An Efficacy and Safety Study of Lanabecestat (LY3314814) in Early Alzheimer's Disease (AMARANTH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02245737

Recruitment Status : Terminated (An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility)

First Posted : September 22, 2014

Results First Posted : August 6, 2019

Last Update Posted : December 3, 2019

Sponsor:

Collaborator:

Eli Lilly and Company

Information provided by (Responsible Party):

AstraZeneca

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Alzheimer´s Disease
Interventions	Drug: Lanabecestat Drug: Placebo
Enrollment	2218

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Placebo	Lanabecestat 20 Milligrams (mg)	Lanabecestat 50 mg
Arm/Group Description	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Period Title: Overall Study
Started	740	739	739
Received at Least 1 Dose of Study Drug	738	736	735
Completed	187	184	168
Not Completed	553	555	571
Reason Not Completed
Adverse Event	23	26	33
Condition Worsened	9	10	9
Death	2	4	4
Eligibility Criteria No Longer Met	2	4	4
Initiation of Symptomatic AD medication	2	0	0
Lost to Follow-up	2	5	4
Other-determined by Investigator	9	10	10
Physician Decision	6	3	6
Protocol Violation	3	2	3
Withdrawal by Subject	40	41	44
Withdrawal due to Caregiver Circumstance	10	20	22
Sponsor Decision	445	430	432

Baseline Characteristics

Arm/Group Title		Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg	Total
Arm/Group Description		Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...	Total of all reporting groups
Arm/Group Description		Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.	Total of all reporting groups
Overall Number of Baseline Participants		740	739	739	2218
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
		71.4 (6.9)	71.2 (7.5)	71.2 (7.0)	71.3 (7.1)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
	Female	398 53.8%	395 53.5%	384 52.0%	1177 53.1%
	Male	342 46.2%	344 46.5%	355 48.0%	1041 46.9%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
	Hispanic or Latino	43 5.8%	26 3.5%	24 3.2%	93 4.2%
	Not Hispanic or Latino	626 84.6%	650 88.0%	644 87.1%	1920 86.6%
	Unknown or Not Reported	71 9.6%	63 8.5%	71 9.6%	205 9.2%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	85 11.5%	85 11.5%	102 13.8%	272 12.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 0.7%	5 0.7%	6 0.8%	16 0.7%
	White	598 80.8%	609 82.4%	593 80.2%	1800 81.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	52 7.0%	40 5.4%	38 5.1%	130 5.9%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
Puerto Rico		13 1.8%	11 1.5%	12 1.6%	36 1.6%
Romania		1 0.1%	2 0.3%	2 0.3%	5 0.2%
Hungary		7 0.9%	12 1.6%	6 0.8%	25 1.1%
United States		171 23.1%	171 23.1%	179 24.2%	521 23.5%
Japan		48 6.5%	57 7.7%	78 10.6%	183 8.3%
United Kingdom		85 11.5%	87 11.8%	78 10.6%	250 11.3%
Spain		74 10.0%	77 10.4%	65 8.8%	216 9.7%
Canada		58 7.8%	59 8.0%	63 8.5%	180 8.1%
South Korea		30 4.1%	24 3.2%	16 2.2%	70 3.2%
Belgium		20 2.7%	15 2.0%	15 2.0%	50 2.3%
Poland		58 7.8%	51 6.9%	50 6.8%	159 7.2%
Italy		45 6.1%	38 5.1%	49 6.6%	132 6.0%
Australia		38 5.1%	55 7.4%	38 5.1%	131 5.9%
France		45 6.1%	36 4.9%	36 4.9%	117 5.3%
Germany		47 6.4%	44 6.0%	52 7.0%	143 6.4%
ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale) ^[1] Mean (Standard Deviation) Unit of measure: Units on a Scale
	Number Analyzed	740 participants	739 participants	739 participants	2218 participants
		28.6 (7.9)	29.0 (7.7)	28.5 (8.2)	28.7 (8.0)
		[1] Measure Description: ADAS-Cog13, a 13-item rating scale, measured the severity of cognitive dysfunction in persons with Alzheimer's disease (AD). Scores ranged from 0 to 85, with a higher score indicating worse cognitive functioning.

Outcome Measures

1.Primary Outcome


Title	Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
Description	ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument ...
Description	ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	723	722	708
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	10.31 (0.55)	9.38 (0.56)	10.72 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.232
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.93
	Confidence Interval	(2-Sided) 95% -2.447 to 0.594
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.77
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.599
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95% -1.124 to 1.947
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.78
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)
Description	The ADCS-ADL is a 23-item inventory developed as a rater-administered ...
Description	The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADCS-iADL measure.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	702	700	674
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	-8.87 (0.60)	-8.84 (0.61)	-8.79 (0.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.971
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95% -1.609 to 1.669
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.83
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.923
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95% -1.580 to 1.743
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.85
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Change From Baseline on the Functional Activities Questionnaire (FAQ) Score
Description	FAQ is a 10-item, caregiver-based questionnaire and was administered t...
Description	FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did [the activity] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). FAQ scale is 0 to 30, with higher scores indicating greater impairment. LS Mean was calculated by MMRM with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline and pooled country.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for FAQ score.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	699	697	674
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	6.09 (0.38)	5.96 (0.39)	6.71 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.796
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95% -1.172 to 0.899
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.53
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.252
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95% -0.437 to 1.660
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.53
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score
Description	The iADRS is a composite that measures both cognition and function. Th...
Description	The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS- Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by- visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for iADRS.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	696	689	662
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	-19.56 (0.99)	-18.45 (1.02)	-19.69 (1.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.428
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95% -1.637 to 3.852
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.40
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.926
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95% -2.918 to 2.655
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.42
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
Description	The CDR-SB is a rater administered scale and impairment is scored in o...
Description	The CDR-SB is a rater administered scale and impairment is scored in of the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR-SB.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	704	705	676
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	3.02 (0.17)	3.17 (0.17)	3.17 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.533
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95% -0.322 to 0.622
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.24
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.537
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95% -0.328 to 0.630
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.24
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage
Description	The CDR global score is a composite score calculated using the Washing...
Description	The CDR global score is a composite score calculated using the Washington University CDR-assignment algorithm applied to the 6 individual domain box scores (Morris 1993). The memory domain is considered the primary category that drives the CDR global outcome, and all other domains are secondary. The CDR global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia).
Time Frame	Baseline through Loss of 1 Global Stage or Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR Global Score.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	716	714	696
Median (95% Confidence Interval) Unit of Measure: Days
	548 (547 to 554)	547 (545 to 550)	548 (545 to 553)

7.Secondary Outcome


Title	Change From Baseline in Neuropsychiatric Inventory (NPI) Score
Description	The NPI is a questionnaire administered to caregivers that quantifies ...
Description	The NPI is a questionnaire administered to caregivers that quantifies behavioral changes. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144, with higher scores indicating greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline NPI score, age at baseline, and baseline NPI score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for NPI.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	697	695	663
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	3.22 (0.81)	4.99 (0.83)	4.67 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.116
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95% -0.441 to 3.986
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.13
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.208
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95% -0.808 to 3.704
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.15
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Change From Baseline on the Mini-Mental State Examination (MMSE)
Description	The MMSE is an instrument used to assess a participant's global cognit...
Description	The MMSE is an instrument used to assess a participant's global cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with a higher score indicating better cognitive performance. LS mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for MMSE.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	723	725	709
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	-5.50 (0.26)	-5.18 (0.26)	-5.49 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.379
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95% -0.391 to 1.027
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.36
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.992
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95% -0.714 to 0.721
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.37
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42
Description	Concentration of the peptide Aβ 1-42 in plasma measured by valida...
Description	Concentration of the peptide Aβ 1-42 in plasma measured by validated immunoassay. LS Mean was determined by Analysis of covariance (ANCOVA) with last observation carried forward (LOCF), terms for treatment, baseline biomarker and age at baseline.
Time Frame	Baseline, Week 97

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-42.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	63	66	79
Least Squares Mean (Standard Error) Unit of Measure: Percent change in Aβ1-42
	-2.64 (2.07)	-53.91 (2.04)	-68.13 (1.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-51.27
	Confidence Interval	(2-Sided) 95% -56.963 to -45.578
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.89
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-65.48
	Confidence Interval	(2-Sided) 95% -70.947 to -60.022
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.77
	Estimation Comments	[Not Specified]

10.Secondary Outcome


Title	PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40
Description	Concentration of the peptide Aβ 1-40 in plasma measured by immuno...
Description	Concentration of the peptide Aβ 1-40 in plasma measured by immunoassay. LS Mean was determined by ANCOVA with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline.
Time Frame	Baseline, Week 97

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-40.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	64	66	79
Least Squares Mean (Standard Error) Unit of Measure: Percent change in Aβ1-40
	-1.92 (1.77)	-59.90 (1.74)	-75.17 (1.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-57.99
	Confidence Interval	(2-Sided) 95% -62.865 to -53.108
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.47
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-73.25
	Confidence Interval	(2-Sided) 95% -77.926 to -68.575
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.37
	Estimation Comments	[Not Specified]

11.Secondary Outcome


Title	Change From Baseline in CSF Total Tau
Description	Cerebrospinal fluid samples are collected for analysis of concentratio...
Description	Cerebrospinal fluid samples are collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame	Baseline, Week 97

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Total Tau.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	64	66	79
Least Squares Mean (Standard Error) Unit of Measure: Picogram per milliliter (pg/mL)
	12.39 (8.05)	-7.48 (8.01)	-2.92 (7.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.081
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-19.87
	Confidence Interval	(2-Sided) 95% -42.210 to 2.464
	Parameter Dispersion	Type: Standard Error of the Mean Value: 11.33
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.157
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-15.31
	Confidence Interval	(2-Sided) 95% -36.555 to 5.938
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.78
	Estimation Comments	[Not Specified]

12.Secondary Outcome


Title	Change From Baseline in CSF Phosphorylated Tau
Description	Cerebrospinal fluid samples are collected for analysis of concentratio...
Description	Cerebrospinal fluid samples are collected for analysis of concentrations of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame	Baseline, Week 97

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Phosphorylated Tau.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	63	66	79
Least Squares Mean (Standard Error) Unit of Measure: Picogram per milliliter (pg/mL)
	0.47 (0.95)	-2.16 (0.94)	-1.66 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.050
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-2.62
	Confidence Interval	(2-Sided) 95% -5.243 to -0.002
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.33
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.095
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-2.12
	Confidence Interval	(2-Sided) 95% -4.618 to 0.373
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.27
	Estimation Comments	[Not Specified]

13.Secondary Outcome


Title	Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan
Description	Amyloid deposition in the brain is one of the defining neuropathologic...
Description	Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease. Florbetapir exhibits high affinity specific binding to amyloid plaques. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by florbetapir amyloid PET imaging in a subset of participants. The Centiloid scale standardizes quantitative brain amyloid PET results to allow cross-tracer and cross-methodology comparisons. The Centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. Florbetapir SUVr was converted to the Centiloid scale using the following conversion: Florbetapir Centiloids = 183 x SUVr - 177. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for brain amyloid burden.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	133	127	116
Least Squares Mean (Standard Error) Unit of Measure: Units on a scale
	-2.08 (1.86)	-15.76 (1.89)	-19.74 (1.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-13.68
	Confidence Interval	(2-Sided) 95% -18.785 to -8.574
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.60
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-17.66
	Confidence Interval	(2-Sided) 95% -22.887 to -12.428
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.66
	Estimation Comments	[Not Specified]

14.Secondary Outcome


Title	Change From Baseline in Tau PET ((Flortaucipir F18)
Description	Tau PET tracer (flortaucipir F18) longitudinal study measured whether ...
Description	Tau PET tracer (flortaucipir F18) longitudinal study measured whether lanabecestat, in participants with mild AD dementia, affected tau density and distribution over time. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the signal intensity in white matter. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Tau PET.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	97	94	93
Least Squares Mean (Standard Error) Unit of Measure: Standard Uptake Value ratio (SUVr)
	0.04 (0.01)	0.03 (0.01)	0.03 (0.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.426
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.033 to 0.014
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.01
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.660
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.029 to 0.018
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.01
	Estimation Comments	[Not Specified]

15.Secondary Outcome


Title	Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)
Description	Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic ra...
Description	Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the pons + vermis assessed with composite meta and composite meta automated anatomical labeling atlas (ALL). Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data of brain metabolism.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	83	95	82
Least Squares Mean (Standard Error) Unit of Measure: Standard Uptake Value ratio (SUVr)
	-0.04 (0.00)	-0.05 (0.00)	-0.05 (0.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.210
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.015 to 0.003
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.00
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.568
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95% -0.013 to 0.007
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.00
	Estimation Comments	[Not Specified]

16.Secondary Outcome


Title	Change From Baseline in Whole Brain Volume
Description	Magnetic resonance imaging (MRI) was used to evaluate the effect of la...
Description	Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on whole brain volumes. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, baseline vMRI, intracranial volume, disease status at baseline and age at baseline.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Whole Brain Volume.


Arm/Group Title	Placebo	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received placebo film-...	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received placebo film-coated oral tablets once daily.	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	565	582	550
Least Squares Mean (Standard Error) Unit of Measure: cm^3 (cubic centimeter)
	-14.16 (0.34)	-16.49 (0.33)	-17.34 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 20 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) 95% -3.258 to -1.413
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.47
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lanabecestat 50 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95% -4.118 to -2.247
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.48
	Estimation Comments	[Not Specified]

17.Secondary Outcome


Title	Pharmacokinetics (PK): Plasma Concentration of Lanabecestat
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Week 4, post dose prior to departure from the clinic

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and have evaluable PK data.


Arm/Group Title	Lanabecestat 20 mg	Lanabecestat 50 mg
Arm/Group Description:	Participants received lanabecestat ...	Participants received lanabecestat ...
Arm/Group Description:	Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Number of Participants Analyzed	697	662
Mean (Standard Deviation) Unit of Measure: nanograms per milliliter (ng/mL)
	67.7 (49.1)	213 (149)

Adverse Events

Time Frame	Up To 104 weeks
Adverse Event Reporting Description	All randomized participants who received at least one dose of study drug. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.

Arm/Group Title	Placebo		Lanabecestat 20 mg		Lanabecestat 50 mg
Arm/Group Description	Participants received placebo film-...		Participants received lanabecestat ...		Participants received lanabecestat ...
Arm/Group Description	Participants received placebo film-coated oral tablets once daily.		Participants received lanabecestat 20 mg film-coated oral tablets once daily.		Participants received lanabecestat 50 mg film-coated oral tablets once daily.
All-Cause Mortality
	Placebo		Lanabecestat 20 mg		Lanabecestat 50 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	2/738 (0.27%)		4/736 (0.54%)		4/735 (0.54%)
Serious Adverse Events Serious Adverse Events
	Placebo		Lanabecestat 20 mg		Lanabecestat 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/738 (14.63%)		117/736 (15.90%)		147/735 (20.00%)
Blood and lymphatic system disorders
Anaemia ^† 1	2/738 (0.27%)	3	1/736 (0.14%)	1	1/735 (0.14%)	1
Cardiac disorders
Acute coronary syndrome ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Acute myocardial infarction ^† 1	2/738 (0.27%)	3	0/736 (0.00%)	0	2/735 (0.27%)	2
Angina pectoris ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	1/735 (0.14%)	1
Angina unstable ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Atrial fibrillation ^† 1	2/738 (0.27%)	3	2/736 (0.27%)	2	1/735 (0.14%)	1
Atrial flutter ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Bifascicular block ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Bradycardia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Cardiac failure ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	2/735 (0.27%)	2
Cardiac tamponade ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Cardio-respiratory arrest ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	0/735 (0.00%)	0
Coronary artery disease ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Coronary artery thrombosis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Myocardial infarction ^† 1	4/738 (0.54%)	4	2/736 (0.27%)	2	0/735 (0.00%)	0
Sinus bradycardia ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Sinus node dysfunction ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Stress cardiomyopathy ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Supraventricular extrasystoles ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Supraventricular tachycardia ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Tachycardia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Tricuspid valve incompetence ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Congenital, familial and genetic disorders
Gastrointestinal arteriovenous malformation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Ear and labyrinth disorders
Vestibular disorder ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Eye disorders
Cataract ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	1/735 (0.14%)	2
Pterygium ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Retinal detachment ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	0/735 (0.00%)	0
Retinal haemorrhage ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Gastrointestinal disorders
Abdominal discomfort ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Alcoholic pancreatitis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Anal incontinence ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	2
Coeliac artery stenosis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Colitis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Colitis microscopic ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Constipation ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	1
Diarrhoea ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Enlarged uvula ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Faecaloma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Femoral hernia incarcerated ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Food poisoning ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Gastric ulcer ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Gastritis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Gastrointestinal haemorrhage ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	1/735 (0.14%)	1
Gastrooesophageal reflux disease ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Haemorrhoids ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Inguinal hernia ^† 1	1/738 (0.14%)	1	2/736 (0.27%)	2	3/735 (0.41%)	3
Intestinal mass ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Intestinal obstruction ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	3/735 (0.41%)	3
Large intestine polyp ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	2	2/735 (0.27%)	2
Lower gastrointestinal haemorrhage ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Pancreatitis acute ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Rectal prolapse ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	3	0/735 (0.00%)	0
Small intestinal obstruction ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Vomiting ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
General disorders
Asthenia ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	1/735 (0.14%)	1
Chest pain ^† 1	1/738 (0.14%)	1	4/736 (0.54%)	4	4/735 (0.54%)	4
Non-cardiac chest pain ^† 1	1/738 (0.14%)	1	2/736 (0.27%)	2	1/735 (0.14%)	1
Pyrexia ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Sudden death ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Systemic inflammatory response syndrome ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hepatobiliary disorders
Cholelithiasis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Drug-induced liver injury ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Immune system disorders
Drug hypersensitivity ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Seasonal allergy ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Infections and infestations
Appendicitis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Bone abscess ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Bronchitis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Cellulitis ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	2/735 (0.27%)	2
Clostridium difficile colitis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Diverticulitis ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	3/735 (0.41%)	4
Endocarditis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hepatic cyst infection ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Human anaplasmosis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Infection ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Influenza ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	4/735 (0.54%)	4
Intervertebral discitis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Lower respiratory tract infection ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Lower respiratory tract infection viral ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Ophthalmic herpes zoster ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Peritonsillitis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Pneumonia ^† 1	6/738 (0.81%)	6	3/736 (0.41%)	3	3/735 (0.41%)	3
Sepsis ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	1/735 (0.14%)	1
Septic arthritis streptococcal ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Septic shock ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	1
Urinary tract infection ^† 1	6/738 (0.81%)	8	1/736 (0.14%)	1	3/735 (0.41%)	3
Urinary tract infection pseudomonal ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Vestibular neuronitis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Injury, poisoning and procedural complications
Accidental overdose ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Accidental poisoning ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Alcohol poisoning ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Ankle fracture ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	1/735 (0.14%)	1
Cervical vertebral fracture ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Chemical burn of gastrointestinal tract ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Clavicle fracture ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Contusion ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Fall ^† 1	6/738 (0.81%)	6	8/736 (1.09%)	8	4/735 (0.54%)	4
Femoral neck fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	2/735 (0.27%)	2
Femur fracture ^† 1	1/738 (0.14%)	1	2/736 (0.27%)	2	1/735 (0.14%)	1
Fibula fracture ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	1
Forearm fracture ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Head injury ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	1
Hip fracture ^† 1	0/738 (0.00%)	0	3/736 (0.41%)	3	2/735 (0.27%)	2
Humerus fracture ^† 1	1/738 (0.14%)	2	0/736 (0.00%)	0	2/735 (0.27%)	2
Jaw fracture ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Lacrimal structure injury ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Ligament rupture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Lumbar vertebral fracture ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	1/735 (0.14%)	1
Multiple injuries ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Overdose ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Pelvic fracture ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Periprosthetic fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Post procedural haemorrhage ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Pubis fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Radius fracture ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	2/735 (0.27%)	2
Rib fracture ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	0/735 (0.00%)	0
Road traffic accident ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Skin laceration ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Skull fracture ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Spinal compression fracture ^† 1	3/738 (0.41%)	3	0/736 (0.00%)	0	1/735 (0.14%)	1
Spinal fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Subdural haematoma ^† 1	3/738 (0.41%)	3	0/736 (0.00%)	0	3/735 (0.41%)	4
Subdural haemorrhage ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Thoracic vertebral fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Tibia fracture ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	1/735 (0.14%)	1
Ulna fracture ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	1
Upper limb fracture ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Wrist fracture ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Investigations
Blood potassium decreased ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Dehydration ^† 1	1/738 (0.14%)	1	4/736 (0.54%)	4	5/735 (0.68%)	5
Electrolyte imbalance ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hypercalcaemia ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hyperglycaemia ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Hypoglycaemia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Hypokalaemia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Hyponatraemia ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	1/735 (0.14%)	1
Hypophosphataemia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Lactic acidosis ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	0/735 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthritis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	2/735 (0.27%)	2
Back pain ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Bone lesion ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Foot deformity ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Infrapatellar fat pad inflammation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Intervertebral disc compression ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Intervertebral disc protrusion ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Lumbar spinal stenosis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	1/735 (0.14%)	2
Mobility decreased ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Musculoskeletal chest pain ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Musculoskeletal pain ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Myofascial pain syndrome ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Osteoarthritis ^† 1	4/738 (0.54%)	4	2/736 (0.27%)	2	1/735 (0.14%)	1
Osteolysis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Osteoporotic fracture ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Pain in extremity ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Spinal column stenosis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Vertebral foraminal stenosis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Acute myeloid leukaemia ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Adenocarcinoma of colon ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	1/735 (0.14%)	1
Basal cell carcinoma ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Bile duct adenocarcinoma ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Bladder neoplasm ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Breast cancer ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Breast cancer male ^† 1	0/341 (0.00%)	0	1/344 (0.29%)	1	0/354 (0.00%)	0
Breast cancer recurrent ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Colon cancer ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	2/735 (0.27%)	2
Endometrial adenocarcinoma ^† 1	1/397 (0.25%)	1	0/392 (0.00%)	0	0/381 (0.00%)	0
Haemangioma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Invasive ductal breast carcinoma ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	2/735 (0.27%)	2
Laryngeal squamous cell carcinoma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Lentigo maligna ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Lung adenocarcinoma ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	3/735 (0.41%)	3
Lung neoplasm ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Lung neoplasm malignant ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	0/735 (0.00%)	0
Lymphoma ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Malignant melanoma ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Malignant melanoma in situ ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Malignant neoplasm of unknown primary site ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Metastases to bone ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Metastases to lymph nodes ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Neuroendocrine tumour ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Ovarian adenoma ^† 1	0/397 (0.00%)	0	0/392 (0.00%)	0	1/381 (0.26%)	1
Pancreatic carcinoma ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Prostate cancer ^† 1	2/341 (0.59%)	2	2/344 (0.58%)	2	2/354 (0.56%)	2
Prostatic adenoma ^† 1	1/341 (0.29%)	1	0/344 (0.00%)	0	0/354 (0.00%)	0
Rectal adenocarcinoma ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	0/735 (0.00%)	0
Rectal adenoma ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Rectal cancer ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Small cell lung cancer ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Squamous cell carcinoma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Transitional cell carcinoma ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Nervous system disorders
Altered state of consciousness ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Central nervous system lesion ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Cerebral haematoma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Cerebral haemorrhage ^† 1	3/738 (0.41%)	3	0/736 (0.00%)	0	2/735 (0.27%)	2
Cerebral microhaemorrhage ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Cerebrovascular accident ^† 1	2/738 (0.27%)	2	3/736 (0.41%)	3	1/735 (0.14%)	1
Cervical radiculopathy ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Cholinergic syndrome ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Cognitive disorder ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Dementia with lewy bodies ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Dizziness ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	1/735 (0.14%)	1
Dyskinesia ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Epilepsy ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Generalised tonic-clonic seizure ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Headache ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hypertensive encephalopathy ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hypoaesthesia ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Intraventricular haemorrhage ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Partial seizures ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Petit mal epilepsy ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Presyncope ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Sciatica ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Seizure ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	2/735 (0.27%)	2
Subarachnoid haemorrhage ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	0/735 (0.00%)	0
Syncope ^† 1	2/738 (0.27%)	2	6/736 (0.82%)	6	7/735 (0.95%)	7
Thalamic infarction ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Transient ischaemic attack ^† 1	2/738 (0.27%)	2	2/736 (0.27%)	2	2/735 (0.27%)	2
Ulnar nerve palsy ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Vasogenic cerebral oedema ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Vocal cord paresis ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Product Issues
Device failure ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Psychiatric disorders
Abnormal behaviour ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	1/735 (0.14%)	1
Acute psychosis ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	0/735 (0.00%)	0
Aggression ^† 1	1/738 (0.14%)	1	1/736 (0.14%)	1	2/735 (0.27%)	2
Agitation ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	2/735 (0.27%)	2
Anxiety ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	2/735 (0.27%)	2
Confusional state ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	0/735 (0.00%)	0
Delirium ^† 1	1/738 (0.14%)	1	2/736 (0.27%)	2	5/735 (0.68%)	5
Depression ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	4/735 (0.54%)	4
Depressive symptom ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	3/735 (0.41%)	3
Hallucination ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Hallucination, auditory ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Hallucination, olfactory ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Paranoia ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	0/735 (0.00%)	0
Psychotic disorder ^† 1	2/738 (0.27%)	2	0/736 (0.00%)	0	0/735 (0.00%)	0
Schizophrenia ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Suicidal ideation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Suicide attempt ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Renal and urinary disorders
Acute kidney injury ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Calculus bladder ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Urge incontinence ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Urinary retention ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	1/735 (0.14%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	2/341 (0.59%)	2	1/344 (0.29%)	1	1/354 (0.28%)	1
Postmenopausal haemorrhage ^† 1	0/397 (0.00%)	0	1/392 (0.26%)	1	0/381 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Asthma ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Cystic lung disease ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Dyspnoea ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	1/735 (0.14%)	1
Obstructive airways disorder ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Pneumonia aspiration ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Pneumothorax ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Pulmonary embolism ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	2/735 (0.27%)	2
Pulmonary oedema ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Respiratory arrest ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Sleep apnoea syndrome ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Stridor ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Skin and subcutaneous tissue disorders
Angioedema ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Drug eruption ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Psoriasis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Surgical and medical procedures
Cardiac pacemaker insertion ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Cataract operation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Hip arthroplasty ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Inguinal hernia repair ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Spinal operation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Synovial cyst removal ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Tumour excision ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Urethral repair ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Vocal cord operation ^† 1	0/738 (0.00%)	0	1/736 (0.14%)	1	0/735 (0.00%)	0
Vascular disorders
Aortic aneurysm ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Deep vein thrombosis ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	0/735 (0.00%)	0
Granulomatosis with polyangiitis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Haematoma ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Hypertension ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Hypertensive crisis ^† 1	1/738 (0.14%)	1	0/736 (0.00%)	0	0/735 (0.00%)	0
Hypotension ^† 1	2/738 (0.27%)	2	1/736 (0.14%)	1	1/735 (0.14%)	1
Orthostatic hypotension ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Peripheral artery stenosis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Temporal arteritis ^† 1	0/738 (0.00%)	0	2/736 (0.27%)	2	0/735 (0.00%)	0
Thrombophlebitis ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
Venous thrombosis limb ^† 1	0/738 (0.00%)	0	0/736 (0.00%)	0	1/735 (0.14%)	1
1 Term from vocabulary, MedDRA 21.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Lanabecestat 20 mg		Lanabecestat 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	340/738 (46.07%)		357/736 (48.51%)		361/735 (49.12%)
Gastrointestinal disorders
Diarrhoea ^† 1	39/738 (5.28%)	44	62/736 (8.42%)	81	54/735 (7.35%)	62
Nausea ^† 1	32/738 (4.34%)	38	33/736 (4.48%)	39	41/735 (5.58%)	50
Infections and infestations
Nasopharyngitis ^† 1	60/738 (8.13%)	69	78/736 (10.60%)	94	76/735 (10.34%)	89
Upper respiratory tract infection ^† 1	46/738 (6.23%)	57	39/736 (5.30%)	43	44/735 (5.99%)	50
Urinary tract infection ^† 1	56/738 (7.59%)	70	36/736 (4.89%)	53	32/735 (4.35%)	36
Injury, poisoning and procedural complications
Fall ^† 1	69/738 (9.35%)	86	71/736 (9.65%)	95	73/735 (9.93%)	111
Musculoskeletal and connective tissue disorders
Back pain ^† 1	40/738 (5.42%)	50	36/736 (4.89%)	38	33/735 (4.49%)	35
Nervous system disorders
Dizziness ^† 1	42/738 (5.69%)	48	43/736 (5.84%)	52	51/735 (6.94%)	61
Headache ^† 1	52/738 (7.05%)	56	40/736 (5.43%)	50	46/735 (6.26%)	72
Psychiatric disorders
Anxiety ^† 1	34/738 (4.61%)	40	57/736 (7.74%)	63	48/735 (6.53%)	50
Depression ^† 1	31/738 (4.20%)	32	36/736 (4.89%)	39	46/735 (6.26%)	49
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	25/738 (3.39%)	25	46/736 (6.25%)	49	25/735 (3.40%)	29
1 Term from vocabulary, MedDRA 21.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The sponsor shall review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60days but less than or equal to 180days from the time submitted to the sponsor.Authors agree not to publish results until data is compiled. No publication/presentation with respect to the research activities shall be made unless & until any information determined at sponsors sole discretion to be confidential information has been removed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	AstraZeneca Information Center
Organization:	AstraZeneca
Phone:	1-877-240-9479
EMail:	information.center@astrazeneca.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wessels AM, Lines C, Stern RA, Kost J, Voss T, Mozley LH, Furtek C, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, Dupre N, Randolph C, Michelson D, Andersen SW, Shering C, Sims JR, Egan MF. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. Alzheimers Dement. 2020 Nov;16(11):1483-1492. doi: 10.1002/alz.12164. Epub 2020 Oct 13.

Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, Landry J, Krull JH, Downing AM, Willis BA, Shcherbinin S, Mullen J, Barker P, Schumi J, Shering C, Matthews BR, Stern RA, Vellas B, Cohen S, MacSweeney E, Boada M, Sims JR. Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurol. 2020 Feb 1;77(2):199-209. doi: 10.1001/jamaneurol.2019.3988. Erratum in: JAMA Neurol. 2020 Sep 1;77(9):1179.

Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, Olsson T, Ye N, Rosen L, Russell M, Maltby J, Eketjäll S, Kugler AR. AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. J Alzheimers Dis. 2017;55(3):1039-1053.

Layout table for additonal information

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT02245737
Other Study ID Numbers:	16023 I8D-MC-AZES ( Other Identifier: Eli Lilly and Company ) 2014-002601-38 ( EudraCT Number ) D5010C00009 ( Other Identifier: AstraZeneca )
First Submitted:	September 18, 2014
First Posted:	September 22, 2014
Results First Submitted:	June 11, 2019
Results First Posted:	August 6, 2019
Last Update Posted:	December 3, 2019

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