Trial Outcomes & Findings for An Efficacy and Safety Study of Lanabecestat (LY3314814) in Early Alzheimer's Disease (NCT NCT02245737)

Last Updated: 2019-12-03

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

2218 participants

Primary outcome timeframe

Baseline, Week 104

Results posted on

2019-12-03

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 Milligrams (mg) Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Study STARTED	740	739	739
Overall Study Received at Least 1 Dose of Study Drug	738	736	735
Overall Study COMPLETED	187	184	168
Overall Study NOT COMPLETED	553	555	571

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 Milligrams (mg) Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Overall Study Adverse Event	23	26	33
Overall Study Condition Worsened	9	10	9
Overall Study Death	2	4	4
Overall Study Eligibility Criteria No Longer Met	2	4	4
Overall Study Initiation of Symptomatic AD medication	2	0	0
Overall Study Lost to Follow-up	2	5	4
Overall Study Other-determined by Investigator	9	10	10
Overall Study Physician Decision	6	3	6
Overall Study Protocol Violation	3	2	3
Overall Study Withdrawal by Subject	40	41	44
Overall Study Withdrawal due to Caregiver Circumstance	10	20	22
Overall Study Sponsor Decision	445	430	432

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=740 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=739 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=739 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.	Total n=2218 Participants Total of all reporting groups
Age, Continuous	71.4 Years STANDARD_DEVIATION 6.9 • n=5 Participants	71.2 Years STANDARD_DEVIATION 7.5 • n=7 Participants	71.2 Years STANDARD_DEVIATION 7.0 • n=5 Participants	71.3 Years STANDARD_DEVIATION 7.1 • n=4 Participants
Sex: Female, Male Female	398 Participants n=5 Participants	395 Participants n=7 Participants	384 Participants n=5 Participants	1177 Participants n=4 Participants
Sex: Female, Male Male	342 Participants n=5 Participants	344 Participants n=7 Participants	355 Participants n=5 Participants	1041 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	43 Participants n=5 Participants	26 Participants n=7 Participants	24 Participants n=5 Participants	93 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	626 Participants n=5 Participants	650 Participants n=7 Participants	644 Participants n=5 Participants	1920 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	71 Participants n=5 Participants	63 Participants n=7 Participants	71 Participants n=5 Participants	205 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	85 Participants n=5 Participants	85 Participants n=7 Participants	102 Participants n=5 Participants	272 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants	16 Participants n=4 Participants
Race (NIH/OMB) White	598 Participants n=5 Participants	609 Participants n=7 Participants	593 Participants n=5 Participants	1800 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	52 Participants n=5 Participants	40 Participants n=7 Participants	38 Participants n=5 Participants	130 Participants n=4 Participants
Region of Enrollment Puerto Rico	13 Participants n=5 Participants	11 Participants n=7 Participants	12 Participants n=5 Participants	36 Participants n=4 Participants
Region of Enrollment Romania	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment Hungary	7 Participants n=5 Participants	12 Participants n=7 Participants	6 Participants n=5 Participants	25 Participants n=4 Participants
Region of Enrollment United States	171 Participants n=5 Participants	171 Participants n=7 Participants	179 Participants n=5 Participants	521 Participants n=4 Participants
Region of Enrollment Japan	48 Participants n=5 Participants	57 Participants n=7 Participants	78 Participants n=5 Participants	183 Participants n=4 Participants
Region of Enrollment United Kingdom	85 Participants n=5 Participants	87 Participants n=7 Participants	78 Participants n=5 Participants	250 Participants n=4 Participants
Region of Enrollment Spain	74 Participants n=5 Participants	77 Participants n=7 Participants	65 Participants n=5 Participants	216 Participants n=4 Participants
Region of Enrollment Canada	58 Participants n=5 Participants	59 Participants n=7 Participants	63 Participants n=5 Participants	180 Participants n=4 Participants
Region of Enrollment South Korea	30 Participants n=5 Participants	24 Participants n=7 Participants	16 Participants n=5 Participants	70 Participants n=4 Participants
Region of Enrollment Belgium	20 Participants n=5 Participants	15 Participants n=7 Participants	15 Participants n=5 Participants	50 Participants n=4 Participants
Region of Enrollment Poland	58 Participants n=5 Participants	51 Participants n=7 Participants	50 Participants n=5 Participants	159 Participants n=4 Participants
Region of Enrollment Italy	45 Participants n=5 Participants	38 Participants n=7 Participants	49 Participants n=5 Participants	132 Participants n=4 Participants
Region of Enrollment Australia	38 Participants n=5 Participants	55 Participants n=7 Participants	38 Participants n=5 Participants	131 Participants n=4 Participants
Region of Enrollment France	45 Participants n=5 Participants	36 Participants n=7 Participants	36 Participants n=5 Participants	117 Participants n=4 Participants
Region of Enrollment Germany	47 Participants n=5 Participants	44 Participants n=7 Participants	52 Participants n=5 Participants	143 Participants n=4 Participants
ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale)	28.6 Units on a Scale STANDARD_DEVIATION 7.9 • n=5 Participants	29.0 Units on a Scale STANDARD_DEVIATION 7.7 • n=7 Participants	28.5 Units on a Scale STANDARD_DEVIATION 8.2 • n=5 Participants	28.7 Units on a Scale STANDARD_DEVIATION 8.0 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline, Week 104

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=723 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=722 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=708 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)	10.31 Units on a scale Standard Error 0.55	9.38 Units on a scale Standard Error 0.56	10.72 Units on a scale Standard Error 0.58

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=702 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=700 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=674 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)	-8.87 Units on a scale Standard Error 0.60	-8.84 Units on a scale Standard Error 0.61	-8.79 Units on a scale Standard Error 0.63

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=699 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=697 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=674 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the Functional Activities Questionnaire (FAQ) Score	6.09 Units on a scale Standard Error 0.38	5.96 Units on a scale Standard Error 0.39	6.71 Units on a scale Standard Error 0.40

SECONDARY outcome

Timeframe: Baseline, Week 104

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=696 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=689 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=662 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score	-19.56 Units on a scale Standard Error 0.99	-18.45 Units on a scale Standard Error 1.02	-19.69 Units on a scale Standard Error 1.05

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=704 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=705 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=676 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score	3.02 Units on a scale Standard Error 0.17	3.17 Units on a scale Standard Error 0.17	3.17 Units on a scale Standard Error 0.18

SECONDARY outcome

Timeframe: Baseline through Loss of 1 Global Stage or Week 104

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=716 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=714 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=696 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage	548 Days Interval 547.0 to 554.0	547 Days Interval 545.0 to 550.0	548 Days Interval 545.0 to 553.0

SECONDARY outcome

Timeframe: Baseline, Week 104

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=697 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=695 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=663 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in Neuropsychiatric Inventory (NPI) Score	3.22 Units on a scale Standard Error 0.81	4.99 Units on a scale Standard Error 0.83	4.67 Units on a scale Standard Error 0.85

SECONDARY outcome

Timeframe: Baseline, Week 104

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=723 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=725 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=709 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline on the Mini-Mental State Examination (MMSE)	-5.50 Units on a scale Standard Error 0.26	-5.18 Units on a scale Standard Error 0.26	-5.49 Units on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: Baseline, Week 97

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=63 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=66 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=79 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42	-2.64 Percent change in Aβ1-42 Standard Error 2.07	-53.91 Percent change in Aβ1-42 Standard Error 2.04	-68.13 Percent change in Aβ1-42 Standard Error 1.87

SECONDARY outcome

Timeframe: Baseline, Week 97

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=66 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=79 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40	-1.92 Percent change in Aβ1-40 Standard Error 1.77	-59.90 Percent change in Aβ1-40 Standard Error 1.74	-75.17 Percent change in Aβ1-40 Standard Error 1.60

SECONDARY outcome

Timeframe: Baseline, Week 97

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=66 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=79 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in CSF Total Tau	12.39 Picogram per milliliter (pg/mL) Standard Error 8.05	-7.48 Picogram per milliliter (pg/mL) Standard Error 8.01	-2.92 Picogram per milliliter (pg/mL) Standard Error 7.30

SECONDARY outcome

Timeframe: Baseline, Week 97

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=63 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=66 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=79 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in CSF Phosphorylated Tau	0.47 Picogram per milliliter (pg/mL) Standard Error 0.95	-2.16 Picogram per milliliter (pg/mL) Standard Error 0.94	-1.66 Picogram per milliliter (pg/mL) Standard Error 0.85

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=133 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=127 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=116 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan	-2.08 Units on a scale Standard Error 1.86	-15.76 Units on a scale Standard Error 1.89	-19.74 Units on a scale Standard Error 1.97

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=97 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=94 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=93 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in Tau PET ((Flortaucipir F18)	0.04 Standard Uptake Value ratio (SUVr) Standard Error 0.01	0.03 Standard Uptake Value ratio (SUVr) Standard Error 0.01	0.03 Standard Uptake Value ratio (SUVr) Standard Error 0.01

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=83 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=95 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=82 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)	-0.04 Standard Uptake Value ratio (SUVr) Standard Error 0.00	-0.05 Standard Uptake Value ratio (SUVr) Standard Error 0.00	-0.05 Standard Uptake Value ratio (SUVr) Standard Error 0.00

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=565 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=582 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=550 Participants Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Change From Baseline in Whole Brain Volume	-14.16 cm^3 (cubic centimeter) Standard Error 0.34	-16.49 cm^3 (cubic centimeter) Standard Error 0.33	-17.34 cm^3 (cubic centimeter) Standard Error 0.34

SECONDARY outcome

Timeframe: Week 4, post dose prior to departure from the clinic

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

Outcome measures

Outcome measures
Measure	Placebo n=697 Participants Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=662 Participants Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Pharmacokinetics (PK): Plasma Concentration of Lanabecestat	67.7 nanograms per milliliter (ng/mL) Standard Deviation 49.1	213 nanograms per milliliter (ng/mL) Standard Deviation 149	—

Adverse Events

Placebo

Serious events: 108 serious events

Other events: 340 other events

Deaths: 2 deaths

Lanabecestat 20 mg

Serious events: 117 serious events

Other events: 357 other events

Deaths: 4 deaths

Lanabecestat 50 mg

Serious events: 147 serious events

Other events: 361 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=738 participants at risk Participants received placebo film-coated oral tablets once daily.	Lanabecestat 20 mg n=736 participants at risk Participants received lanabecestat 20 mg film-coated oral tablets once daily.	Lanabecestat 50 mg n=735 participants at risk Participants received lanabecestat 50 mg film-coated oral tablets once daily.
Gastrointestinal disorders Diarrhoea	5.3% 39/738 • Number of events 44 • Up To 104 weeks 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.	8.4% 62/736 • Number of events 81 • Up To 104 weeks 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.	7.3% 54/735 • Number of events 62 • Up To 104 weeks 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.
Gastrointestinal disorders Nausea	4.3% 32/738 • Number of events 38 • Up To 104 weeks 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.	4.5% 33/736 • Number of events 39 • Up To 104 weeks 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.	5.6% 41/735 • Number of events 50 • Up To 104 weeks 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.
Infections and infestations Nasopharyngitis	8.1% 60/738 • Number of events 69 • Up To 104 weeks 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.	10.6% 78/736 • Number of events 94 • Up To 104 weeks 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.	10.3% 76/735 • Number of events 89 • Up To 104 weeks 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.
Infections and infestations Upper respiratory tract infection	6.2% 46/738 • Number of events 57 • Up To 104 weeks 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.	5.3% 39/736 • Number of events 43 • Up To 104 weeks 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.	6.0% 44/735 • Number of events 50 • Up To 104 weeks 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.
Infections and infestations Urinary tract infection	7.6% 56/738 • Number of events 70 • Up To 104 weeks 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.	4.9% 36/736 • Number of events 53 • Up To 104 weeks 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.	4.4% 32/735 • Number of events 36 • Up To 104 weeks 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.
Injury, poisoning and procedural complications Fall	9.3% 69/738 • Number of events 86 • Up To 104 weeks 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.	9.6% 71/736 • Number of events 95 • Up To 104 weeks 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.	9.9% 73/735 • Number of events 111 • Up To 104 weeks 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.
Musculoskeletal and connective tissue disorders Back pain	5.4% 40/738 • Number of events 50 • Up To 104 weeks 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.	4.9% 36/736 • Number of events 38 • Up To 104 weeks 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.	4.5% 33/735 • Number of events 35 • Up To 104 weeks 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.
Nervous system disorders Dizziness	5.7% 42/738 • Number of events 48 • Up To 104 weeks 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.	5.8% 43/736 • Number of events 52 • Up To 104 weeks 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.	6.9% 51/735 • Number of events 61 • Up To 104 weeks 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.
Nervous system disorders Headache	7.0% 52/738 • Number of events 56 • Up To 104 weeks 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.	5.4% 40/736 • Number of events 50 • Up To 104 weeks 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.	6.3% 46/735 • Number of events 72 • Up To 104 weeks 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.
Psychiatric disorders Anxiety	4.6% 34/738 • Number of events 40 • Up To 104 weeks 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.	7.7% 57/736 • Number of events 63 • Up To 104 weeks 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.	6.5% 48/735 • Number of events 50 • Up To 104 weeks 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.
Psychiatric disorders Depression	4.2% 31/738 • Number of events 32 • Up To 104 weeks 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.	4.9% 36/736 • Number of events 39 • Up To 104 weeks 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.	6.3% 46/735 • Number of events 49 • Up To 104 weeks 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.
Respiratory, thoracic and mediastinal disorders Cough	3.4% 25/738 • Number of events 25 • Up To 104 weeks 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.	6.2% 46/736 • Number of events 49 • Up To 104 weeks 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.	3.4% 25/735 • Number of events 29 • Up To 104 weeks 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.

Additional Information

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Principal investigator is a sponsor employee 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.
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