
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.071
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.0609
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.285 to 0.006
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.074
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pooled BI 409306, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments	H1-0: Mean NTB response of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg QD = Mean NTB response of placebo
Statistical Test of Hypothesis	p-Value	0.5687
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.135 to 0.074
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.053
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences

2. Primary Outcome

Title	Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Sister Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907)
Description	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. The number of low test scores decreased with higher levels of intellectual abilities. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

FAS (OC) and for pooled group FAS

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Pooled BI 409306	Placebo Matching BI 409306
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Measure Participants	76	71	76	76	299	144
Least Squares Mean (Standard Error) [Z-score]	0.20 (0.046)	0.19 (0.048)	0.19 (0.046)	0.10 (0.047)	0.17 (0.025)	0.19 (0.035)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.8694
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.101 to 0.120
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.056
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg QD, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.9512
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.116 to 0.109
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg QD, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.9321
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.105 to 0.115
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.056
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
	Type of Statistical Test	Superiority
	Comments	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.1288
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.199 to 0.025
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pooled BI 409306, Placebo Matching BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
	Type of Statistical Test	Superiority
	Comments	H1-0: Mean NTB response of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg QD = Mean NTB response of placebo.
Statistical Test of Hypothesis	p-Value	0.6492
	Comments	p-value was nominal and not adjusted.
	Method	Mixed Model Repeated Measurement (MMRM)
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.098 to 0.061
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.041
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences

3. Secondary Outcome

Title	Change From Baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Total Score After 12-week Treatment
Description	Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score can range from 0 to 78. Higher scores indicate better function. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Placebo Matching BI 409306
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Measure Participants	54	50	55	55	101
Least Squares Mean (Standard Error) [Unit on scale]	0.10 (0.853)	-0.99 (0.892)	0.35 (0.847)	-1.07 (0.855)	-0.58 (0.639)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 10 Milligram (mg) Once Daily (QD), Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.5287
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; -1.43 to 2.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.066
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg QD, Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.7105
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -2.57 to 1.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.099
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg QD, Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.3822
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; -1.16 to 3.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.064
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg Twice Daily (BID), Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.6472
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -2.59 to 1.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.066
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

4. Secondary Outcome

Title	Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment
Description	The CDR-SB is obtained through semi-structured interviews of patients and informants, and cognitive functioning was rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Each domain was rated on a 5-point scale of functioning as follows: 0-no impairment; 0.5-questionable impairment; 1-mild impairment; 2-moderate impairment and 3-severe impairment. Only personal care was scored on a 4-point scale without a 0.5 rating available. The higher the score, the greater the severity of dementia. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Placebo Matching BI 409306
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Measure Participants	54	50	55	55	101
Least Squares Mean (Standard Error) [Unit on scale]	0.1 (0.23)	0.3 (0.23)	0.1 (0.21)	0.2 (0.22)	0.1 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 10 Milligram (mg) Once Daily (QD), Pooled BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7551
	Comments	p-value was nominal and not adjusted.
	Method	Mixed-effects Model for Repeated Measure
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg QD, Pooled BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3643
	Comments	p-value was nominal and not adjusted.
	Method	Mixed-effects Model for Repeated Measure
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg QD, Pooled BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7822
	Comments	p-value was nominal and not adjusted.
	Method	Mixed-effects Model for Repeated Measure
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.45 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg Twice Daily (BID), Pooled BI 409306
	Comments	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6889
	Comments	p-value was nominal and not adjusted.
	Method	Mixed-effects Model for Repeated Measure
	Comments	Kenward-Roger was used to model degrees of freedom.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

5. Secondary Outcome

Title	Change From Baseline in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment
Description	Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog11) is an 11-item cognitive subscale that objectively measures memory, language, orientation, and praxis with a total score range of 0 to 70. The greater the dysfunction, the greater the score. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)	BI 409306 25 mg QD	BI 409306 50 mg QD	BI 409306 25 mg Twice Daily (BID)	Placebo Matching BI 409306
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Measure Participants	54	50	55	55	101
Least Squares Mean (Standard Error) [Unit on scale]	1.14 (0.738)	0.94 (0.776)	1.11 (0.746)	2.29 (0.746)	-0.18 (0.568)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 409306 10 Milligram (mg) Once Daily (QD), Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.1595
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; -0.52 to 3.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.933
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg QD, Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.2455
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; -0.77 to 3.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.962
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BI 409306 50 mg QD, Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.1732
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; -0.57 to 3.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.940
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BI 409306 25 mg Twice Daily (BID), Pooled BI 409306
	Comments	The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
	Type of Statistical Test	Superiority
	Comments	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis	p-Value	0.0088
	Comments	p-value was nominal and not adjusted.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.47
	Confidence Interval	(2-Sided) 95%; 0.63 to 4.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.936
	Estimation Comments	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Adverse Events

Time Frame	From the first dose of study medication until 7 days after last administration of BI 409306, up to 16 weeks.
Adverse Event Reporting Description	The treated set (TS) used (all patients who were randomised and treated with at least one dose of trial medication.) for safety assessment.
Arm/Group Title	BI 409306 10 Milligram (mg) Once Daily (QD)		BI 409306 25 mg QD		BI 409306 50 mg QD		BI 409306 25 mg Twice Daily (BID)		Placebo Matching BI 409306		Donepezil QD
Arm/Group Description	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.		Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.		Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.		Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.		Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.		Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.
All Cause Mortality
	BI 409306 10 Milligram (mg) Once Daily (QD)		BI 409306 25 mg QD		BI 409306 50 mg QD		BI 409306 25 mg Twice Daily (BID)		Placebo Matching BI 409306		Donepezil QD
	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	1/55 (1.8%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Serious Adverse Events
	BI 409306 10 Milligram (mg) Once Daily (QD)		BI 409306 25 mg QD		BI 409306 50 mg QD		BI 409306 25 mg Twice Daily (BID)		Placebo Matching BI 409306		Donepezil QD
	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	1/55 (1.8%)		3/53 (5.7%)		1/55 (1.8%)		3/55 (5.5%)		8/106 (7.5%)		0/5 (0%)
Cardiac disorders
Angina pectoris	0/55 (0%)		1/53 (1.9%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Ear and labyrinth disorders
Vertigo positional	0/55 (0%)		0/53 (0%)		0/55 (0%)		1/55 (1.8%)		0/106 (0%)		0/5 (0%)
Gastrointestinal disorders
Haemorrhoids	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Infections and infestations
Respiratory tract infection viral	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Fall	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Investigations
Electrocardiogram QT prolonged	0/55 (0%)		0/53 (0%)		1/55 (1.8%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Nervous system disorders
Cerebrovascular accident	0/55 (0%)		1/53 (1.9%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Dementia Alzheimer's type	1/55 (1.8%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Encephalopathy	1/55 (1.8%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Epilepsy	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Loss of consciousness	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Psychiatric disorders
Delirium	0/55 (0%)		1/53 (1.9%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Suicidal ideation	0/55 (0%)		0/53 (0%)		0/55 (0%)		2/55 (3.6%)		1/106 (0.9%)		0/5 (0%)
Renal and urinary disorders
Nephrolithiasis	0/55 (0%)		0/53 (0%)		0/55 (0%)		1/55 (1.8%)		0/106 (0%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Vascular disorders
Deep vein thrombosis	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Peripheral artery aneurysm	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	BI 409306 10 Milligram (mg) Once Daily (QD)		BI 409306 25 mg QD		BI 409306 50 mg QD		BI 409306 25 mg Twice Daily (BID)		Placebo Matching BI 409306		Donepezil QD
	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	6/55 (10.9%)		9/53 (17%)		7/55 (12.7%)		2/55 (3.6%)		8/106 (7.5%)		1/5 (20%)
Infections and infestations
Nasopharyngitis	1/55 (1.8%)		4/53 (7.5%)		3/55 (5.5%)		0/55 (0%)		1/106 (0.9%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/55 (5.5%)		0/53 (0%)		0/55 (0%)		1/55 (1.8%)		2/106 (1.9%)		0/5 (0%)
Nervous system disorders
Headache	2/55 (3.6%)		5/53 (9.4%)		1/55 (1.8%)		1/55 (1.8%)		5/106 (4.7%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/55 (0%)		0/53 (0%)		3/55 (5.5%)		0/55 (0%)		0/106 (0%)		0/5 (0%)
Rhinitis allergic	0/55 (0%)		0/53 (0%)		0/55 (0%)		0/55 (0%)		0/106 (0%)		1/5 (20%)

Limitations/Caveats

There were 5 patients who were randomised to donepezil arm which was dropped from the trial with protocol amendment. No further patients were randomised to this arm, but patients already randomised continued in the trial as originally planned.

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.